Second we found a wide range of CMV DNA loads

Second, we found a wide range of CMV DNA loads measured in BAL fluid specimens from patients with pneumonia in whom CMV causality was unlikely or reasonably ruled out attending to clinical (including therapeutic response to nonanti-CMV drugs), radiographic, lung autopsy histopathology or BAL fluid cdk7 (in some patients) and microbiological criteria. Interestingly, median CMV DNA loads were comparable irrespective of the nature and the number of co-detected microorganisms (at both participating centers), and were overall higher in the presence of concurrent DNAemia. As for the latter observation, in agreement with Boeckh et al., we found this not to be due to pulmonary hemorrhage (not shown). Overall, CMV DNA loads in BAL fluid specimens processed at HLF were of greater magnitude than those analyzed at HCU. Since CMV DNA loads produced by the Argene PCR assay are slightly lower than those measured by the Abbott PCR assay (not shown), differences in the net state of immunosuppression of patients at the time of BAL sampling across centers, as reflected by the immunodeficiency score index (higher for HLF patients), may account for this observation. In fact, a trend towards an inverse correlation was found between the ISI score and the CMV DNA load quantified in BAL specimens. 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 0 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 CMV DNA loads provided by PCR 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.