cCMV Infection Research Articles

Updates of Congenital Cytomegalovirus (cCMV) infection: Literature Review

Updates of Congenital Cytomegalovirus (cCMV) infection: Literature Review

Human Cytomegalovirus IE1 Impairs Neuronal Migration by Downregulating Connexin 43.

Human cytomegalovirus (HCMV) is a leading cause of congenital birth defects. Though the underlying mechanisms remain poorly characterized, mouse models of congenital CMV infection have demonstrated that the neuronal migration process is damaged. In this study, we evaluated the effects of HCMV infection on connexin 43 (Cx43), a crucial adhesion molecule mediating neuronal migration. We show in multiple cellular models that HCMV infection downregulated Cx43 posttranslationally. Further analysis identified the immediate early protein IE1 as the viral protein responsible for the reduction of Cx43. IE1 was found to bind the Cx43 C terminus and promote Cx43 degradation through the ubiquitin-proteasome pathway. Deletion of the Cx43-binding site in IE1 rendered it incapable of inducing Cx43 degradation. We validated the IE1-induced loss of Cx43 in vivo by introducing IE1 into the fetal mouse brain. Noteworthily, ectopic IE1 expression induced cortical atrophy and neuronal migration defects. Several lines of evidence suggest that these damages result from decreased Cx43, and restoration of Cx43 levels partially rescued IE1-induced interruption of neuronal migration. Taken together, the results of our investigation reveal a novel mechanism of HCMV-induced neural maldevelopment and identify a potential intervention target. IMPORTANCE Congenital CMV (cCMV) infection causes neurological sequelae in newborns. Recent studies of cCMV pathogenesis in animal models reveal ventriculomegaly and cortical atrophy associated with impaired neural progenitor cell (NPC) proliferation and migration. In this study, we investigated the mechanisms underlying these NPC abnormalities. We show that Cx43, a critical adhesion molecule mediating NPC migration, is downregulated by HCMV infection in vitro and HCMV-IE1 in vivo. We provide evidence that IE1 interacts with the C terminus of Cx43 to promote its ubiquitination and consequent degradation through the proteasome. Moreover, we demonstrate that introducing IE1 into mouse fetal brains led to neuronal migration defects, which was associated with Cx43 reduction. Deletion of the Cx43-binding region in IE1 or ectopic expression of Cx43 rescued the IE1-induced migration defects in vivo. Our study provides insight into how cCMV infection impairs neuronal migration and reveals a target for therapeutic interventions.

Distribution of CMV envelope glycoprotein B, H and N genotypes in infants with congenital cytomegalovirus symptomatic infection.

Cytomegalovirus (CMV) is the leading cause of congenital infections worldwide and contributes to long-term sequelae in neonates and children. CMV envelope glycoproteins play a vital role in virus entry and cell fusion. The association between CMV polymorphisms and clinical outcomes remains controversial. The present study aims to demonstrate the distribution of glycoprotein B (gB), H (gH) and N (gN) genotypes in congenitally CMV (cCMV) infected symptomatic infants and attempts to figure out the association between viral glycoprotein genotypes and clinical outcomes. Genotyping of gB, gH and gN was performed in 42 cCMV symptomatic infants and 149 infants with postnatal CMV (pCMV) infection in Children's hospital of Fudan university. Nested PCR, gene sequencing and phylogenetic analyses were used to identify the genotypes. Our study demonstrated that: 1. The CMV gB1, gH1 and gN1 were the predominant genotypes among symptomatic cCMV infected infants, while gB1, gH1 and gN3a were more prevalent in pCMV group. gH1 genotype has a significant association with symptomatic cCMV infection (p = 0.006). 2. No significant correlation was found between CMV genotypes and hearing impairment. However, gH1 was more prevalent among cCMV infected infants with moderate/severe hearing loss although without statistical difference (p = 0.130). 3. gB3 was more prevalent among infants with skin petechiae (p = 0.049) and found to be associated with an increased risk of skin petechiae (OR = 6.563). The gN4a subtype was significantly associated with chorioretinitis due to cCMV infection (p = 0.007). 4. Urine viral loads were not significantly associated with different genotypes or hearing impairment among symptomatic cCMV infected infants. Our findings demonstrated the overall distribution of gB, gH and gN genotypes in infants with symptomatic cCMV infection in Shanghai for the first time. The findings in our study may suggest a possible association between gH1 genotype and early infancy hearing loss. gB3 genotype was associated with a 6.5-fold increased risk of petechiae while gN4a strongly correlated with chorioretinitis due to cCMV infection. No significant correlation was found between urine viral loads and CMV genotypes or hearing impairment in cCMV infected infants.

Factors associated with congenital cytomegalovirus infection detected by dried blood spot testing in children with hearing loss.

Congenital cytomegalovirus (cCMV) infection in infants leads to an increased risk of developing sensorineural hearing loss (SNHL), even if they are asymptomatic at birth. There are currently no national guidelines for universal screening for CMV, placing children with cCMV at a high risk for unidentified and untreated HL, which in turn places them at greater risk for lasting impacts on quality of life and cognitive and behavioral abilities. We sought to describe the sociodemographic and hearing loss characteristics of children with HL due to cCMV. We performed a retrospective cohort study of patients 0-18 years of age who completed CMV dried blood spot (DBS) testing in our HL clinic before April 1, 2022. Home ZIP codes were entered into the Healthy Places Index (HPI) database to quantify the health of the community in which the patient lived. Severity of HL was determined by pure tone averages (PTA) of hearing thresholds for frequencies of 500Hz, 1000Hz, 2000Hz, and 4000Hz. Progression was defined as those who referred on newborn hearing screen and then had a >15dB increase in PTA, and those who passed newborn hearing screen and were found to have HL later in life. Logistic regression was used to compare variables. Of 365 children who received a CMV DBS test, 15 (4%) had a positive test, indicating the presence of cCMV infection, and 350 (96%) had a negative test. 192 (53%) were male, 212 (58%) were URM, 202 (55%) had public insurance, the median number of ICD-10 codes was 2 (range 0-53), and the median HPI percentile score was 71.2 (range: 3.4-99.9). Although CMV DBS testing was ordered for those with suspicion of SNHL, ultimately diagnostic testing found 333 (91%) with SNHL, 4 (1%) with CHL, 13 (4%) with mixed HL, 9 (3%) with auditory neuropathy spectrum disorder, and 5 (4%) with unspecified HL, and 11 (3%) without HL. Of the 353 patients with HL, 126 (36%) had unilateral, 156 (44%) had symmetric bilateral, and 71 (20%) had asymmetric bilateral HL; 183 (52%) had progressive and 138 (39%) had stable HL. In children with SNHL (n=333), we tested the association of socio-demographic and audiologic factors with cCMV. Those with asymmetric bilateral SNHL (OR 5.19, 95% CI 1.81-14.90) or profound SNHL (>90dB) in either ear (OR 13.91, 95% CI 3.82-50.67) had higher odds of having cCMV. Those with symmetric bilateral SNHL had lower odds of a positive CMV DBS test result (OR 0.17, 95% CI 0.02-0.76). All sociodemographic variables, medical comorbidities, and other audiologic variables were not associated with CMV DBS test results. Congenital CMV infection is associated with asymmetric bilateral and profound SNHL. More research is warranted to determine best practices for universal screening for cCMV to identify these children.

Healthcare costs of congenital cytomegalovirus (cCMV) disease in infants during the first two years of life: a retrospective German claims database analysis

BackgroundCongenital cytomegalovirus (cCMV) infection can cause severe neurological damage, growth retardation, hearing loss, and microcephaly in infants. We aimed at assessing healthcare costs of infants with recorded cCMV diagnosis in an administrative claims database in the first 2 years of life.MethodsWe conducted a retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database. Incremental healthcare costs during the first and second year of life were assessed by matching (1:60) infants with cCMV diagnoses ≤ 90 days after birth (cCMV90 cohort) to infants without cCMV diagnosis (“representative” controls) and infants with cCMV diagnoses ≤ 21 days after birth plus specific symptoms (cCMV21-S) to infants without cCMV and any ICD-10-GM records (besides Z00-Z99) until 4th preventive health check-up (“healthy” controls). Due to missing data, mean imputation was applied for aids and remedies costs.ResultsWe identified 54 and 24 infants born 2014–2018 for the cCMV90 and cCMV21-S cohorts, respectively. During the first year, mean (median) healthcare costs were significantly higher in cCMV90 cases vs. “representative” controls (€22,737 (€9759) vs. €3091 (€863), p < 0.001), with 87.2% inpatient costs. Healthcare costs for cCMV21-S cases compared to “healthy” controls were €34,498 (€20,924) vs. €680 (€569), p < 0.001. Differences decreased for both comparisons in the second year but remained statistically significant.ConclusionscCMV comprises a considerable economic burden for the German healthcare system (€19,646 to €33,818 higher mean costs for infants with recorded cCMV diagnosis in the first year of life). Attempts should be made to reduce this burden.

Evaluation of the Association Between Congenital Cytomegalovirus Infection and Pediatric Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, and a leading cause of death in children. Understanding the causes of pediatric ALL is necessary to enable early detection and prevention; congenital cytomegalovirus (cCMV) has recently been identified as a potential moderate-to-strong factor associated with risk for ALL. To compare the prevalence of cCMV infection between ALL cases and matched controls. In this population-based case-control study of ALL cases and matched controls, cases consisted of children aged 0 to 14 years between 1987 and 2014 with an ALL diagnosis identified through the Michigan Cancer Surveillance Program and born in Michigan on or after October 1, 1987. Cancer-free controls were identified by the Michigan BioTrust for Health and matched on age, sex, and mother's race and ethnicity. Data were analyzed from November to May 2022. cCMV infection measured by quantitative polymerase chain reaction in newborn dried blood spots. ALL diagnosed in children aged 0 to 14 years. A total of 1189 ALL cases and 4756 matched controls were included in the study. Bloodspots were collected from participants at birth, and 3425 (57.6%) participants were male. cCMV was detected in 6 ALL cases (0.5%) and 21 controls (0.4%). There was no difference in the odds of cCMV infection comparing ALL cases with controls (odds ratio, 1.30; 95% CI, 0.52-3.24). Immunophenotype was available for 536 cases (45.1%) and cytogenetic data for 127 (27%). When stratified by subtype characteristics, hyperdiploid ALL (74 cases) was associated with 6.26 times greater odds of cCMV infection compared with unmatched controls (95% CI, 1.44-27.19). In this case-control study of cCMV and pediatric ALL, cCMV was associated with increased risk of hyperdiploid ALL. These findings encourage continued research.

Hearing outcomes in children with congenital cytomegalovirus infection: From management controversies to lack of parents' knowledge.

Congenital cytomegalovirus (cCMV) is the leading nongenetic cause of sensorineural hearing loss (HL). However, there are no universally accepted approaches to diagnosis, follow-up and treatment. The aim of this study was to evaluate the main characteristics of cCMV-infected children, focusing on their management and long-term hearing outcomes. This retrospective study included all children with cCMV infection who were referred to a third-level referral audiologic center for a 6-year hearing follow-up. The main information collected from the medical records included gestational age, birth weight, trimester of maternal seroconversion, hearing status at birth and after 6 years, hearing fluctuations, treatment with oral valganciclovir (within the first month of life and for 6 months), use of hearing devices, presence of speech-language delay, motor delay, cognitive delay and balance disorders, awareness of cCMV among parents, and parents' engagement in behaviors that could increase the risk of CMV infection during pregnancy. A total of 141 children with cCMV infection (72 males and 69 females; mean gestational age: 37+3 weeks; mean birth weight: 2893g) were assessed. Overall, 48 children (34.0%) had a diagnosis of speech-language delay, 32 (22.7%) of sensorineural HL (59.4% bilaterally; 50% of profound degree), 18 (12.8%) of motor delay, 16 (11.3%) of balance disorders, and 6 (4.3%) of cognitive delay. Among children with HL, 8 (25.0%) were fitted with hearing aids (5 unilaterally and 3 bilaterally), and 5 (15.6%) had undergone cochlear implantation (1 unilaterally and 4 bilaterally), while a bimodal hearing solution was adopted for 2 (6.3%) patients. Compared to children with asymptomatic cCMV infection, symptomatic children had a higher prevalence of neurological and auditory sequelae (P<0.01) and bilateral (P=0.003) and severe-to-profound HL (P=0.004). Overall, 23 children (16.3%) received oral valganciclovir, and only one of them experienced hearing deterioration. Only 14.9% of mothers and 5% of fathers were aware that cCMV could cause progressive or late-onset HL, and 87.9% of parents (248/282) had engaged in behaviors that increased the risk of CMV infection during pregnancy. This study confirmed the importance of performing a long audiological follow-up in children diagnosed with cCMV infection due to the possible late-onset, progressive and fluctuating nature of HL. Moreover, the study highlighted many current controversies in preventive (poor prenatal education), diagnostic (routine maternal serological screening) and therapeutic (valganciclovir administered to asymptomatic children) approaches to cCMV infection. More efforts should be made to improve prevention strategies and raise awareness of cCMV infection risks among the population.

Infezione congenita da citomegalovirus e ipoacusia

Background - Cytomegalovirus (CMV) infection is the most common of congenital infections, with a prevalence of 0.3-1.2% in industrialized countries and is the most frequent non-genetic cause of permanent hearing loss in children, with an incidence ranging from 0.2 to 2%. Since there is no antenatal therapy or vaccine against CMV and since many patients with congenital CMV (cCMV) do not experience sequelae even in the absence of specific therapy, a universal screening programme has not been established. Current protocols provide test for the detection of cCMV in case of failure at newborn hearing screening. Aim - This article aims to analyze the pros and cons of the different screening approaches for cCMV, through an overview of the topic based on the most recent literature. Materials and Methods - The recent national and international literature on cCMV screening has been examined through a narrative review. Results - As part of the screening and early identification programmes for neonatal hearing loss, current procedures include a search for cCMV on urine or saliva within 3 weeks of life, following a positive result (Refer) at newborn audiological screening. This approach enables to recognize cCMV infection in newborns suffering from isolated hearing loss, which is already present at birth, however it does not allow cases of CMV-related hearing loss occurring in the postnatal period or late in childhood to be recognized. A universal newborn cCMV screening, in conjunction with audiological screening, would have the advantage of identifying all infants infected with cCMV, including 10%-15% of asymptomatic conditions at birth who may develop late hearing loss. One of the major obstacles to the establishment of universal cCMV screening is the unknown cost of its application and a clear understanding of the sensitivity and specificity of the cCMV test. Conclusions - Strategies are needed to identify children with congenital CMV infection at risk for developing late-onset hearing loss. A universal newborn screening to ensure timely recognition of children with cCMV, close audiological surveillance and possible early treatment at the onset of the first hearing symptoms should be provided.

Risk Factors for Hearing Loss at Birth in Newborns With Congenital Cytomegalovirus Infection

With a prevalence between 0.2% and 6.1% of all live births, congenital cytomegalovirus (cCMV) infection is a major cause of congenital nonhereditary sensorineural hearing loss. Despite the large amount of research on cCMV-related hearing loss, it is still unclear which newborns are at risk of hearing loss. To identify independent risk factors for cCMV-related congenital hearing loss and predictors of hearing loss severity at birth. This cross-sectional study of newborns with cCMV infection used data included in the Flemish CMV registry that was collected from 6 secondary and tertiary hospitals in Flanders, Belgium, over 15 years (January 1, 2007, to February 7, 2022). Data were analyzed March 3 to October 19, 2022. Patients were included in the study after confirmed diagnosis of cCMV infection and known hearing status at birth. Patients who presented with other possible causes of sensorineural hearing loss were excluded. Primary outcome was hearing status at birth. Clinical, neurological, and laboratory findings along with the timing of seroconversion and blood viral load were separately considered as risk factors. Binary logistic regression was performed to identify independent risk factors for congenital hearing loss in newborns with cCMV. Effect sizes were measured using Hedges g, odds ratio, or Cramer V. Of the 1033 newborns included in the study (553 of 1024 [54.0%] boys), 416 (40.3%) were diagnosed with symptomatic cCMV infection and 617 (59.7%) with asymptomatic cCMV infection. A total of 15.4% of the patients (n = 159) presented with congenital hearing loss; half of them (n = 80 [50.3%]) had isolated hearing loss. The regression model revealed 3 independent risk factors for congenital hearing loss: petechiae at birth (adjusted odds ratio [aOR], 6.7; 95% CI, 1.9-23.9), periventricular cysts on magnetic resonance imaging (MRI; aOR, 4.6; 95% CI, 1.5-14.1), and seroconversion in the first trimester (aOR, 3.1; 95% CI, 1.1-9.3). Lower viral loads were seen in patients with normal hearing compared with those with congenital hearing loss (median [IQR] viral load, 447.0 [39.3-2345.8] copies per milliliter of sample [copies/mL] vs 1349.5 [234.3-14 393.0] copies/mL; median difference, -397.0 [95% CI, -5058.0 to 174.0] copies/mL). Findings of this cross-sectional study suggest that newborns with cCMV infection and petechiae at birth, periventricular cysts on MRI, or a seroconversion in the first trimester had a higher risk of congenital hearing loss. Clinicians may use these risk factors to counsel parents in the prenatal and postnatal periods about the risk of congenital hearing loss. Moreover, linking clinical features to hearing loss may provide new insights into the pathogenesis of cCMV-related hearing loss. The importance of viral load as a risk factor for congenital hearing loss remains unclear.

Late-onset and congenital hearing loss detected using AABR due to congenital cytomegalovirus infection that improved with valganciclovir.

Congenital cytomegalovirus (cCMV) infection is the most common congenital viral infection and is the leading non-genetic cause of sensorineural hearing loss and an important cause of neurodevelopmental disabilities. Auto auditory brainstem response (AABR) is a simple hearing test and used for the purpose of neonatal hearing screening, but can use it for early detection hard of hearing within the study age of the model. We experienced two case of asymptomatic CMV infection in which congenital and late-onset hearing loss were diagnosed early with AABR, and hearing loss improved with valganciclovir.

Targeted new screening for congenital cytomegalovirus infection: clinical, audiological and neuroimaging findings

ObjectiveTo evaluate clinical, audiological and neuroimaging findings in a cohort of infants diagnosed with congenital cytomegalovirus (cCMV) infection after failure at newborn hearing screening.MethodsA prospective observational study in the Netherlands,...

2124. Active surveillance for Congenital Cytomegalovirus infections as part of institutional protocol for newborns with failed hearing screening

Abstract Background Congenital cytomegalovirus (cCMV) is the leading infectious cause of sensorineural hearing loss in newborns. Universal screening for cCMV is not recommended in the United States. It is important to establish effective strategies for early detection of newborns with cCMV, as most of them are asymptomatic at birth. Methods As per institutional protocol at Louisiana State University Health Sciences Center in Shreveport, every newborn who fails auditory brainstem response (ABR) hearing screen is referred to Audiology and is evaluated with CMV polymerase chain reaction (PCR) from urine samples to rule out cCMV before they are discharged home. We intended to evaluate the proportion of newborns failing hearing screening during a two-year period that are positive for CMV by urine PCR and that are referred to Pediatric Infectious Diseases for cCMV treatment. Results From January 1st, 2020, to March 6th, 2022, 4,010 newborns had ABR based hearing screening at birth, with 125 (3%) failing on two attempts. Subsequently, 85 of them, corresponding to 68%, passed repeat testing at Audiology clinic, while 25 did not show up for their appointments. Out of the 67 infants that passed repeat hearing test and were tested for cCMV, none had positive urine CMV PCR results. Among the 15 newborns who failed repeat hearing test in Audiology clinic, 2 (13%) had positive urine CMV PCR results, 9 had negative results and 2 infants did not have tests done (Figure 1). Both infants diagnosed with cCMV showed severe to profound sensorineural hearing loss and are being followed by Otorhinolaryngology. They are also receiving oral valganciclovir for cCMV infection with a plan to receive treatment for 6 months, being followed periodically by Pediatric Infectious Diseases. Evaluations with urine CMV PCR in newborns with repeat hearing screening showed that all 67 that passed were negative; and out of the 15 infants that failed repeat testing, 2 had positive CMV PCR results. Conclusion Our institutional protocol recommends sending urine samples for CMV PCR in every baby that fails newborn ABR hearing screen, and this has helped identified neonates with cCMV infections in the setting of severe to profound sensorineural hearing loss. These patients diagnosed with cCMV are planned to receive treatment for 6 months. Our future goals involve evaluating if early treatment of cCMV for 6 months can prevent progression of hearing loss and help achieving improved audiological outcomes at 2 years of age. Disclosures All Authors: No reported disclosures.

2145. Economic Burden of Congenital Cytomegalovirus Infection in Commercially- and Medicaid-insured Patients in the United States

Abstract Background Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of congenital birth defects. Approximately 20-25% of infants born with cCMV develop long-term health complications such as hearing loss, developmental issues, and microcephaly. Despite this, studies on the economic burden of cCMV are limited. The aim of this study is to assess the healthcare resource utilization (HRU) and cost burden among a sample of cCMV patients in the US using insurance claims data. Methods This retrospective study utilized IBM Watson Health MarketScan® Commercial Claims and Encounters and Multi-State Medicaid data from January 1, 2010 to December 31, 2019. Separately for each payer population, patients were included in the cCMV cohort if their first diagnosis (index date) of cCMV (ICD-9: 771.1; ICD-10: P35.1) or CMV (ICD-9: 78.5; ICD-10: B25.x) was within 1 month of birth. The index date for non-cCMV controls was selected at random from all medical claims within 1 month of birth. cCMV patients were matched 1:1 to controls on demographics, insurance type, birth year, and index year. All patients were required to have ≥ 1 year of continuous health plan enrollment post-index (study period). HRU and costs in 2021 USD ($) were summarized over the study period. Costs for birth admissions were also described. Results 195 Commercial and 549 Medicaid matched pairs were included in the analyses. Mean ± SD age at first diagnosis was 8.4 ± 8.6 days and 5.9 ± 7.8 days for Commercial and Medicaid cases, respectively. Mean birth length of stay for Commercial and Medicaid cases was 24 days (vs. 5 for controls), with mean birth admission costs of $149,192 (vs. $17,996) and $49,885 (vs. $5,052), respectively. On average, cCMV patients had higher study period HRU and costs compared to controls (Table 1). Excess costs due to cCMV were estimated at $33,223 for Commercial and $9,748 for Medicaid. Conclusion cCMV patients have substantial HRU and costs during the 1-year post-diagnosis. While the majority of patients did not require hospitalization, inpatient care contributed substantially to the overall cost burden. Future studies should evaluate longer-term costs beyond the first year as well as the reasons underlying the high economic burden among cCMV patients. Disclosures John D. Diaz-Decaro, PhD, MS, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Gail J. Demmler-Harrison, MD, Elsevier: Book royalties|Merck: Grant/Research Support|Microgen: Advisor/Consultant|Microgen: Grant/Research Support|Moderna: Advisor/Consultant|UpToDate Wolters Kluwer Health: Royalties Jessica R. Marden, ScD, MPH, Moderna, Inc.: Advisor/Consultant Annika Anderson, MPH, Moderna, Inc.: Advisor/Consultant Sandeep Basnet, MD, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Katherine Gaburo, n/a, Moderna, Inc.: Advisor/Consultant Danielle Peterson, n/a, Moderna, Inc.: Advisor/Consultant Kosuke Kawai, ScD, MS, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Noam Kirson, PhD, Moderna, Inc.: Advisor/Consultant Urvi Desai, PhD, Moderna, Inc.: Advisor/Consultant Philip Buck, PhD, MPH, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds.

Congenital Cytomegalovirus Infection and Maternal Primary Cytomegalovirus Infection in Universal Newborn Hearing Screening Referral Patients: A Prospective Cohort Study

Background: There are no detailed reports in the literature on maternal cytomegalovirus antibody screening for universal newborn hearing screening (UNHS) referral patients. We examined maternal cytomegalovirus antibody screening results and estimated the incidence of maternal primary cytomegalovirus infection among UNHS referral patients. Methods: During September 2013–March 2021, fresh urine samples were collected in the first week after birth from 98 neonates with UNHS referral results at 15 obstetrical institutions in Mie, Japan (the first hearing screening). We performed a real-time polymerase chain reaction analysis to detect cytomegalovirus DNA in the samples. Infants with ≥200 copies/mL of cytomegalovirus DNA were diagnosed with congenital cytomegalovirus (cCMV) infection. A second hearing screening was performed, and patients with positive results were sent to the otorhinolaryngologists for further examinations of congenital hearing loss. We calculated incidence rates (%) with 95% confidence intervals (CIs) for cCMV infection among patients with UNHS referral results and maternal primary cytomegalovirus infection among patients who underwent maternal cytomegalovirus antibody screening. Results: Among the 98 neonates with UNHS referral results (the first hearing screening), 5 were diagnosed with cCMV infection (incidence rate: 5.1%; 95% CI: 0.8–9.5). All five patients with cCMV had positive second hearing screening results and were sent to their otorhinolaryngologists. All five were diagnosed with congenital hearing loss, and four were diagnosed with congenital hearing loss secondary to cCMV infection. The remaining patient with cCMV infection was diagnosed with congenital hearing loss unrelated to cCMV infection. Of the 98 patients, 60 underwent maternal cytomegalovirus antibody screening. Among the 60 patients, six had maternal primary cytomegalovirus infection during pregnancy (incidence rate: 10.0%; 95% CI: 2.4–17.6). Of the six patients, four were positive for cytomegalovirus immunoglobulin (CMV Ig) G and IgM antibodies in maternal blood with low CMV IgG antibody avidity results during early pregnancy, while the remaining two had maternal CMV IgG antibody seroconversion during pregnancy. Conclusions: This is the first study to examine the maternal primary cytomegalovirus infection incidence rate in patients with UNHS referral results (the first hearing screening). We identified a 10-fold higher risk in this population (10.0%) than in the general population (0.98%).

Is CMV PCR of inner ear fluid during cochlear implantation a way to diagnose CMV-related hearing loss?

Sampling of inner ear fluid during cochlear implant surgery is an interesting, simple and safe way to diagnose CMV-related hearing loss, especially when the diagnosis of congenital infection can no longer be confirmed. However, the sensitivity decreases with age. NCT04724265 What is Known: •Congenital cytomegalovirus infection is the leading infectious cause of neurological disabilities and sensorineural hearing loss in children.In the absence of systematic screening at birth, many cCMV infections go undetected and are often undiagnosed despite the development of sensorineural sequelae. • Nearly 40% of indications for cochlear implantation are of unknown etiology. •Performing CMV PCR on inner ear fluid at the time of cochlear implantation is a safe way with high diagnostic performance (PPV = 90%, NPV = 92%) to detect a CMV-related hearing loss. • This sample may be interesting in cases of unknown cause of hearing loss in order to identify undiagnosed cCMV infections.

Cytomegalovirus Specific Serological and Molecular Markers in a Series of Pregnant Women With Cytomegalovirus Non Primary Infection.

(1) Background: In a period where systematic screening of CMV during pregnancy is still debated, diagnosis of non primary infection (NPI) remains challenging and an obstacle to systematic screening. Our aim is to report kinetics of serological and molecular CMV markers of NPI. (2) Methods: We identified immunocompetent pregnant women with CMV NPI as women known to be seropositive for CMV before pregnancy who gave birth to cCMV infected infants. We performed CMV-IgG, CMV-IgM, CMV-IgG avidity and CMV PCR retrospectively on sequential serum samples collected during pregnancy. (3) Results: We collected 195 serum samples from 53 pregnant women with NPI during pregnancy. For 29/53 (55%) patients, no markers of active infection were observed (stable IgG titers, negative IgM and negative PCR). CMV PCR was positive in at least one serum for 18/53 (34%) patients and median viral load was 46 copies/mL, IQR (21-65). (4) Conclusions: For more than half of patients with confirmed CMV NPI during pregnancy, available diagnostic tools are liable to fail in detecting an active infection. These should therefore not be used and universal neonatal screening for CMV remains the only way to detect all cCMV infections.

A systematic review and meta-analysis of the prevalence of human cytomegalovirus shedding in seropositive pregnant women.

The detection of human cytomegalovirus (HCMV) in an individual's bodily fluid by culture techniques or through HCMV DNA detection by polymerase chain reaction, is known as HCMV shedding. Human cytomegalovirus shedding has the potential to transmit HCMV infection, where an individual can become infected with HCMV through contact with the bodily fluid of another individual containing HCMV. Human cytomegalovirus shedding can occur in primary infection and in non-primary infection for individuals with prior infection (HCMV seropositive). Human cytomegalovirus infection causes few or no symptoms in a pregnant woman, but can cause significant harm to her foetus if congenital CMV (cCMV) infection occurs. The association between HCMV shedding in HCMV seropositive pregnant women and the vertical transmission of HCMV to result in cCMV infection is poorly investigated, challenged by a limited understanding of the distribution of HCMV shedding in HCMV seropositive pregnant women. We systematically reviewed the published literature to describe the prevalence of HCMV shedding in HCMV seropositive women during pregnancy up to delivery. This analysis identified nine studies that met our eligibility criteria. In these studies, the prevalence of HCMV shedding in any bodily fluid of HCMV seropositive women during pregnancy and at delivery ranged from 0% to 42.5%. A meta-analysis, performed on six of the nine studies with suitable sample sizes, estimated a pooled prevalence of 21.5% [95% CI 12.7%,30.3%]. To our knowledge, this is the first review to systematically search the literature to summarise the prevalence of HCMV shedding in HCMV seropositive pregnant women. These estimates can help in the development of disease burden models and therapeutic or preventative strategies against cCMV infection in the context of non-primary maternal HCMV infection.

Cytokine Profiling of Amniotic Fluid from Congenital Cytomegalovirus Infection.

Background: Congenital cytomegalovirus (cCMV) infection is frequent and potentially severe. The immunobiology of cCMV infection is poorly understood, involving cytokines that could be carried within or on the surface of extracellular vesicles (EV). We investigated intra-amniotic cytokines, mediated or not by EV, in cCMV infection. Methods: Forty infected fetuses following early maternal primary infection and forty negative controls were included. Infected fetuses were classified according to severity at birth: asymptomatic, moderately or severely symptomatic. Following the capture of EV in amniotic fluid (AF), the concentrations of 38 cytokines were quantified. The association with infection and its severity was determined using univariate and multivariate analysis. A prediction analysis based on principal component analysis was conducted. Results: cCMV infection was nominally associated with an increase in six cytokines, mainly soluble (IP-10, IL-18, ITAC, and TRAIL). EV-associated IP-10 was also increased in cases of fetal infection. Severity of fetal infection was nominally associated with an increase in twelve cytokines, including five also associated with fetal infection. A pattern of specific increase in six proteins fitted severely symptomatic infection, including IL-18soluble, TRAILsoluble, CRPsoluble, TRAILsurface, MIGinternal, and RANTESinternal. Conclusion: Fetal infection and its severity are associated with an increase in pro-inflammatory cytokines involved in Th1 immune response.

Efficacy of transtympanic infusion of dexamethasone into the tympanic cavity in mice with acute sensorineural hearing loss associated with cytomegalovirus infection

Background There is no report on acute sensorineural hearing loss with congenital cytomegalovirus (cCMV) infection in basic experiments. Aims/Objectives The aim of this study was to evaluate the effect of dexamethasone, an anti-inflammatory steroid, on acute sensorineural hearing loss in the mouse cytomegalovirus (MCMV) infection model mice. Material and Methods Sensorineural hearing loss model mice were divided into two groups, one with and one without intratympanic dexamethasone. Dexamethasone was injected into the tympanic cavity of only the right ear, and hearing ability was assessed at the ages of three, six, and eight weeks by auditory brainstem response measurement. Results Among the 23 mice intratympanically injected with dexamethasone (15 μg/mouse) at the age of three weeks, five (21.7%) had a hearing improvement of at least 10 dB and 18 (78.3%) had no improvement at the age of six weeks. Among the 19 mice that did not receive a dexamethasone injection, one (5.3%) showed improvement and 18 (94.7%) showed no improvement (p = 0.129). Conclusions and Significance In this study, transtympanic infusion of dexamethasone into the tympanic cavity was effective in some mice with sensorineural hearing loss, suggesting that, in addition to angiogenesis, anti-inflammatory activity might be a mechanism of treatment for hearing loss.

Relevance of CMV DNA Detection in Symptomatic Children up to 3 Months of Age

&#x0D; &#x0D; &#x0D; Cytomegalovirus (CMV) is the most frequent cause of congenital infection worldwide. The burden of disease related to congenital CMV (cCMV) is substantial, as it is the leading cause of sensorineural hearing loss and an important cause of neurodevelopmental disabilities in children. Despite its clinical significance, cCMV infection often goes undetected because the majority of infected infants are asymptomatic at birth and screening programmes have not been implemented in any country.&#x0D; The aim of this study is to define the role of CMV in congenital and early postnatal morbidity in clinically relevant symptomatic children up to 3 months of age in Varna region, comparatively in ELISA (anti CMV IgM/IgG) and PCR.&#x0D; We found CMV DNA in 12 out of 50 tested children (24%, 95% CI: 12.16–35.84%). The viral load ranged in 65–1 628 879 IU/ml, average viral load 144 707.2 IU/ml.&#x0D; It is important to note that only half of the PCR positive children 6/12 (50%) had an anti CMV IgM positive result.&#x0D; Our data demonstrate that serological tests defining active CMV infection with CMV IgM detection are not sufficiently indicative in all newborns, and it is therefore mandatory to conduct modern PCR for all relevant infants after birth.&#x0D; &#x0D; &#x0D;