Symptomatic Congenital Cytomegalovirus Infection Research Articles

Treatment with valacyclovir during pregnancy for prevention of congenital cytomegalovirus infection: a real-life multicenter Italian observational study

Valacyclovir is the only treatment demonstrated to be effective for the prevention of vertical transmission of cytomegalovirus within a clinical randomized, placebo-controlled trial and has been reimbursed by the Italian National Health System since December 2020. This study reported the results of a real-life Italian multicenter observational study on cytomegalovirus infection in pregnancy evaluating the effect of the introduction of valacyclovir in the clinical practice for the prevention of vertical transmission of cytomegalovirus. The outcomes of women who received valacyclovir treatment and their fetuses or newborns were compared with those of a retrospective cohort observed between 2010 and 2020 who did not receive the antiviral treatment. The inclusion criterion was the diagnosis of cytomegalovirus primary infection occurring in the periconceptional period or up to 24 weeks of gestation. The primary outcome was the transmission by the time of amniocentesis. The secondary outcomes were termination of pregnancy, transmission at birth, symptomatic infection at birth, and a composite outcome (termination of pregnancy or transmission at birth). A total of 447 pregnant women from 10 centers were enrolled, 205 women treated with valacyclovir (called the valacyclovir group, including 1 twin pregnancy) and 242 women not treated with valacyclovir (called the no-valacyclovir group, including 2 twin pregnancies). Valacyclovir treatment was significantly associated with a reduction of the diagnosis of congenital cytomegalovirus infection by the time of amniocentesis (weighted odds ratio, 0.39; 90% confidence interval, 0.22-0.68; P=.005; relative reduction of 61%), termination of pregnancy (weighted odds ratio, 0.36; 90% confidence interval, 0.17-0.75; P=.0021; relative reduction of 64%), symptomatic congenital cytomegalovirus infection at birth (weighted odds ratio, 0.17; 90% confidence interval, 0.06-0.49; P=.006; relative reduction of 83%). The treatment had no significant effect on the rate of diagnosis of congenital cytomegalovirus infection at birth (weighted odds ratio, 0.85; 90% confidence interval, 0.57-1.26; P=.500), but the composite outcome (termination of pregnancy or diagnosis of congenital cytomegalovirus infection at birth) occurred more frequently in the no-valacyclovir group (weighted odds ratio, 0.62; 90% confidence interval, 0.44-0.88; P=.024). Of note, the only symptomatic newborns with congenital cytomegalovirus infection in the valacyclovir group (n=3) were among those with positive amniocentesis. Moreover, 19 women (9.3%) reported an adverse reaction to valacyclovir treatment, classified as mild in 17 cases and moderate in 2 cases. Lastly, 4 women (1.9%) presented renal toxicity with a slight increase in creatinine level, which was reversible after treatment suspension. Our real-life data confirm that valacyclovir significantly reduces the rate of congenital cytomegalovirus diagnosis at the time of amniocentesis with a good tolerability profile and show that the treatment is associated with a reduction of termination of pregnancy and symptomatic congenital cytomegalovirus infection at birth.

The Audiological Follow-Up of Children with Symptomatic Congenital Cytomegalovirus Infection: An Experience in Two Italian Centers.

Congenital cytomegalovirus (cCMV) infection is the leading cause of non-hereditary sensorineural hearing loss in children. While about 10% of children reportedly display symptoms at birth, 85-90% of cCMV infection cases are asymptomatic. However, 10-15% of these asymptomatic infants may later develop hearing, visual, or neurodevelopmental impairments. This study aimed to evaluate the impact of cCMV infection on newborns' hearing function with a particular emphasis on progressive and late-onset cases. This study is a retrospective chart analysis with longitudinal character and was conducted in two Italian centers: Center 1 (from 1 November 2007 to 31 December 2021) and Center 2 (from 1 January 2012 to 31 December 2021). Data collected included newborn hearing screening results, characterization of hearing loss (unilateral/bilateral, degree of impairment), and audiological follow-up. The cohort consisted of 103 children (42% males, 58% females). In total, 28 children presented with hearing impairment; 71.4% (20 out of 28) of the cases of hearing loss were severe/profound, with 35.7% of the cases due to unilateral hearing loss. Out of twenty-eight, six experienced progression of hearing loss and four had late-onset hearing loss. In the absence of universal cCMV screening, hearing screening at birth for cCMV remains a critical factor for early diagnosis. A significant percentage of children affected by cCMV with normal audiological evaluations at birth is easily lost to follow-up. Close collaboration between neonatologists, pediatricians, and audiological services is fundamental to ensure timely diagnosis and treatment of cCMV-related hearing loss.

Effectiveness and safety of prenatal valacyclovir for congenital cytomegalovirus infection: systematic review and meta-analysis.

Universal screening for cytomegalovirus (CMV) infection in pregnancy is not recommended in most countries. One of the major deterrents is the lack of effective prenatal therapy. The role of valacyclovir therapy in reducing the risk of vertical transmission, symptomatic congenital CMV infection and adverse outcome is controversial. The main aim of this systematic review and meta-analysis was to investigate the safety and effectiveness of prenatal valacyclovir therapy in pregnancies with maternal CMV infection. MEDLINE, EMBASE and Cochrane databases and ClinicalTrials.gov were searched. The inclusion criteria were pregnancy with confirmed maternal CMV infection, treated or untreated with valacyclovir. The primary outcome was the incidence of congenital CMV infection confirmed by a positive CMV polymerase chain reaction result of the amniotic fluid. The secondary outcomes were symptomatic and asymptomatic infection, perinatal death, termination of pregnancy, anomalies detected on follow-up ultrasound, on fetal magnetic resonance imaging or at birth, severe and mild-to-moderate symptoms due to congenital CMV infection, neurological, visual and hearing symptoms, and adverse events related to valacyclovir. Risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) or Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool, as appropriate. Head-to-head meta-analyses were used to compare the risk of each of the explored outcomes according to whether pregnancies with maternal CMV infection were treated with prenatal valacyclovir therapy. Eight studies (620 women) were included. Pregnancies treated with valacyclovir had a significantly lower risk of congenital CMV infection compared with those not receiving valacyclovir (three studies; 325 fetuses; pooled odds ratio (OR), 0.37 (95% CI, 0.21-0.64); I2 = 0%; P < 0.001). When stratifying the analysis according to gestational age at maternal infection, the risk of vertical transmission was significantly lower in pregnancies receiving valacyclovir following first-trimester maternal infection (three studies; 184 fetuses; pooled OR, 0.34 (95% CI, 0.15-0.74); I2 = 20.9%; P = 0.001), while there was no significant difference between the two groups in those acquiring CMV infection in the periconceptional period or in the third trimester of pregnancy. Only one study reported on the risk of vertical transmission in women infected in the second trimester, demonstrating a lower risk of congenital infection in women taking valacyclovir, although this was based on a small number of cases. Pregnancies treated with valacyclovir therapy had an increased likelihood of asymptomatic congenital CMV infection compared with those not receiving valacyclovir (two studies; 132 fetuses; pooled OR, 2.98 (95% CI, 1.18-7.55); I2 = 0%; P = 0.021), while there was no significant difference between the two groups in the risk of perinatal death (P = 0.923), termination of pregnancy (P = 0.089), anomalies detected at follow-up imaging assessment during pregnancy or at birth (P = 0.934) and symptoms due to CMV infection in the newborn (P = 0.092). The occurrence of all adverse events in pregnant individuals taking valacyclovir was 3.17% (95% CI, 1.24-5.93%) (six studies; 210 women), with 1.71% (95% CI, 0.41-3.39%) experiencing acute renal failure, which resolved after discontinuation of the drug. On GRADE assessment, the quality of evidence showing that valacyclovir reduced the risk of congenital CMV infection and adverse perinatal outcome was very low. Prenatal valacyclovir administration in pregnancies with maternal CMV infection reduces the risk of congenital CMV infection. Further evidence is needed to elucidate whether valacyclovir can affect the course of infection in the fetus and the risk of symptomatic fetal or neonatal infection. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Treatment of congenital cytomegalovirus infection.

Congenital cytomegalovirus (CMV) is the most common cause of congenital infection worldwide, the most common nongenetic cause of sensorineural hearing loss in children, and a cause of neurodevelopmental disorders in the brain. Infants with symptomatic congenital CMV infection may benefit from hearing and neurodevelopmental outcomes, particularly if antiviral treatment is initiated within the first month of life. Infants with life-threatening symptoms are recommended to receive 2-6 weeks of intravenous ganciclovir and then switch to oral valganciclovir, and those without life-threatening symptoms are recommended to use oral valganciclovir during the entire 6-month period. During antiviral drug treatment, absolute neutrophil count, platelet count, blood urea nitrogen, creatinine, and liver function tests were performed to identify neutropenia, thrombocytopenia, renal failure, and liver failure. This review investigated the evidence to date of treating congenital CMV infection.

Evaluation of Patients Treated for the Symptomatic Congenital Cytomegalovirus Infection

Evaluation of Patients Treated for the Symptomatic Congenital Cytomegalovirus Infection

Pitfalls in the Serological Evaluation of Maternal Cytomegalovirus Infection as a Potential Cause of Fetal and Neonatal Involvements: A Narrative Literature Review.

Cytomegalovirus (CMV) is the most common cause of intrauterine infection and serological assays are the primary tools for assessing CMV infections during pregnancy. CMV-specific immunoglobulin M (IgM) antibodies have been used as a diagnostic marker for primary CMV infection in pregnant women, although CMV-IgM has been detected in non-primary CMV infections. IgG avidity testing may aid the distinguishing of primary from non-primary CMV infection; however, there is no standardized assay for detecting this difference. Moreover, when maternal serology shows positive CMV-IgG with negative CMV-IgM findings, vertical transmission probability following primary CMV infection is often excluded. However, symptomatic congenital CMV infections in the context of negative findings for maternal CMV-IgM have been reported recently. The absence of CMV-IgM is recognized in both primary and non-primary CMV infections. Furthermore, maternal non-primary CMV infections during pregnancy may yield a greater proportion of symptomatic congenital CMV infections than previously thought. If universal prenatal screening is performed, ultrasonography for abnormal fetal findings should be conducted regardless of CMV-IgM antibody status. If not universally screened, CMV antibody screening should be performed whenever routine fetal ultrasound reveals abnormal findings. For suspected fetal CMV infection, amniotic fluid or postnatal infant urine CMV-DNA testing is required.

Assessment of mitochondrial toxicity in newborns and infants with congenital cytomegalovirus infection treated with valganciclovir

BackgroundGanciclovir/valganciclovir is currently indicated during the first 6 months of life in symptomatic children with congenital cytomegalovirus (CMV) infection. However, this treatment may have the potential to induce mitochondrial toxicity...

Hearing Loss in Congenital CMV Disease Post-Ganciclovir

Source: Lanzieri TM, Caviness AC, Blum P, et al. Progressive, long-term hearing loss in congenital CMV disease after ganciclovir therapy. J Pediatric Infect Dis Soc. 2021;piab095. doi:10.1093/jpids/piab095Investigators from the CDC, Atlanta, GA, and Baylor College of Medicine, Houston, TX, conducted a study to assess long-term hearing outcomes in children with symptomatic congenital cytomegalovirus (CMV) infection, and the impact of ganciclovir therapy on hearing loss. For the study, they analyzed data from children born 1983–2005 who were enrolled in the Congenital CMV Longitudinal Study. All study participants had CMV infection detected in urine samples in the first 3 weeks of life and had microcephaly, chorioretinitis, neurologic abnormalities or evidence of reticuloendothelial system involvement (eg, petechiae/purpura). Study children had longitudinal assessments of hearing with auditory brainstem response testing and behavioral audiometry; those with hearing thresholds >20 dB were classified as having sensorineural hearing loss (SNHL). SNHL was defined as congenital if diagnosed in the first month of life. Study children were placed into 3 groups: Group A included patients who had been enrolled in a clinical trial and received ganciclovir; group B included children with SNHL, microcephaly and/or chorioretinitis but who were untreated; and group C comprised those without any of these findings who also were not treated with ganciclovir. The primary study outcome was long-term assessment of hearing loss among children in these 3 groups.Data were analyzed on 76 children; 17 (22%) in group A, 27 (36%) in group B, and 32 (42%) in group C. Among the 17 children in group A, 16 had microcephaly, chorioretinitis, or congenital SNHL; median duration of ganciclovir treatment in these patients was 40 days. Overall, the most common findings in study patients when they were neonates were purpura/petechiae (82% of those in group A, 78% in group B, and 63% in group C); 71% and 70%, respectively, of those in groups A and B had microcephaly. Congenital SNHL was diagnosed in 65% of patients in group A and 56% for those in group B, although hearing was not assessed in the first month of life in all study participants. The median age at last hearing assessment was 13 years for children in groups A and C and 11 years for those in group B. At that time, 16 (94%) patients in group A, 24 (89%) children in group B, and 16 (50%) group C patients had SNHL. SNHL was categorized as severe (>70 dB) in 12 (71%), 16 (59%), and 7 (22%) children, respectively, in groups A, B, and C.The authors conclude that most children in this study with congenital CMV infection developed substantial SNHL with or without ganciclovir treatment.Dr Brady has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The current investigators provide long-term hearing outcomes for infants born 1983–2005 who were enrolled in the Congenital CMV Longitudinal Study. Participants were selected based on having severe disease as newborns.1,2 Not surprisingly, most developed substantial SNHL. As previously discussed, symptomatic congenital CMV infection at birth is a risk factor for SNHL. (See AAP Grand Rounds. 2019;42[5]:57.)3 Many infants also had microcephaly and/or head CT scan findings suggesting tissue destruction or dysplastic growth, which also are associated with an increased risk of SNHL.4 The results of early clinical trials of intravenous ganciclovir1,2 had suggested short-term stabilization or improvement in hearing at 6 months but were not borne out by the current investigation.With the introduction of oral valganciclovir, a phase III, randomized, placebo-controlled clinical trial, conducted during 2008– 2011, evaluated 6 weeks versus 6 months of therapy with valganciclovir.5 There was modest improvement in hearing and developmental outcomes at 12 and 24 months. Based on this trial, the AAP currently recommends 6 months of oral valganciclovir for infants with moderately to severely symptomatic congenital CMV infection who can start treatment in the first month of life.6 The current authors state that their findings cannot be extrapolated to infants who receive current standard of care therapy. Infants receiving valganciclovir are being followed to determine their long-term hearing outcomes.Another area that is not addressed is the role of valganciclovir for infants with congenital CMV infection who have isolated SNHL. The 2017 consensus guidelines do not routinely recommend valganciclovir for these infants based on insufficient evidence. Pasternak et al reported that 12 months of antiviral therapy for infants with congenital CMV infection and isolated SNHL led to improved hearing, but their study did not include a control group.(See AAP Grand Rounds. 2018;40[5]:55.)8Infants with congenital CMV infection are at risk for SNHL despite receipt of antiviral therapy. These infants deserve close audiology follow-up.The apparent lack of major benefit of antiviral therapy in children with symptomatic congenital CMV infection underscores the need for prevention. Neither CMV-IGIV nor investigational vaccines have yet proven efficacious.6

Efficacy and Tolerability of Valganciclovir 6 Months vs 6 Weeks in Symptomatic Cytomegalovirus Infection in Infants: An Open Level Randomized Controlled Trial

Congenital cytomegalovirus (CMV) infection is the most common transplacental infection affecting neurodevelopment in infant, commonly hearing and cognitive impairment. This study aimed to compare 6 weeks with 6 months duration of oral valganciclovir in respect of efficacy and tolerability. This randomized controlled trial was conducted in both outpatient and inpatient pediatrics department of a tertiary hospital, on123 infants aged 0-12 months with polymerase chain reaction proven congenital CMV infection over a period of 18 months. The children were divided into two groups, according to the treatment group they belonged to, one is 6 weeks group and other is 6 months group. The children were followed up for 12 months at 3-month interval to compare the virological clearance, psychological, visual, and hearing status, and side effects of drug. The viral load assessment was done at 6 weeks, 6 months, and 12 months of the initial treatment. Mean age of the infants of 6 weeks group is 7.33±1.74months and that of 6 months group is 6.70±2.23 months. Primary outcome is the clearance of virus, exhibited in both groups significantly at 12 weeks of follow up but 100% clearance of virus observed in 6 months group at 6 months of follow up. Whereas 5 patients at 12 weeks and 3 patients at 6 months have shown non clearance of virus among the 6 weeks treatment group. Total 50(80.6%) patients hearing return to normal at 12 months follow up in 6 months treatment group compared to 31(50.8%) in 6 weeks group (p=0.001). Visual improvement also observed among 58(93.5%) patients of 6 months group and 48(78.7%) in 6 weeks group and this difference is statistically significant (p=0.01). At 12 months of follow up 6 months group had shown better neurodevelopmental outcome (p=0.00). Both groups exhibit good tolerance to drug. &#x0D; Conclusion: 6 months duration treatment of valganciclovir in symptomatic CMV infection have shown better neurodevelopmental outcome and visual, auditory improvement compared to 6 weeks duration.

First-line noninvasive management of cytomegalovirus primary infection in pregnancy.

To introduce a first-line noninvasive antenatal management of maternal cytomegalovirus (CMV) primary infection based on ultrasound (US) and magnetic resonance imaging (MRI). Amniocentesis (AC) is used as a second-line tool in cases of abnormalities compatible with fetal CMV infection on US and/or MRI screening. Between January 2011 and October 2018, pregnant women referred with a CMV primary infection on antibody screening were followed up by monthly US scans and a brain MRI at approximately 32weeks. In cases with US and/or MRI abnormalities compatible with congenital CMV infection, AC was performed to confirm the diagnosis. Ninety pregnant women with a primary CMV infection were included (89 singleton and one twin pregnancy). The first-line screening by US and/or MRI was normal for 72 of 91 fetuses (79%). At birth, 19 of these 72 neonates (26%) had a positive urine sample for CMV but were asymptomatic. US and/or MRI abnormalities were identified in 19 fetuses (21%). AC confirmed a fetal CMV infection in 16 fetuses (84%); 12 pregnancies were terminated, and four were continued, with three symptomatic neonates at birth and one poor neurodevelopmental outcome at postnatal follow-up. First-line noninvasive management of maternal CMV primary infection based on serial US scans and brain MRI can be offered to identify fetuses with severe symptomatic congenital CMV infection and reduce the number of ACs without compromising the fetal outcome.

The Current Challenges in Developing Biological and Clinical Predictors of Congenital Cytomegalovirus Infection.

Congenital cytomegalovirus (CMV) infection may cause severe long-term sequelae. Recent studies have demonstrated that early antiviral therapy for infants with symptomatic congenital CMV (cCMV) infection may improve neurological outcomes; thus, accurate identification of newborns at high risk of cCMV infection may contribute to improved outcomes in affected children. However, maternal serological screening for cCMV infection by diagnosing primary infection during pregnancy, which is a popular screening strategy, is inefficient, because the number of cCMV infections with nonprimary causes, including reactivation of or reinfection with CMV, is larger than that of cCMV infections with primary causes. Low levels of neutralizing antibodies against pentameric complex and potent CMV-specific T cell-mediated immune responses are associated with an increased risk of cCMV infection. Conversely, our prospective cohort studies revealed that the presence of maternal fever/flu-like symptoms, threatened miscarriage/premature delivery, or actual premature delivery are risk factors for cCMV infection among both women with normal pregnancies and those with high-risk ones, regardless of whether the infection is primary or nonprimary. This review focused on host immune responses to human CMV and current knowledge of potential biological and clinical factors that are predictive of cCMV infection.

Change in Viral Load during Antiviral Therapy Is Not Useful for the Prediction of Hearing Dysfunction in Symptomatic Congenital Cytomegalovirus Infection.

For symptomatic congenital cytomegalovirus infections (CCMVI), the usefulness of changes in viral load during valganciclovir (VGCV) treatment for the prediction of hearing dysfunction (HD) is unclear. To determine the utility of viral load change in the whole blood or urine for the prediction of HD, we performed a retrospective study to compare viral load changes during VGCV treatment between CCMVI infants with (n = 12) or without (n = 8) HD at six months of corrected age, whose blood and urine viral loads were measured continuously for eight weeks from April 2009 to December 2019. There was no significant difference in the changes in both the blood and urine viral loads after the initiation of VGCV treatment between CCMVI infants between the groups. Moreover, this negative result was maintained in the analysis for each six weeks or six months treatment period. In conclusion, the change in viral load during antiviral therapy is not useful for the prediction of HD at six months of corrected age in symptomatic CCMVI.

Ganciclovir Treatment in Symptomatic Congenital CMV Infection at Siriraj Hospital: 11 Year-Review (2008 to 2019)

Background: Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of permanent sensorineural hearing loss in infants and children. A 6-month course of intravenous ganciclovir or valganciclovir is recommended for treatment of patients with moderate to severe symptomatic congenital CMV disease. Hearing status improvement has been reported in those that received treatment within the first month of life. In Thailand, there has been no data of antiviral treatment in symptomatic congenital CMV patients. Objective: To determine the incidence of symptomatic congenital CMV infection in the past 11 years and to evaluate the hearing, neurological, and developmental outcomes of the antiviral treatment and factors associated with hearing outcomes. Materials and Methods: A retrospective observational study was performed at Siriraj Hospital, between January 2008 and December 2019. The medical records of the patients diagnosed of symptomatic congenital CMV infection (ICD10-P351) were reviewed. Results: The incidence of symptomatic congenital CMV infection was 0 to 1.01 case per 1,000 livebirths. Of the 52 patients, 18 received 6-week course of ganciclovir and five continued with oral valganciclovir for three to six months. Developmental delayed was found in 69.2% (36). No difference in hearing outcomes at 6 and 12 months of age between the patients who did or did not receive treatment. Among 24 (46.1%) children who underwent hearing test at two to three years of age, the birth characteristics, as well as antiviral treatment (attributable risk 0.007, 95% CI –0.4 to 0.4, p=0.973), had no difference in hearing outcome. Long-term disability was diagnosed in the lower proportion among the patients receiving antiviral treatment (attributable risk –0.3, 95% CI –0.5 to –0.1, p=0.030). Conclusion: Symptomatic congenital CMV infection resulted in poor hearing and developmental outcomes. Antiviral treatment reduced risk of disability but did not improve hearing outcomes. The results underscore the need for early diagnosis and initiation of antiviral treatment in infants with symptomatic congenital CMV. Keywords: Congenital infection; CMV; Hearing loss; Ganciclovir; Valganciclovir; Disability

Potentially predictive factors for hearing function improvement in pediatric cytomegalovirus infection therapy

Background Symptomatic congenital cytomegalovirus (CMV) infection has an impact mainly on neurological sequelae, including sensorineural deafness. Because of the long-term impact, early treatment of CMV infection is mandatory. However, predictive factors for hearing function improvement in CMV infection therapy remain unexamined.&#x0D; Objective To evaluate potential predictive factors for hearing improvement in pediatric CMV infection therapy.&#x0D; Methods All medical record data of patients aged 0-6 years with CMV infection who completed a 6-week course of ganciclovir therapy or a combination of a 4-week course of ganciclovir and a 2-week course valganciclovir from January 2013 to December 2017 were collected. Age at onset of therapy, gender, gestational age, nutritional status, multi-organ involvement, and neurological symptoms were studied as potential predictive factors of hearing improvement in CMV therapy. The effectiveness of CMV infection therapy on improving hearing function was measured with the brainstem evoked response audiometry (BERA) test.&#x0D; Results BERA tests proportion in the right, left, and best ear showed significant improvement after therapy. All variables analyzed were not statistically significant as predictive factors for hearing improvement in CMV infection therapy.&#x0D; Conclusion Ganciclovir/valganciclovir therapy in CMV infection patients accounted for the improvement of hearing impairment. However, none of the assessed factors were considered predictive for improving hearing function in CMV infection therapy.

Cytomegalovirus Genotype and Virulence in Infants with Congenital Infection

Abstract Objective Cytomegalovirus (CMV) virulence may depend on genetic variability in several regions of the genome. This study aimed to assess specific CMV genotypes' association with the severity of symptomatic congenital CMV disease at birth. Methods CMV glycoprotein B (gB), glycoprotein N (gN), glycoprotein H (gH), and UL144 strains were identified by nested polymerase chain reaction, restriction fragment length polymorphism, and heteroduplex mobility assay single-stranded conformation polymorphism in 50 infants infected congenitally and 25 asymptomatic infants. Results gN1 (p = 0.010) and UL144-B (p = 0.034) genotypes were associated, by logistic regression, with reduced risk of developing symptomatic congenital CMV infection. gN1 (p = 0.020) and gN3 (p = 0.022) genotypes were associated with reduced risk of severe symptomatic disease. Conversely, gB1 (p = 0.018) was the most virulent genotype and was associated with severe symptoms. Conclusion An association among gB1, gN1, gN3, and UL144-B genotypes of CMV and severity of congenital CMV disease might exist. gB, gN, and UL144 genotypes could be important virological markers of infant infection.

Cytomegalovirus-A Risk Factor for Childhood Hearing Loss: A Systematic Review.

Permanent hearing loss is an important public health issue in children with consequences for language, social, and academic functioning. Early hearing detection, intervention, and monitoring are important in mitigating the impact of permanent childhood hearing loss. Congenital cytomegalovirus (CMV) infection is a leading cause of hearing loss. The purpose of this review was to synthesize the evidence on the association between CMV infection and permanent childhood hearing loss. We performed a systematic review and examined scientific literature from the following databases: MEDLINE, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R), Embase, and CINAHL. The primary outcome was permanent bilateral or unilateral hearing loss with congenital onset or onset during childhood (birth to 18 years). The secondary outcome was progressive hearing loss. We included studies reporting data on CMV infection. Randomized controlled trials, quasi-experimental studies, nonrandomized comparative and noncomparative studies, and case series were considered. Data were extracted and the quality of individual studies was assessed with the Qualitative Assessment Tool for Quantitative Studies (McMaster University). The quality and strength of the evidence were graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A narrative synthesis was completed. Sixty-five articles were included in the review. Prevalence of hearing loss at birth was over 33% among symptomatic CMV-infected newborns and less than 15% in asymptomatic infections. This difference in prevalence was maintained during childhood with more than 40% prevalence reported for symptomatic and less than 30% for asymptomatic CMV. Late-onset and progressive hearing loss appear to be characteristic of congenital CMV infections. Definitions of hearing loss, degree of loss, and reporting of laterality varied across studies. All degrees and both bilateral and unilateral loss were reported, regardless of symptomatic and asymptomatic status at birth, and no conclusions about the characteristics of hearing loss could be drawn. Various patterns of hearing loss were reported including stable, progressive, and fluctuating, and improvement in hearing (sometimes to normal hearing) was documented. These changes were reported in children with symptomatic/asymptomatic congenital CMV infection, presenting with congenital/early onset/late-onset hearing loss and in children treated and untreated with antiviral medication. Symptomatic and asymptomatic congenital CMV infection should be considered a risk factor for hearing loss at birth and during childhood and for progressive hearing loss. Therefore, CMV should be included as a risk factor in screening and surveillance programs and be taken into account in clinical follow-up of children with hearing loss.

Immunoglobulin fetal therapy and neonatal therapy with antiviral drugs improve neurological outcome of infants with symptomatic congenital cytomegalovirus infection

Infants with symptomatic congenital cytomegalovirus infection (cCMV) suffer from long-term sequelae. This study aimed at evaluating the efficacy of combining immunoglobulin (Ig) fetal therapy (FT) and neonatal therapy (NT) with antiviral drugs to improve neurological outcomes of affected infants.Women whose fetuses had symptomatic cCMV received Ig injection into the fetal peritoneal cavity and/or maternal blood as FT, while affected newborns received oral valganciclovir or intravenous ganciclovir as NT. We compared the neurological outcomes at ≥18 months old between infants receiving FT with or without NT (FT group) and those receiving NT only (NT group).From 2009–2019, 15 women whose fetuses had symptomatic cCMV received FT, while 19 newborns received NT only. In FT group, two newborns died, and two were <18 months old. Neurological outcomes of the remaining 11 infants in FT group were as follows: normal 45.5 %, mild impairments 36.4 %, and severe impairments 18.2 %. In NT group, one newborn died, one’s parents refused the follow-up, one was <18 months old, and two had only chorioretinitis as symptoms. Neurological outcomes of the remaining 14 infants in NT group were as follows: normal 21.4 %, mild impairments 14.3 %, and severe impairments 64.3 %. The proportion of infants with severe impairments in FT group was significantly lower than that in NT group (18.2 % vs 64.3 %, p < 0.05).This is the first trial demonstrating that the combination of Ig FT and NT with antiviral drugs may be more effective in improving neurological outcomes of newborns with symptomatic cCMV as compared to NT only.

Efficacy, safety, and pharmacokinetics of oral valganciclovir in patients with congenital cytomegalovirus infection

ObjectivesValganciclovir (VGCV) has been shown to improve sensorineural hearing loss (SNHL) and neurological outcomes in patients with neonatal symptomatic congenital cytomegalovirus (cCMV) infection. However, reports on the pharmacokinetics, efficacy and safety of oral VGCV are limited. The aim of this study is to evaluate the pharmacokinetics of VGCV for use in the treatment of cCMV. MethodsThis was a single-center, retrospective observational study conducted at Saitama Children's Medical Center in Japan between 2012 and 2017. CMV DNA copy number, maximum plasma VGCV concentration (Cmax), and adverse events (ADEs) during treatment were evaluated. ResultsA total of 26 patients with cCMV who received VGCV were included in this study. The median age at VGCV initiation was 9.5 months (range 0–46). Twenty-one patients (81%) had SNHL at baseline. Of these, five patients (19%) presented with improved SNHL, and none experienced worsened SNHL during treatment. The mean VGCV Cmax was 3.5 μg/mL (range 2–5.3), with no significant variation among individual values, and the values were maintained during treatment. Furthermore, there were no correlations between the Cmax values and age, sex, SNHL improvement or ADEs. Neutropenia (<1000/mm3) was observed in six patients (23%); however, no serious ADEs occurred. ConclusionsVGCV prevented the progression of SNHL without serious ADEs due to its stable pharmacokinetics. This study provides safety and tolerability of VGCV for the treatment of cCMV patients.

Long-Term Clinical, Audiological, Visual, Neurocognitive and Behavioral Outcome in Children With Symptomatic and Asymptomatic Congenital Cytomegalovirus Infection Treated With Valganciclovir.

Cytomegalovirus (CMV) is the most common cause of congenital infection in humans. There are no enough data on long-term outcome of newborns with congenital CMV (cCMV) infection, particularly for those asymptomatic at birth. For this reason, we performed this study to evaluate long-term audiological, visual, neurocognitive, and behavioral outcome in patients with symptomatic and asymptomatic cCMV infection treated with oral Valganciclovir (VGC). Thirty-six newborns with confirmed cCMV infection were evaluated: 12 (33.3%) symptomatic at birth and 24 asymptomatic (66.7%). No one had cognitive impairment. Cognitive assessment scales resulted abnormal in 4/35 patients (11.4%). 11/21 patients (52.4%) achieved abnormal scores in neuropsychological tests. The language evaluation gave pathological results in 6/21 (28.5%) patients. 6/35 patients (17.1%) developed SNHL, all symptomatic at birth except one. None of the 34 patients evaluated developed CMV retinopathy. Our study shows that both symptomatic and asymptomatic newborns with cCMV infection develop long-term sequelae, particularly in the behavioral and communicative areas, independently from the trimester of maternal infection.

Clinical profile of symptomatic congenital cytomegalovirus infection: cases from a tertiary hospital in north India.

We retrospectively analysed the records of nine infants with polymerase chain reaction proven congenital cytomegalovirus (CMV) infection, of which 66% were born preterm. Microcephaly was a universal finding, followed by hepatosplenomegaly in 89%, while chorioretinitis was seen in only 44% cases. The mean age at diagnosis was 3.5 months. Neuroimaging was abnormal in 78%, with ventriculomegaly being the most common finding followed by T2/FLAIR white matter abnormalities, periventricular cysts and intracranial haemorrhage.