Features of Cytomegalovirus DNAemia Blips in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Implications for Optimization of Preemptive Antiviral Therapy Strategies

Huntley, Dixie; Talaya, Alberto; Giménez, Estela; Martínez, Ariadna Pérez; Hernández‐Boluda, Juan Carlos; Hernani, Rafael; Torres, Ignacio; Alberola, Juan; Albert, Eliseo; Piñana, José Luís; Solano, Carlos; Navarro, David

doi:10.1016/j.bbmt.2020.01.015

Cited by 15 publications

(16 citation statements)

References 21 publications

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“…15 Blips were defined as single time-point episodes of quantifiable CMV DNAemia and were considered as CMV reactivation. 16 Detectable, nonquantifiable CMV DNA results were not considered CMV reactivation. Time to nonquantifiable CMV viral load was calculated based on days between quantifiable and nonquantifiable CMV viral load PCR test results.…”

Section: Me Thodsmentioning

confidence: 99%

Cytomegalovirus events in high‐risk allogeneic hematopoietic‐cell transplantation patients who received letermovir prophylaxis

Chen

Arbona‐Haddad

Cheng

et al. 2021

Transplant Infectious Dis

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Letermovir is approved for the prevention of cytomegalovirus (CMV) reactivation and clinical disease in patients undergoing allogeneic hematopoietic-cell transplantation (HCT). However, there is uncertainty about letermovir's ability to prevent clinical events during the period of prophylaxis as well as after the discontinuation of prophylaxis in the post-transplant setting. We performed a retrospective cohort study in CMV-seropositive allogeneic HCT recipients at high risk of CMV events, who received letermovir for primary prophylaxis from November 2017 through December 2019. We analyzed CMV outcomes for these patients during and after prophylaxis was discontinued. Patient outcomes were followed through June 2020. Sixty patients received letermovir for a median of 13 weeks (range, 1-72 weeks). Thirteen (22%) patients had quantifiable CMV DNAemia (reactivation) during letermovir prophylaxis a median of 9 days (range, 1-59 days) after starting letermovir. Five (8%) of these patients discontinued prophylaxis and received preemptive therapy (PET) with valganciclovir; eight (13%) continued letermovir as prophylaxis and CMV DNAemia resolved without PET. Thirteen patients (22%) had post-prophylaxis CMV reactivation a median of 33 days (range, 14-109 days) after letermovir discontinuation. In four (7%) of these patients, CMV DNAemia resolved without PET, and nine (15%) received PET. No patient developed CMV disease. Patients who developed CMV reactivation during prophylaxis did so shortly after initiation of letermovir, and most patients who developed CMV reactivation post-prophylaxis did so within 60 days after discontinuation of letermovir. Letermovir prophylaxis has changed the presentation of CMV infection in high-risk HCT patients.

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Section: Me Thodsmentioning

confidence: 99%

Cytomegalovirus events in high‐risk allogeneic hematopoietic‐cell transplantation patients who received letermovir prophylaxis

Chen

Arbona‐Haddad

Cheng

et al. 2021

Transplant Infectious Dis

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“…Finally, this study analyzed only CMV high‐risk recipients, which limits generalizability and information on moderate‐risk recipients. While this limits the results, it is likely necessary to separate these populations because moderate‐risk patients already have CMV antibodies, and infection represents reactivation of latent CMV in the recipient 8 , 9 . Therefore, a blip may mean something completely different in a moderate‐risk patient.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, viral blips can occur in patients with hepatitis B or hepatitis C infections 14 – 21 . Importantly, however, CMV viral blips remain relatively understudied in solid‐organ transplant patients 8 , 9 …”

Section: Introductionmentioning

confidence: 99%

“…4,7 Due to its high sensitivity, CMV QNAT can result in positive values below the level of quantification (1.37 × 10 2 IU/ml), or a "CMV blip." [8][9][10] Viral blips were originally identified in human immunodeficiency virus (HIV) QNAT with positives below the level of quantification indicating low-level viral replication rather than false positives. [11][12][13] Similarly, viral blips can occur in patients with hepatitis B or hepatitis C infections.…”

mentioning

confidence: 99%

“…[14][15][16][17][18][19][20][21] Importantly, however, CMV viral blips remain relatively understudied in solid-organ transplant patients. 8,9 In the case of CMV, low-level positives may be an early indication of DNAemia or they may be a false positives due to differences in QNAT testing. [22][23][24] These possible differences introduce ambiguity in decisions of when antiviral treatment should begin, as well as variability in how each clinician approaches a blip.…”

mentioning

confidence: 99%

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Evaluation of cytomegalovirus “Blips” in high‐risk kidney/kidney‐pancreas transplant recipients

Payne

Lindner

Gilbert

et al. 2022

Transplant Infectious Dis

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Background: Cytomegalovirus (CMV) is a significant cause of morbidity and mortality after solid organ transplantation. While guidelines suggest using highly sensitive QNAT assays for CMV detection, there is no defined viral load to guide initiation of preemptive therapy. This study evaluates the progression to quantifiable CMV (DNAemia) following a CMV "blip" in high-risk (D+/R) kidney/kidney-pancreas (KP) transplant recipients.Methods: This is a single center, retrospective study. A CMV "blip" was defined as the first positive QNAT assay below the level of quantification (<1.37 × 10 2 IU/ml or <200 viral copies). Subsequent CMV QNAT assays were followed to assess the progression from blip to CMV DNAemia for 1 year following transplant.Results: A total of 134 patients were included in the study. Fifty-three (39.6%) patients had their first positive CMV QNAT value below the level of quantification, a "CMV blip." Of these 53 patients, 69.8% (n = 37) progressed to DNAemia while 30.2% (n = 16) did not. The median time from transplant to the first CMV blip was 68 (46-97) days and most patients with viral blips (71.1%) were on prophylaxis. No differences in patient characteristics were found among those who progressed from blip to DNAemia and those who only had a blip. Conclusions:In CMV high-risk kidney/KP transplant recipients, CMV blips progressed to CMV DNAemia in the majority of cases. This progression typically occurred 2-3 weeks following the initial blip. CMV blips are common early posttransplant despite prophylaxis and likely represent an early marker of CMV infection.

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Amplicon size and non‐encapsidated DNA fragments define plasma cytomegalovirus DNA loads by automated nucleic acid testing platforms: A marker of viral cytopathology?

Leuzinger,

Hirsch

2023

Journal of Medical Virology

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Management of cytomegalovirus (CMV) in transplant patients relies on measuring plasma CMV‐loads using quantitative nucleic acid testing (QNAT). We prospectively compared the automated Roche‐cobas®6800‐CMV and Roche‐CAP/CTM‐CMV with laboratory‐developed Basel‐CMV‐UL54‐95bp, and Basel‐CMV‐UL111a‐77bp. Roche‐cobas®6800‐CMV and Roche‐CAP/CTM‐CMV were qualitatively concordant in 142/150 cases (95%). In‐depth comparison revealed higher CMV‐loads of the laboratory‐developed assay and correlated with smaller amplicon size. After calibration to the 1.WHO‐approved CMV international standard, differences were reduced but remained significant. DNase‐I pretreatment significantly reduced CMV‐loads for both automated Roche‐CAP/CTM‐CMV and Roche‐cobas®6800‐CMV assays, whereby 90% and 95% of samples became undetectable. DNase‐I pretreatment also reduced CMV‐loads quantified by Basel‐CMV‐UL54‐95bp and Basel‐CMV‐UL111a‐77bp, but remaining detectable in 20% and 35%, respectively. Differences were largest for 110 samples with low‐level CMV‐DNAemia being detectable but not‐quantifiable by Roche‐cobas®6800‐CMV, whereby the smaller amplicon sizes yielded higher viral loads for concordant positives. We conclude that non‐encapsidated fragmented CMV‐DNA is the major form of plasma CMV‐loads also measured by fully‐automated platforms. Amplicons of <150 bp and calibrators are needed for reliable and commutable QNAT‐results. We hypothesize that non‐encapsidated fragmented CMV‐DNA results from lysis of CMV‐replicating cells and represent a direct marker of viral cell damage, which contribute to delayed viral load responses despite effective antivirals.

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Features of Cytomegalovirus DNAemia Blips in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Implications for Optimization of Preemptive Antiviral Therapy Strategies

Cited by 15 publications

References 21 publications

Cytomegalovirus events in high‐risk allogeneic hematopoietic‐cell transplantation patients who received letermovir prophylaxis

Cytomegalovirus events in high‐risk allogeneic hematopoietic‐cell transplantation patients who received letermovir prophylaxis

Evaluation of cytomegalovirus “Blips” in high‐risk kidney/kidney‐pancreas transplant recipients

Amplicon size and non‐encapsidated DNA fragments define plasma cytomegalovirus DNA loads by automated nucleic acid testing platforms: A marker of viral cytopathology?

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