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  • The different diagnostic outcomes of the two assays are also

    2020-01-19

    The different diagnostic outcomes of the two assays are also dependent on the used stimuli. The QuantiFERON-CMV assay targets CD8 + T d mannitol sale by using peptides whereas the T-Track-CMV targets CD4+ and CD8 + T cells by stimulation with two d mannitol sale viral proteins [18]. In our study, a specificity of 100% was chosen to give the clinician a clear cut-off for protected patients. In consequence, many patients without risk of reactivation may be followed up too closely. The T-Track-CMV had a higher sensitivity. Responses to the IE-1 protein had a very good predictive value for protection against reactivation, especially in the pre-emptive group (AUC = 0.960, Supplementary Table S1). This finding sustains the importance of IE-1 and the conclusions of a previous study in KTx recipients, where ELISpot responses to IE-1 pre-Tx indicated protection against reactivation in the post-Tx period [13]. Decreasing or undetectable CMV-specific CMI in the post-Tx follow-up period are also associated with an increased risk of CMV replication [19]. According to our cut-offs, 2/30 patients (7%) (QuantiFERON-CMV) and 4/18 (22%) (T-Track-CMV) would be protected against CMV infection. The 5 SFU cut-off for the T-Track-CMV-IE-1 could be used as an alternative, with a higher study power (6/18 or 33% of patients protected). The cut-offs are much higher than those proposed in previous studies. Cut-offs of >150 spots/200,000 PBMCs for the ELISpot (IE-1 and pp65 counted together) and 1–6 IU/ml for the QuantiFERON-CMV were proposed for protection against CMV infection (CMV-DNA >1000 copies/ml). [20]. Another study with 80 KTx patients showed that patients without CMV reactivation had a higher median baseline CMV ELISpot value than those with CMV reactivation. Cut-offs of 20 or 100 SFU/200,000 PBMCs were calculated for the occurrence of CMV viremia with sensitivities of 48.2%/77.8% and specificities of 81.8%/45.5%, respectively [21]. For the QuantiFERON-CMV, the manufacturer’s cut-off of 0.2 IU/ml or a lower cut-off of 0.1 IU/ml were used to predict patients at higher risk of developing CMV complications and one study in hematopoetic stem cell transplantation defined a cut-off of 9 IU/ml protecting against CMV disease [8,10,12,15,[22], [23], [24]]. The reverse conclusion, that low levels of CMV-specific CMI means higher proportion of CMV reactivation/infection, failed. Differences in the results in different studies are partly due to different cut-offs for CMV replication and especially to our definition of cut-offs truly protecting against CMV replication.
    Author contributions
    Funding The QuantiFERON sample sets were provided by Qiagen, Hilden, Germany.
    Conflicts of interest
    Acknowledgments
    Background Congenital cytomegalovirus (cCMV) infection is common, with an estimated birth prevalence of 0.2% in US, Canada, Australia, and Western Europe [1], while limited studies in developing countries (Latin America, Africa, Asia) report prevalences ranging from 0.6 to 6.1% [2]. The vast majority of newborns with cCMV infection are asymptomatic, approximately 10% however show clinical, laboratory or imaging abnormalities. Long term sequelae (e.g. late onset sensorineural hearing loss (SNHL), visual impairment, cognitive and motor deficits) occur in 40–60% of infants with and in 10–15% of infants without symptoms at birth [3]. Without a general screening, the majority of cCMV infections is not diagnosed at birth and affected newborns do not receive the necessary follow-up for timely detection of possible sequelae (mostly SNHL in infants with asymptomatic cCMV) that would allow early interventions (e.g. hearing aids, speech therapy). A large-scale study on about 35,000 newborns has shown that saliva polymerase chain reaction (PCR) is a sensitive and specific method to identify infants with cCMV infection [4]. This method is more convenient than obtaining urine (urine culture has been gold standard) and amenable to high-throughput assays. However, the influence of pre-analytic factors on the analytical sensitivity of the CMV PCR has not been reported. Therefore, the current study aimed to evaluate the performance of different swabbing materials, transport time and initial virus concentration with regard to the efficacy of recovery of CMV DNA. In future, this should improve the accuracy of quantitative assessment of CMV DNA in swab material and facilitate investigations on the predictive value of CMV viral load of swab samples on the risk of late-onset cCMV disease.