Cytomegalovirus (CMV) remains a serious opportunistic infection in hematopoietic cell transplant (HCT) and solid-organ transplant (SOT) recipients. Traditional anti-CMV drugs are limited by toxicities and the development of resistance. Letermovir and maribavir are newly approved antivirals for the prevention and treatment of CMV.

Prior reviews have discussed use of letermovir for prevention of CMV after HCT and maribavir for resistant or refractory (R/R) CMV post HCT or SOT. Subsequent data have expanded their use including letermovir for primary CMV prophylaxis in high-risk renal transplant recipients and new recommendations for extending prophylaxis through day + 200 in certain HCT patients. Data on the use of maribavir for first asymptomatic CMV infection post-HCT has also been published. This review compares the pharmacology of anti-CMV agents and discusses the updated literature of these new drugs in the prevention and treatment of CMV.

Letermovir and maribavir are much needed tools that spare toxicities of ganciclovir, foscarnet, and cidofovir. High cost is a challenge preventing their integration into clinical practice in resource-limited countries. Transplant centers need to exercise restraint in overuse to avoid resistance, particularly in the setting of high viral loads.

Cytomegalovirus (CMV) can cause serious complications in immunocompromised individuals and fetuses with congenital infections. These can include neurodevelopmental impairments and congenital abnormalities in newborns. This paper emphasizes the importance of concurrently evaluating ultrasonography findings and laboratory parameters in diagnosing congenital CMV infection. To examine the prenatal characteristics of CMV DNA-positive patients, we assessed serum and amniotic fluid from 141 pregnant women aged 19-45 years, each with fetal anomalies. ELISA and PCR tests, conducted in response to these amniocentesis findings, were performed at an average gestational age of 25 weeks. Serological tests revealed that all 141 women were CMV IgG-positive, and 2 (1.41%) had low-avidity CMV IgG, suggesting a recent infection. CMV DNA was detected in 17 (12.05%) amniotic fluid samples using quantitative PCR. Of these, 82% exhibited central nervous system abnormalities. Given that most infections in pregnant women are undetectable and indicators non-specific, diagnosing primary CMV in pregnant women using clinical findings alone is challenging. We contend that serological tests should not be the sole means of diagnosing congenital CMV infection during pregnancy.

To search for existing evidence of a beneficial effect of (val)ganciclovir on hearing in children with congenital cytomegalovirus (cCMV) infection and to identify future research questions.

Systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, searches were performed in PUBMED, EMBASE, and WEB OF SCIENCE on December 15, 2021.

Studies providing ear-specific hearing results after treating children with cCMV-related hearing loss with (val)ganciclovir were retained. A meta-analysis [Peto odds ratio (OR), Review Manager 5.3] was performed to compare hearing outcome between treated and untreated children. The National Institutes of Health tool was used for quality assessment and heterogeneity was assessed with I² statistics.

Eighteen studies with a total of 682 treated patients were included for the systematic review. Our meta-analysis showed that treating symptomatic children with hearing loss resulted in more hearing improvement [Peto OR 7.72, 95% confidence interval (CI) 3.08-19.34] and less hearing deterioration (Peto OR 0.23, 95% CI 0.10-0.57). Relative to an improvement and deterioration rate of 9.4% and 28.2% in an untreated group, the rate of the treated group was 44.5% and 6.3%, respectively.

There is sufficient evidence in literature to support treatment with (val)ganciclovir of children with symptomatic cCMV and hearing loss. However, still today, there is insufficient evidence of the potential beneficial role of (val)ganciclovir on hearing outcome of children with isolated hearing loss, late-onset hearing loss, and asymptomatic cCMV. The urgent need for future prospective, randomized clinical trials still exists. A standardization of definitions and treatment protocols would create uniformity in future studies. Laryngoscope, 2022.

To describe the vestibular and postural impairment related to the congenital Cytomegalovirus infection (cCMV), including the inner ear damages CMV-induced.

A PRISMA systematic review was performed, with the PubMed, Embase, and Cinahl databases searched from inception through to March 2021; after the application of inclusion and exclusion criteria a total of 12 papers were included in this review.

Vestibular and postural disorders have been reported in cCMV children, with a high variability of clinical manifestation. Presently, the available reported data on vestibular and postural impairment in cCMV children differ in terms of the sample size and the features of the studied populations.

At present, the vestibular and postural impairment in cCMV cases is underestimated; a complete vestibular assessment, a follow-up and management of all children affected by cCMV or, at least, of all cCMV patients showing sensorineural hearing loss, is recommended.

The objective of this review is to help practitioners of neonatal and pediatric medicine become more familiar with diagnosing and managing neonatal skin conditions. This article will discuss normal neonatal skin care and benign and common rashes, as well as some of the serious dermatologic conditions that require specialists for further evaluation and/or treatment.

To date, cCMV represents the most frequent non-genetic congenital cause of permanent sensorineural hearing loss (SNHL) in childhood and the leading infectious cause of developmental and neurologic disabilities. The aim of this paper is to describe the outcome of cochlear implantation in children affected by severe-to-profound sensorineural hearing loss, due to a symptomatic or asymptomatic cCMV infection, particularly comparing their performance results to that of matched mutated Connexin 26 (Cx26) implanted patients.

Retrospective case control study. The clinical data of symptomatic cCMV and asymptomatic cCMV patients were collected and compared to those of Cx26 patients matched for age and pre-CI (cochlear implant) linguistic category; all subjects were affected by bilateral severe-to-profound SNHL and were treated by CI and speech therapy rehabilitation. The Speech Perception Category, the language stage and the linguistic level scores, at 6 months, 1 year, and 3-4 years after CI of the three groups (symptomatic cCMV, asymptomatic cCMV and Cx26 mutation) were collected and compared.

Statistical analysis did not show any significant difference in pre-CI perception category and linguistic level among the three groups; the symptomatic cCMV group showed a statistically worse performance of the language stage over time (p = 0.017).

Our data support that children affected by cCMV have improved language abilities over time, although the symptomatic cCMV group achieved a lower language stage 3-4 years after CI compared to the asymptomatic cCMV and Cx26 mutation groups. Nonetheless, to date, CI supported by speech therapy can be considered an effective intervention for children affected by cCMV-related severe-to-profound hearing loss.

Human cytomegalovirus is one of the causes of opportunist infections in immunocompromised patients, and is triggered by factors such as state of viral latency, weakened immune responses, and development of antiviral resistance to ganciclovir, the only drug offered by the public health system in Brazil to treat the infection. The goal of this study was to identify mutations that may be associated with antiviral resistance in immunocompromised patients.

Molecular analysis was performed in 82 blood samples and subjected to genomic DNA extraction by a silica-based method. Three sequences of the HCMV UL97 gene, which encodes a phosphotransferase protein required for activation of ganciclovir, were amplified by polymerase chain reaction. Pyrosequencing methods were applied to one external 2096-bp segment DNA and two internal sequences between nucleotides 1087 to 1828 to detect mutations in this gene.

Approximately 10% of sequences contained mutations between nucleotides 377 and 594, in conserved regions of the UL97 gene, leading to amino acid changes. Eleven coding mutations were identified, including changes leading to amino acid substitutions, E596K and S604F, which were observed in 100% of samples and are described for the first time in Brazil. In addition, one mutation (A594V) that is associated with ganciclovir resistance was detected in a kidney transplant patient.

Further studies to detect mutations associated with HCMV resistance to antiviral drugs are required to demonstrate the need to increase the variety and availability of drugs used to treat viral infections in the public health care system in Brazil.

Congenital cytomegalovirus (cCMV) infection is common among infants born to HIV-infected women. Nelfinavir (NFV), an antiretroviral drug that is safe during pregnancy, inhibits CMV replication in vitro at concentrations that standard doses achieve in plasma. We hypothesized that infants born to women receiving NFV for prevention of mother-to-child transmission of HIV (PMTCT) would have a reduced prevalence of cCMV infection.

The prevalence of cCMV infection was compared among HIV-uninfected infants whose HIV-infected mothers either received NFV for >4 weeks during pregnancy (NFV-exposed) or did not receive any NFV in pregnancy (NFV-unexposed). CMV PCR was performed on infant blood samples collected at <3 weeks from birth.

Of the 1,255 women included, 314 received NFV for >4 weeks during pregnancy and 941 did not receive any NFV during pregnancy. The overall prevalence of cCMV infection in the infants was 2.2%, which did not differ by maternal NFV use. Maternal CD4 T cell counts were inversely correlated with risk of cCMV infection, independent of the time NFV was initiated during gestation. Infants with cCMV infection were born 0.7 weeks earlier (P = 0.010) and weighed 170 g less (P = 0.009) than uninfected infants.

Among HIV-exposed uninfected infants, cCMV infection was associated with adverse perinatal outcomes. NFV use in pregnancy was not associated with protection against cCMV. Safe and effective strategies to prevent cCMV infection are needed.

This study aims to analyze and evaluate the clinic and demographic features of immunocompetent children that have been diagnosed with cytomegalovirus (CMV) infection. The data of children diagnosed with CMV infection between January 2005 and December 2010 and their follow-ups for 2 years were retrospectively evaluated. Ninety-eight patients were included, and the median age at admission was 5.6 months (5 days-36 months). 54.1% was male. The diagnosis of CMV infection was performed by measurement of serum anti-CMV specific Ig M and IgG titers and PCR method in blood and/or urine. In 3.06% of the patients, congenital infection was detected, whereas possible congenital infection was observed in 36.7% of the patients. Furthermore, 44 patients (44.8%) were detected to have perinatal infection while postnatal infection was spotted in 15.3% of the patients. The common presenting manifestations were prolonged jaundice, diarrhea, vomiting, abdominal distension, skin eruption, and seizure. And the most common physical examination findings were hepatosplenomegaly, microcephaly, jaundice, and petechia. The mainstream laboratory results were elevated transaminases (50%), anemia (30.6%), leukocytosis (27.5%), and thrombocytopenia (18.3%). There were intracranial calcification in 5.1% and eye findings in 5.1%. On follow-up of patients, complete improvement (59.1%), neuromotor developmental delay (11.2%), epilepsy (10.2%), hearing loss (3.06 %), hemolytic anemia (2.04%), and growth retardation (1.02%) were detected.

CMV infection is a significant disease both in congenital and perinatal period. It must be considered that diagnosed patients need to be monitored for a long time with special attention to their neurodevelopmental follow-ups.

Cytomegalovirus can cause debilitating and life-threatening disease in newborns infected in utero and immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The study involved a single ascending dose stage (1, 3, 5, and 10 mg/kg each antibody; n = 21), a multiple ascending dose stage (5 and 10 mg/kg each antibody monthly for 3 doses; n = 10), and a multiple dose expansion stage (10 mg/kg each antibody monthly for 3 doses; n = 150). Subjects were followed for 85 to 141 days to evaluate safety, tolerability, pharmacokinetics, and immunogenicity. Most adverse events were mild, and the incidence of adverse events was similar among the RG7667 and placebo groups. RG7667 had dose-proportional pharmacokinetics in all three dosing stages, a mean terminal half-life of 20 to 30 days, and an overall pharmacokinetic profile consistent with that of a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well-tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus infection in susceptible populations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01496755.).

Cytomegalovirus (CMV) is the leading cause of known congenital viral infections. Approximately 90% of congenitally infected newborns exhibit no clinical abnormalities at birth. In 5% to 15%, a wide spectrum of clinical signs is present at birth. Ophthalmological signs are seen in a large percentage of symptomatic patients but rarely in otherwise asymptomatic infants. Chorioretinitis, optic atrophy, and cortical visual impairment are the most frequent causes of visual problems in congenitally infected infants. There is no clear consensus in the literature on screening or treatment modalities concerning the ophthalmological aspects of congenital CMV. Further prospective studies are needed to set up guidelines for ophthalmological screening and treatment of infants with congenital CMV.

Human cytomegalovirus encodes an alkaline nuclease, UL98, that is highly conserved among herpesviruses and has both endonuclease (endo) and exonuclease (exo) activities. This protein is thought to be important for viral replication and therefore represents a potential target for antiviral development; however, little is known about its structure or role in viral replication. Comparative structural modelling was used to build a model of UL98 based on the known structure of shutoff and exonuclease protein from Kaposi's sarcoma-associated herpesvirus. The model predicts that UL98 residues D254, E278 and K280 represent the critical aspartic acid, glutamic acid and lysine active-site residues, respectively, while R164 and S252 correspond to residues proposed to bind the 5' phosphate of the DNA substrate. UL98 with an amino-terminal hexahistidine tag was expressed in Escherichia coli, purified by affinity chromatography and confirmed to have exo and endo activities. Amino acid substitutions D254A, E278A, K280A and S252A virtually eliminated exo and endo activities, whereas R164A retained full endo activity but only 10 % of the exo activity compared with the wild-type enzyme. A mutant virus lacking UL98 was viable but severely attenuated for replication, while one expressing UL98(R164A) replicated normally. These results confirm the utility of the model in representing the active-site region of UL98 and suggest a mechanism for the differentiation of endonuclease and exonuclease activities. These findings could facilitate the exploration of the roles of alkaline nucleases in herpesvirus replication and the rational design of inhibitors that target their enzymic activities.

Cytomegalovirus (CMV) is the most frequent cause of congenital viral infection in developed countries. Vaccines are currently under development and antiviral treatment or passive immunizations for pregnant women with CMV primary infection are about to be evaluated in randomized trials. However, as it has been shown in few studies, preventing transmission through behavioral changes could be, at the moment, the most effective and inexpensive way to decrease risk of CMV infection during pregnancy. Despite difficulties, such counseling programs deserve to be established.

Cytomegalovirus (CMV) infection is very common throughout the world, and has become more of a pediatric clinical concern given the high incidence of congenital CMV infections as well as the increasing numbers of immunocompromised patients. Because of this, the need for antiviral therapies in infants and neonates is growing. Currently, there are four antivirals available that are active against CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. At this time, none have approved indications for use in children. Although there are limited data regarding the dose, pharmacokinetics (PK), safety, and adverse events for some of these antivirals, ganciclovir, and its oral prodrug valganciclovir, have been the best studied in the infant and neonate populations. In general, pharmaceutical PK studies in young children are limited by the constraints of sampling difficulties and blood volume requirements; fewer sampling times and studies may be available for drug evaluation. Given this caveat, ganciclovir and valganciclovir PK in children thus far appears to follow a monocompartmental model, contrary to what has been described in adults. However, when normalized for weight, the volume of distribution, clearance, and half-life of ganciclovir are similar to those found in adults. Given the findings that ganciclovir (and thus valganciclovir) clearance is directly proportionate to renal function, care must be taken when administering the drug to patients with impaired renal function. Recent studies evaluating valganciclovir PK in infants (at a dose of 16 mg/kg every 12 hours) have shown similar areas under the plasma concentration-time curve (AUCs) to intravenous ganciclovir (at a dose of 6 mg/kg every 12 hours), and that these AUCs remain quite stable over a number of weeks. As seen in adults, oral ganciclovir has a low bioavailability (4.8% in a pediatric analysis) and is therefore a poor alternative for treating serious CMV infections. Neutropenia is the most frequent toxicity associated with ganciclovir and valganciclovir therapy, whereas significant (and possibly irreversible) renal toxicity can be seen with cidofovir. Foscarnet administration can also result in renal toxicity as well as significant electrolyte imbalances. Several of these drugs have potential toxicities that are of concern, including carcinogenesis, teratogenesis, and azospermia (ganciclovir, valganciclovir, and cidofovir) and deposition into bone or dentition (foscarnet) that may have significant implications when treating an infant. Given these potential ill effects, careful consideration of the indications for the clinical use of these antivirals is necessary before using them for CMV infection in neonates and infants.

Cytomegalovirus (CMV) is a common opportunistic infection among HIV-infected individuals, a major source of serious complications among organ-transplant recipients, and a leading cause of hearing loss, vision loss, and mental retardation among congenitally infected children. Women infected for the first time during pregnancy are especially likely to transmit CMV to their fetuses.

In this study, it was aimed to determine the rate of CMV seroprevalence in pregnant women, the prevalence of maternal CMV infection and also the incidence of congenital CMV infection in their newborns in the Kazeroon, south of Iran.

Between January 2007 and July 2007, all (n = 1472) pregnant women who attended the obstetric ward of Valiasr hospital in Kazeroon for delivery, were enrolled in this study, and according to the presence or absence of anti CMV-IgM and CMV-IgG, were classified as seropositive, seronegative and having active maternal CMV infection. Differentiation of primary and recurrent CMV infection in women with both CMV-IgM (+) and CMV-IgG (+) antibody was determined by the avidity index (AI) of anti-CMV IgG.

The rate of seropositivity was found as 97.69% and the rate of seronegativity as 2.31% in pregnant women. The prevalence of active maternal CMV infection was found as 4.35% and among these pregnant women, the incidence of primary and recurrent maternal CMV infection was 34.4% and 65.6% respectively.

Seroprevalence rate of CMV in pregnant women is high and most infections are recurrent. Thus, it does not seem to be cost-effective to screen all pregnant women for CMV infection, as in the other countries with high seropositivity rate.

A 2-month-old female infant was admitted with progressive respiratory distress, fever, and diagnosed with acute respiratory distress syndrome (ARDS). The primary pulmonary pathogen was proven to be cytomegalovirus (CMV) from bronchoalveolar lavage fluid, urine, and blood specimens. Other immunologic findings were normal. CMV-induced ARDS has not been reported previously in immunocompetent infants.

Congenital cytomegalovirus (CMV) infections are underrecognized as a cause of serious morbidity in newborn infants. The era of therapeutic nihilism regarding these infections has come to an end, however, as useful therapies are now available that may modify the outcome. The infected fetus can be treated in utero, or the newborn infant can be treated when CMV is recognized in the neonatal period. Expanded screening of newborns for congenital CMV infection will make it even more important for clinicians to be aware of current therapeutic options. The most effective option for the treatment of life-threatening or sight-threatening CMV disease at any age is the nucleoside analog ganciclovir. For the newborn with congenital CMV infection, the value of ganciclovir appears to relate to its ability to preserve hearing; other improvements in overall neurodevelopmental status are inferred but remain to be proven. In the pregnant woman with primary CMV infection, the use of CMV-specific immune globulin, though still investigational, is garnering attention and may prove to be a valuable therapy.

The living style, health-care system and socio-economic environments have changed substantially in Taiwan over past 20 years. This study was aimed to estimate the current perinatal cytomegalovirus (CMV) seroprevalence in northern Taiwan.

In a Taiwan Birth Panel Study, 483 pairs of mothers and neonates were prospectively recruited from one tertiary medical center, one local hospital, and two obstetric clinics located in northern Taiwan from April 2004 through January 2005. Sera of their paired maternal and cord blood were tested by an enzyme-linked immunosorbent assay method for CMV IgG and IgM antibodies. Additional data were collected for health measures and epidemiological characteristics through trained interviewers utilising structured questionnaires.

Among 483 mothers studied, 93% were Taiwanese, 6.4% were immigrants from the south-eastern Asia and Mainland China, and 0.6% was aborigines. The seropositive rate of CMV IgG and IgM among the mothers was 91.1% and 3.5%, respectively. The immigrant mothers and the mothers younger than 20 years of age had a higher IgM seroprevalence (P < 0.05). Furthermore, 90.8% of the offspring had CMV IgG seropositivity and yet none of the neonates were CMV IgM positive.

The seroprevalence of CMV among childbearing women is high in northern Taiwan. The immigrant mothers and the teenage mothers appear to have higher seropositivity of CMV IgM.

Congenital cytomegalovirus (CCMV) infection is a common neonatal infection affecting 1% of all live births, 10% of which are symptomatic. Many of these infants have long-term sequelae. The objective is to document the clinical presentation of SCCMV infection in neonates, the frequency of sequelae and severity of adverse neurologic outcomes and risk factors.

A review and analysis of all symptomatic infants diagnosed with SCCMV infection are given. SCCMV was defined as a diagnosis of CCMV infection in the first three weeks of life in the presence of any clinical manifestations. Outcome data from 2 years of age and later are analyzed.

There were 104 patients identified as having SCCMV infection and of these 42 cases had definite infection. The common findings at presentation were hepatosplenomegaly 19/42 (45%), thrombocytopenia 21/42 (50%), elevated transaminases 21/42(50%), abnormal cranial US scan 24/41(56%), abnormal head CT scan 29/41(71%) and abnormal brain MRI 17/19(89%). The risk factors for an adverse outcome including death or deafness or blindness or moderate to severe neurological deficits included an abnormal cranial US scan (OR 8.5), abnormal head CT scan (OR 21) and abnormal brainstem auditory evoked responses (BAER) (OR 8.7).

There was only three (7%) patients without any deficits and severely affected infants have been identified with a diverse clinical presentation, reinforcing the importance of CMV as a major public health problem.

Persistently infecting DNA viruses depend heavily on host cell DNA synthesis machinery. Replication of cellular and viral DNA is inhibited by mutagenic stress. It is hypothesized that diurnal regulation of viral DNA replication may occur at the level of cell cycle checkpoints and DNA repair, to protect DNA from exposure to UV light or other mutagens. This highly conserved mechanism is traced back to viruses that persist in prokaryotes and eukaryotes. Inhibition of viral DNA replication and the cell cycle in response to UV light may represent a functional building block in the evolution of circadian-gated DNA replication. Viral DNA replication appears to be closely linked to the circadian clock by interaction of viral promoters, early viral proteins and transcription factors. It is proposed here that under certain conditions viral oncogene expression is phase-shifted relative to that of tumor suppressor and DNA repair genes. The resulting desynchrony of checkpoint controls and DNA repair from diurnal genotoxic exposure produces cyclic periods of suboptimal response to DNA damage. This temporal vulnerability to genotoxic stress produces a "mutator phenotype" with inherent genome instability. The proposed model delineates areas of research with implications for viral pathogenesis and therapeutics.

A 3-month-old male infant was admitted to hospital with anemia. Follow-up controls revealed the presence of specific cytomegalovirus (CMV) antibodies. Virus was isolated from urine, blood, and saliva. At 7 months of age, he presented with melena. Polymerase chain reaction (PCR) of biopsy samples from the duodenum was positive for CMV. Anemia resolved after starting antiviral therapy with oral valganciclovir.