Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Jan 18;66(3):368-375.
doi: 10.1093/cid/cix804.

Kinetics of Double-Stranded DNA Viremia After Allogeneic Hematopoietic Cell Transplantation

Joshua A Hill  1   2 , Bryan T Mayer  2 , Hu Xie  3 , Wendy M Leisenring  3 , Meei-Li Huang  4 , Terry Stevens-Ayers  2 , Filippo Milano  3 , Colleen Delaney  3   5 , Keith R Jerome  2   4 , Danielle M Zerr  2   5 , Garrett Nichols  6 , Michael Boeckh  1   2   3 , Joshua T Schiffer  1   2   3
Affiliations

Kinetics of Double-Stranded DNA Viremia After Allogeneic Hematopoietic Cell Transplantation

Joshua A Hill et al. Clin Infect Dis. .

Abstract

Background: Improved understanding of double-stranded DNA (dsDNA) virus kinetics after hematopoietic cell transplantation (HCT) would facilitate development of therapeutic strategies.

Methods: We tested weekly plasma samples from 404 patients through day 100 after allogeneic HCT for cytomegalovirus (CMV), human herpesvirus (HHV) 6A and 6B, BK polyomavirus (BKV), adenovirus (AdV), and Epstein-Barr virus (EBV) using quantitative polymerase chain reaction. Episodes lasting ≤1 week were defined as blips and >1 week as persistent. We described virus-specific kinetics, analyzed the association of virus area under the curve (AUC) with overall mortality, and identified risk factors for persistent episodes.

Results: We identified 428 episodes of CMV, 292 of BKV, 224 of HHV-6B, 46 of AdV, and 53 of EBV. CMV and BKV had the highest proportions of persistent episodes (68% and 80%, respectively). Detection and kinetics varied by virus. HHV-6B episodes reached maximum levels fastest and had the shortest intervals between detection and end-organ disease. End-organ disease occurred within 14 days of viremia in 68% of cases, generally during persistent episodes. For all viruses, higher viral load AUC increased risk for overall mortality through day 365, persistent episodes had higher viral load than blips, and higher first positive viral load significantly increased risk for persistent episodes. First viral load >2 log10 copies/mL (range, 2.04-3.06 per virus) had high specificity for persistent episodes.

Conclusions: Persistent high viral load dsDNA viremia episodes after allogeneic HCT predict mortality. Virus-specific kinetics can guide timing and thresholds for early intervention in studies of novel agents.

Keywords: kinetics; mortality; threshold; transplant; virus.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Kaplan-Meier estimated cumulative distribution of episode duration for each virus. Blip episodes had a duration ≤1 week. The vertical line at 1 week denotes the cutoff for blips; the percentage of blips is listed to the left. Estimated median episode duration occurs where the curves cross 50%. All episodes >4 weeks (vertical line at 4 weeks) were categorized together; the percentage is listed to the right. Curves are color coded by virus type. Using cytomegalovirus as an example, 32% of episodes were blips (therefore, 68% were persistent), the estimated median episode duration was 3 weeks, and 35% of episodes lasted >4 weeks. Abbreviations: AdV, adenovirus; BKV, BK polyomavirus; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV-6B, human herpesvirus 6B.
Figure 2.
Figure 2.
The temporal relationship of end-organ disease with virus detection and episode type among viremic patients. A, The distribution of first plasma virus detection and episode type relative to end-organ disease diagnosis among patients with viremia and end-organ disease during the study period. Boxes represent the interquartile range (IQR), and whiskers extend to within 1.5 times the IQR of the first and third quartiles (Tukey box plot). Shapes depict episode type and whether the episode occurred within a 14-day window preceding end-organ disease diagnosis. Circles depict start date of episodes in which virus detection occurred outside a 14-day window prior to end-organ disease diagnosis. Most end-organ disease diagnoses had episodes (square and diamond shapes) within a 14-day window prior to disease: cytomegalovirus (CMV), 62%; BK polyomavirus (BKV), 68%; human herpesvirus 6B (HHV-6B), 67%; adenovirus (AdV), 100%. B, The percentage of blip or persistent viremia episodes preceding end-organ disease cases within 14 days. Fractions indicate the number of end-organ disease cases occurring within 14 days after episode onset (numerator) over the total number of episodes (denominator). For 1 HHV-6B case, first plasma detection and end-organ disease diagnosis date were the same; we classified this episode as a nonpreceding episode. In the single case of Epstein-Barr virus (EBV) end-organ disease, the patient never had EBV detected in plasma.
Figure 3.
Figure 3.
Forest plot of the association of cumulative viral load area under the curve (AUC) with overall mortality through day 365 post–hematopoietic cell transplantation (HCT). We calculated the cumulative viral load AUC on a log10 copies/mL scale for each virus per patient by summating quantitative polymerase chain reaction results and dividing by the number of days followed. Cumulative viral load AUC was incorporated as a time-dependent variable through day 100 (grey) and a time-invariant variable through day 365 (because testing ended at day 100 [black]). All models were adjusted for age, HCT comorbidity index score, underlying disease risk, type of conditioning regimen (myeloablative vs not), time-dependent acute graft-vs-host disease grade 3–4, and time-dependent cumulative steroid dose AUC during the first 100 days post-HCT (steroid use was categorized as 0, <1 mg/kg, 1 to <2 mg/kg, and ≥2 mg/kg prednisone equivalent per day). Abbreviations: AdV, adenovirus; aHR, adjusted hazard ratio; AUC, area under the curve; BKV, BK polyomavirus; CI, confidence interval; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV-6 human herpesvirus 6.
Figure 4.
Figure 4.
Characteristics associated with advancing from a blip to a persistent episode at the time of first positive test result. We used generalized estimating equations to estimate the association of each variable with risk of developing a persistent episode at the time of the first positive test. All covariates were included in a multivariable model. Acute graft-versus-host disease grade, neutrophil engraftment date, absolute lymphocyte count <200 cells/μL, maximum prednisone-equivalent steroid dose within the preceding 14 days, viral load, number of concurrent double-stranded DNA viruses detected, and antiviral use (ganciclovir, foscarnet, or cidofovir) were time-dependent variables based on the date of the first positive test. Most antiviral use (ie, ganciclovir and foscarnet) in this cohort did not target BK polyomavirus or adenovirus, so antiviral use was not incorporated into analyses for these viruses. Concurrent detection of other viruses did not increase risk for developing persistent episodes for any of the viruses and was excluded from the final model. Dots represent the relative risk and error bars represent the 95% confidence interval. Bolded bars were statistically significant (P < .05). Abbreviations: AdV, adenovirus; BKV, BK polyomavirus; CMV, cytomegalovirus; EBV, Epstein-Barr virus; GVHD, graft-vs-host disease; HHV-6B human herpesvirus 6B.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Green ML, Leisenring W, Xie H et al. . Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol 2016; 3:e119–27. - PMC - PubMed
    1. Zerr DM, Boeckh M, Delaney C et al. . HHV-6 reactivation and associated sequelae after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18:1700–8. - PMC - PubMed
    1. Erard V, Huang ML, Ferrenberg J et al. . Quantitative real-time polymerase chain reaction for detection of adenovirus after T cell-replete hematopoietic cell transplantation: viral load as a marker for invasive disease. Clin Infect Dis 2007; 45:958–65. - PubMed
    1. Erard V, Kim HW, Corey L et al. . BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. Blood 2005; 106:1130–2. - PMC - PubMed
    1. Wagner HJ, Wessel M, Jabs W et al. . Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation 2001; 72:1012–9. - PubMed

Publication types

MeSH terms

LinkOut - more resources