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Letermovir (LMV) inhibits HCMV replication by binding to components of the HCMV-terminase complex showing a potential role in prevention of HCMV-related complications in allogenic hematopoietic stem cell transplant recipients (allo-HSCTRs). However, little is known about breakthrough HCMV infection and the relevance of HCMV DNAemia during prophylaxis. We reported the results of a multicenter prospective study involving five Italian centers in the management of HCMV DNAemia in 75 adult HCMV-seropositive allo-HSCTRs undergoing LMV prophylaxis. The aim of the present study was to characterize the presence of real HCMV reactivation during LMV prophylaxis. Then, the presence of circulating infectious HCMV particles was determined by virus isolation and degradation of free-floating viral DNA. This report provides the first evidence that during LMV prophylaxis the clinical relevance of HCMV DNAemia should be critically considered., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

This retrospective multicenter cohort study investigated the kinetics (ascending and descending phases) of cytomegalovirus (CMV) and Epstein-Barr virus (EBV)-DNA in whole blood (WB) and plasma samples collected from adult kidney transplant (KT) recipients. CMV-DNA kinetics according to antiviral therapy were investigated. Three hundred twenty-eight paired samples from 42 episodes of CMV infection and 157 paired samples from 26 episodes of EBV infection were analyzed by a single commercial molecular method approved by regulatory agencies for both matrices. CMV-DNAemia followed different kinetics in WB and plasma. In the descending phase of infection, a slower decay of viral load and a higher percentage of CMV-DNA positive samples were observed in plasma versus WB. In the 72.4% of patients receiving antiviral therapy, monitoring with plasma CMV-DNAemia versus WB CMV-DNAemia could delay treatment interruption by 7-14 days. Discontinuation of therapy based on WB monitoring did not result in relapsed infection in any patients. Highly different EBV-DNA kinetics in WB and plasma were observed due to lower positivity in plasma; EBV positive samples with a quantitative result in both blood compartments were observed in only 11.5% of cases. Our results emphasize the potential role of WB as specimen type for post-KT surveillance of both infections for disease prevention and management., Competing Interests: The supporting source (i.e. Qiagen S.r.l., Italy) of the study is a commercial source. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Cytomegalovirus (CMV) infection is a major complication in immunocompromised patients, including those with autoimmune diseases. Here, we describe the first case of granulomatosis with polyangiitis treated with steroids and cyclophosphamide, complicated by a multidrug-resistant (MDR) CMV infection in presence of weak antiviral cellular immunity. Since reports regarding CMV infection in rheumatological patients are rarely described and no guidelines on its management exist, the described case contributes to identify potential strategies to predict the risk of CMV disease and developing of MDR-CMV in these patients, through virological and immunological surveillance.

The present multicentric (n = 11 laboratories) study aimed to identify conversion factors from copies/mL to international units (IU)/mL for the normalization of HCMV DNA load using the first WHO International Standard for HCMV nucleic acid amplification techniques and to enhance interlaboratory agreement of HCMV DNA quantification methods. Study protocols for whole blood and plasma (extraction and amplification) were performed to calculate conversion factors from HCMV DNA copy number to IU. The greatest variability was observed in samples with lower HCMV concentrations (3.0 Log 10 ) in both biological matrices. Overall, 73.1% (206/282) of whole blood and 82.2% (324/394) of plasma samples analyzed fell within an acceptable variation range (±0.5 Log 10 difference). An average of 0.64 (range 0.21-1.17) was the conversion factor calculated for the HCMV whole blood panel and 0.82 (range 0.39-2.2) for the HCMV plasma panel., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Currently, no consensus has been reached on the optimal blood compartment to be used for surveillance of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNAemia. Although several comparative studies have been performed correlating CMV and EBV DNA loads in whole blood (WB) versus plasma, to our knowledge, no studies to date have analyzed the kinetics of both viruses in the 2 blood compartments. In this retrospective noninterventional multicenter cohort study, the kinetics of CMV and EBV DNA in 121 hematopoietic stem cell transplantation (HSCT) recipients were investigated by analyzing in parallel 569 and 351 paired samples from 80 and 58 sequential episodes of CMV and EBV DNAemia, respectively. Unlike previous studies, this study used a single automated molecular method that was CE-marked and Food and Drug Administration-approved for use in quantifying CMV and EBV DNA in both plasma and WB. Furthermore, the complete viral replication kinetics of all episodes (including both the ascending and the descending phases of the active infection) was examined in each patient. The previously observed overall correlation between CMV DNA levels in WB and plasma was confirmed (Spearman's ρ = .85; P < .001). However, although WB and plasma CMV DNAemia reached peak levels simultaneously, in the ascending phase, the median CMV DNA levels in plasma were approximately 1 log10 lower than WB. Furthermore, in patients who received preemptive therapy, CMV DNA showed a delayed decrease in plasma compared with WB. A lower correlation between EBV DNA levels in plasma versus WB was found (Spearman's ρ = .61; P < .001). EBV DNA kinetics was not consistent in the 2 blood compartments, mostly due to the lower positivity in plasma. Indeed, in 19% of episodes, EBV DNA was negative at the time of the EBV DNA peak in WB. Our results suggest a preferential use of WB for surveillance of CMV and EBV infection in HSCT recipients., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The clinical utility of the QuantiFERON-CMV (QFN-CMV) assay in heart transplant recipients was assessed. Forty-four cytomegalovirus (CMV)-seropositive patients were enrolled: 17 received antiviral prophylaxis, and 27 were managed preemptively. CMV-DNAemia monitoring was performed by the use of a quantitative real-time PCR assay. The QFN-CMV assay was retrospectively performed on blood samples collected at five posttransplant time points. A higher proportion of patients with an indeterminate QFN-CMV result after the suspension of prophylaxis than of patients who showed a global T-cell responsiveness developed CMV infection ( P = 0.036). Patients who reconstituted a CMV-specific response following the first CMV-DNAemia-positive result (42.9%) showed a median CMV-DNAemia peak 1 log of magnitude lower than that seen with patients with indeterminate results, and all controlled viral replication spontaneously. The 25% of patients with an indeterminate result developed CMV disease. In the preemptive strategy group, no differences in the development of subsequent infection, magnitude of viral load, and viral control were observed on the basis of QFN-CMV measurements performed before and after the first CMV-DNAemia-positive result. Considering both CMV prevention strategies, viral relapse was associated with the failure to reconstitute CMV-specific cell-mediated immunity (CMI) after the resolution of the first episode of CMV infection ( P = 0.032). QFN-CMV measurements can be a useful tool for identifying patients (i) at higher risk of developing infection after discontinuing antiviral prophylaxis, (ii) with late CMV infection who would benefit from appropriate antiviral interventions, and (iii) at higher risk of viral relapses. QFN-CMV measurements taken within 1 month posttransplantation (early period) are not revealing., (Copyright © 2018 American Society for Microbiology.)

Clinical evaluation of the Elecsys ® CMV IgM, IgG, IgG Avidity and COBAS AmpliPrep/COBAS TaqMan CMV (COBAS CMV) assays (Roche Diagnostics AG) in the diagnosis and prognosis of congenital CMV infection was performed. In this study, 150 preselected clinical samples (50 primary infection sera, 50 amniotic fluid [AF] and 50 newborn urine) were processed using Roche serological/molecular CMV-specific tests. Results were compared with those obtained by routine assays (comparator assays). The Elecsys ® CMV IgM and IgG assays showed a perfect agreement (100%) with the comparator assays. Using the combination of the Elecsys ® CMV IgM and IgG Avidity assays results, a primary infection was identified in 100% of cases. Inappropriate avidity CMV IgG values in two samples with very low IgG values (<6 AU/mL) were observed. COBAS CMV assay showed an agreement equal to 98% and 100% with comparator assays by processing AF and urine samples, respectively. Among AF with quantitative results, Lin's concordance correlation was 0.933 and comparator-COBAS CMV assays gave CMV-DNA loads differing by <0.5 log 10 DNA. Finally, higher CMV-DNA levels in AF samples were associated with a symptomatic outcome (p=0.003). The Roche CMV-specific assays compared well with the comparator assays, thus providing to be suitable for clinical use., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cytomegalovirus (CMV) represents the major infectious cause of birth defects, as well as an important pathogen for immune-compromised individuals. Several studies described the use of dried blood spots (DBS) for the detection of CMV DNA for late diagnosis of congenital CMV infection in cases of strong clinical suspicion. In the article under evaluation, Limaye et al. perform for the first time the quantification of CMV in pairs of finger-stick DBS and plasma samples collected from transplant patients. The work concluded that finger-stick DBS could be an alternative sample type for quantification of CMV load that correlates well with plasma levels. Prospective trials to evaluate the use of DBS for monitoring CMV load in transplant recipients will be required.

Background: Congenital cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL). The mechanisms of pathogenesis of CMV-related SNHL are still unclear. The aim is to study congenital CMV-related damage in the fetal inner ear, in order to better understand the underlying pathophysiology behind CMV-SNHL., Results: We studied inner ears and brains of 20 human fetuses, all at 21 week gestational age, with a high viral load in the amniotic fluid, with and without ultrasound (US) brain abnormalities. We evaluated histological brain damage, inner ear infection, local inflammatory response and tissue viral load.Immunohistochemistry revealed that CMV was positive in 14/20 brains (70%) and in the inner ears of 9/20 fetuses (45%). In the cases with inner ear infection, the marginal cell layer of the stria vascularis was always infected, followed by infection in the Reissner's membrane. The highest tissue viral load was observed in the inner ear with infected Organ of Corti. Vestibular labyrinth showed CMV infection of sensory cells in the utricle and in the crista ampullaris.US cerebral anomalies were detected in 6 cases, and in all those cases, the inner ear was always involved. In the other 14 cases with normal brain scan, histological brain damage was present in 8 fetuses and 3 of them presented inner ear infection., Conclusions: CMV-infection of the marginal cell layer of the stria vascularis may alter potassium and ion circulation, dissipating the endocochlear potential with consequent SNHL. Although abnormal cerebral US is highly predictive of brain and inner ear damage, normal US findings cannot exclude them either.

Congenital cytomegalovirus (CMV) infection is the main cause of non-hereditary sensorineural hearing loss (SNHL). In order to shed light on SNHL pathophysiology, we examined the auditory pathway in CMV-infected fetuses; the temporal lobe, in particular the auditory cortex, and the inner ear. We investigated both inner ears and temporal lobes of 20 human CMV-infected fetuses at 21 weeks of gestation. As a negative group, five fetuses from spontaneous miscarriages without CMV infection were studied. Inner ears and temporal lobes were histologically examined, immunohistochemistry for CMV and CMV-PCR were performed. On the auditory cortex, we evaluated the local microglial reaction to the infection. CMV-positive cells were found in 14/20 brains and the damage was classified as severe, moderate, or mild, according to histological features. Fetuses with severe brain damage had a statistically higher temporal lobe viral load and a higher number of activated microglial cells in the auditory cortex compared to fetuses with mild brain damage (p: 0.01; p: 0.01). In the inner ears, the marginal cells of the stria vascularis were the most CMV positive. In our study, CMV affected the auditory pathway, suggesting a tropism for this route. In addition, in the auditory cortex, microglial activation may favor further tissue damage contributing to hearing loss. [ABSTRACT FROM AUTHOR]

Salivary glands are a site of human cytomegalovirus (CMV) replication, latency, and persistence. Prolonged secretion of virus in saliva for months following a primary infection contribute to horizontal transmission. In order to better understand the early effects of CMV on salivary glands and the mechanisms of viral persistent replication, submandibular glands of six CMV congenitally infected fetuses at 21 weeks gestation were studied. Three fetuses at the same gestational age from CMV-seronegative women were compared as negative controls. Tissue viral load and the type of inflammatory infiltrate were evaluated. Moreover, development and branching of salivary glands, the number of myoepithelial cells, cellular proliferation, and expression of secretory proteins of the saliva (Gross Cystic Disease Fluid Protein-15 and lysozyme) were studied. A low viral load and rare CMV-positive cells associated with T CD8 cytotoxic lymphocytes were observed. Branching was impaired with a decrease in terminal acinar structures, the number of myoepithelial cells, and cellular proliferation were reduced. In addition, a compromised secretion of defense proteins involved in the oral humoral immunity was observed. These findings suggest that CMV may affect salivary glands, impairing structure development and secretion of defense proteins, probably responsible for the prolonged viral shedding in saliva. J. Med. Virol. 89:318-323, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Background: Congenital cytomegalovirus (CMV) infection is a major cause of central nervous system damage leading to sensorineural hearing loss, mental retardation and cerebral palsy. Objectives: Identify the type of organ involvement and understand the histopathogenesis of damage in foetuses of women with a CMV-highly positive amniotic fluid. Study design: 34 foetuses with congenital CMV infection documented by prenatal diagnosis were studied. Three foetuses died in utero. The remaining pregnancies were electively terminated at 20–21 weeks gestation. Results: Foetal organs positive for CMV antigens were: placenta (100%), pancreas (100%), lung (87%), kidney (87%), liver (71%), brain (55%) and heart (44%). Inflammatory infiltrate was almost always present in CMV-infected foetal organs and the severity of the inflammatory response was correlated with the organ damage. Brain damage with necrosis was observed in 33% (9/27) and a mild telencephalic leukoencephalopathy in 22% (6/27) of foetuses studied. Conclusions: Focal necrosis was observed very frequently in organs such as pancreases, livers, hearts and kidneys. However the damage in these organs is likely to be resolved by parenchymal regeneration. Brain damage, which seems to be the results of a combined effect of viral infection, inflammatory infiltration and hypoxia due to severe placentitis, is less likely to be resolved because of the low regeneration ability of this organ. [Copyright &y& Elsevier]