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  • As stated above the limited number of


    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 it GDC-0623 sale 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. Limitations of the current study, in addition to the ones highlighted above, are its retrospective nature, the potential biased selection of patients requiring bronchoscopy for the etiological diagnosis of pneumonia, the lack of normalization of CMV DNA loads in BAL fluids to cellular DNA content (although this was reported to be expendable in a previous study) and the use of different DNA extraction platforms and real-time PCR assays for CMV DNA quantitation. Nevertheless, this study has several strengths, including the inclusion of consecutive specimens, the use of fresh BAL fluid specimens and highly-sensitive real-time PCR assays for CMV DNA load quantitation, and the performance of a comprehensive and systematic evaluation of specimens for the presence of RVs pathogens using molecular assays.
    Conflict of interest
    Author\'s contributions
    Acknowledgments This research was supported by a grant (12/1992) from FIS (Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo, Spain). Estela Giménez holds a Río Hortega research contract from the Carlos III Health Institute (Ref. CM16/00200).