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  • In a recent study a CMV DNA load cut off


    In a recent study, a CMV DNA load cut-off of 500 IU/ml in BAL fluid was found to have a positive predictive value of ∼50% for the presence of probable CMV pneumonia (considering a prevalence of this event of 10% among patients at risk and undergoing BAL testing). Tan et al., in contrast, found CMV DNA levels in BAL fluid samples to have a limited value to distinguish between CMV and non-CMV pneumonia cases. It is pertinent to mention here that the above threshold is between one and two log10 lower than those tentatively proposed for diagnosing CMV pneumonia in lung transplant recipients.34, 35, 36, 37– Interestingly, control patients with non-CMV pneumonia in the Boeckh study showed a median CMV DNA load of log10 IU/ml (IQR, 0–1.6 IU/mL), with CMV DNA levels between 100 and 500 IU/ml in roughly 64% of cases and >500 IU/ml in 36% of them. Here, the opposite was true, with nearly 60% of BAL fluid samples from patients with non-proven CMV pneumonia having CMV viral loads >500 IU/ml, of which 75% had >1000 IU/ml. It is worth highlighting that these figures were comparable at both participating centers, despite the above-referred differences in Parthenolide CMV DNA loads provided by Parthenolide assays used at each center. To gauge the potential relevance of these data, it must be taken into consideration that in nearly 70% of pneumonia episodes in our cohort, BAL sampling was performed while patients were under anti-CMV therapy (>3 days), whereas in the aforementioned study, only 24% of patients with CMV pneumonia and 35% of patients with non-CMV pneumonia had been treated with antivirals for at least two days. Despite this fact, higher CMV DNA loads in BAL fluid specimens were quantified in the current study, likely reflecting major differences regarding the DNAemia cut-off triggering the inception of antiviral therapy between these studies (much higher in the current cohort). In fact, in this series, the median CMV DNA load in BAL was significantly higher in patients who were under antiviral therapy than in non-treated patients. As stated above, the limited number of proven CMV pneumonia cases in our series precluded any attempt to establish a diagnostic CMV DNA load cutoff; nevertheless, in light of the data presented herein, a threshold value of 500 IU/ml is unlikely to be discriminative between CMV pneumonia and pulmonary CMV DNA shedding in our setting. In this sense, we fully support the idea that the magnitude of such a diagnostic cut-off is likely to vary depending upon the patient's characteristics, the BAL procedure and processing, the assay used for CMV DNA quantitation and the severity of CMV pneumonia at the time of sampling. CMV is a highly pro-inflammatory and immunosuppressive virus; as such antibody-mediated immunity may act as a synergistic co-pathogen in the absence of documented CMV-induced cytopathogenicity, and may have a relevant impact on patient outcome. In this sense, we found that the presence of CMV DNA in BAL fluid specimens at levels >500 IU/ml, in addition to receipt of corticosteroids and low lymphocyte counts at the time of BAL sampling, was associated with increased pneumonia-attributable mortality in Cox multivariate models. The relative scarce number of pneumonia cases in which BAL specimens had CMV DNA loads >500 IU/ml did not allow to investigate whether this apparent effect exhibited a dose-response pattern. Again, this finding must be interpreted cautiously, as in order to avoid overfitting, Cox models were not adjusted to a number of factors that may have had an impact on mortality (i.e., adequacy of antimicrobial treatment, severity of pneumonia, among others). The limited size of the current cohort also precluded any meaningful statistical analysis evaluating the impact of CMV DNA load in BAL at each center, separately. Further studies are urgently needed to validate this observation, since this subset of patients may benefit from short courses of anti-CMV therapy.