Dynamics of Cytomegalovirus (CMV) Plasma DNAemia in Initial and Recurrent Episodes of Active CMV Infection in the Allogeneic Stem Cell Transplantation Setting: Implications for Designing Preemptive Antiviral Therapy Strategies

Abstract

Preemptive antiviral therapy strategies for active cytomegalovirus (CMV) infection occurring in allogeneic stem cell transplant recipients should be optimized to avoid overtreatment. The current study was aimed at determining whether the analysis of the kinetics of CMV DNA load in plasma may provide useful information for the therapeutic management of active CMV infection in this setting. A total of 59 consecutive patients were included in the study, of which 40 (67.8%) developed 1 (n = 21) or more (n = 19) episodes of CMV DNAemia. The need for antiviral therapy for initial or secondary episodes of CMV DNAemia could not be predicted on the basis of the CMV DNA load value in the first plasma testing positive by polymerase chain reaction (PCR). In contrast, in the absence of antiviral therapy, an increase of ≥3-fold between the baseline CMV DNA load and that measured a median of 6 days later discriminated between initial episodes eventually requiring antiviral treatment and those resolving spontaneously (sensitivity, 76.4%; specificity, 89.4%; positive predictive value, 86.6%; negative predictive value, 80.9%). This criterion was not useful for identifying recurrent episodes of CMV DNAemia that required antiviral therapy. The CMV doubling time and CMV DNA loads at the time of the first positive PCR and at initiation of preemptive therapy did not differ significantly between episodes that responded immediately to antiviral therapy from those showing a delayed response. The analysis of the dynamics of CMV DNA load in plasma in the absence of antiviral therapy allowed early recognition of episodes of CMV DNAemia that eventually needed to be treated, but did not permit prediction of the kinetics of CMV DNA clearance in response to antiviral therapy.

Early Kinetics of Plasma Cytomegalovirus DNA Load in Allogeneic Stem Cell Transplant Recipients in the Era of Highly Sensitive Real-Time PCR Assays: Does It Have Any Clinical Value?

“…Thus, no reliable initial CMV DNA load threshold predicting the eventual need for antiviral therapy could be established by this study. This is in accordance with data published previously by our group for a cohort of patients in which the initiation of antiviral therapy was triggered either by the AG assay or by a qRT-PCR assay (6). CMV DNA loads measured in the second positive qRT-PCR tests were below the cutoff for the initiation of antiviral therapy in 41 of 47 episodes.…”

“…The limits of detection and quantitation of both qRT-PCR assays are approximately 20 copies/ml (95% confidence interval [CI]) (4,11). Data from 17 patients guided by the Abbott CMV PCR kit had been previously reported (6).…”

“…Second qRT-PCR analyses were performed at a median of 6 days (range, 4 to 8 days) after the first. This allowed us to calculate the viral doubling time (dt) in the absence of antiviral treatment (6). These calculations were only performed for episodes in which there was an increase between the first and second CMV DNA load values of Ͼ3-fold (Ͼ0.5 log 10 copy/ml, which is above the interassay coefficient of variation of both PCR assays) (n ϭ 36) (2, 13).…”

Fully Automated Quantification of Cytomegalovirus (CMV) in Whole Blood with the New Sensitive Abbott RealTi m e CMV Assay in the Era of the CMV International Standard

“…CMV DNAemia dynamics should be taken into consideration in the initiation of preemptive therapy, as underlined by recent studies (21,22). Thus, the reproducibility of the assay used for monitoring CMV infection is of great concern.…”

Preemptive antiviral therapy for CMV infection in allogeneic stem cell transplant recipients guided by the viral doubling time in the blood

“…The CMV dts were calculated using the CMV DNA load values measured in the first two positive QRT-PCR results (Table 2). 7,10 Antiviral therapy was interrupted upon the first undetectable (o 20 copies/mL) QRT-PCR result. 11 Out of the 67 episodes of active CMV infection, 27 (40%) were initial episodes, occurring at a median of 26 days (range, 5-56 days) following Allo-SCT, and 40 (60%) were recurrent episodes, developing at a median of 167 days (range, 32-723 days) after Allo-SCT.…”