Asymptomatic cCMV Research Articles

Risk factors associated with late-onset hearing loss in children with congenital cytomegalovirus: a systematic review.

To search for existing evidence of prognostic factors related to the development of late-onset hearing loss (LOHL) in infants with congenital cytomegalovirus (cCMV). A PRISMA systematic review was performed, with the PubMed, Embase, and Web of Science databases searched from inception through to December 2023; after the application of inclusion and exclusion criteria a total of 9 papers were included in this review. PROSPERO registration number CRD42024492244. 9 studies encompassing a total of 292 children with late-onset hearing loss were included. A total of 12 risk factors were identified in the literature, with 6 found to be statistically significant. Late-onset hearing loss was more frequently reported in children with symptomatic than asymptomatic cCMV. Moreover, in asymptomatic cCMV cases, elevated DNAemia and salivary viral load were associated with late-onset hearing loss. Additionally, first-trimester seroconversion was identified as a risk factor for late- onset hearing loss. Further, gestational age < 37weeks and low birth weight were found to correlate with late-onset hearing loss. Remarkably, only one study documented a relationship between late-onset hearing loss and ultrasonographic abnormalities. Although six statistically significant risk factors have been identified, the available evidence is limited and inconsistent, preventing the establishment of reliable neonatal and maternal parameters to predict the development of LOHL in patients with CMV. There are few studies addressing this topic, and those available exhibit a low level of evidence and heterogeneous designs. More studies should be done.

Prenatal and postnatal antiviral therapies for the prevention and treatment of congenital cytomegalovirus infections.

Congenital cytomegalovirus infection (cCMV) is the leading infectious cause of sensorineural hearing loss and lifelong neurodevelopmental disabilities. Studies suggest antiviral therapy can prevent fetal infection after maternal primary infection, as well as halt the progression of hearing loss and neurodevelopmental disabilities in newborns with symptomatic cCMV. With growing worldwide momentum on early detection and diagnosis of cCMV, this review describes the exciting recent advances in antiviral therapies in CMV infected pregnant mothers and babies, as well as emerging evidence on anti-CMV vaccines. New opportunities for prenatal and neonatal interventions have driven a rising interest in screening and identification of asymptomatic CMV infection. Routine screening of pregnant women to identify primary infection in first trimester is now advocated in Western Europe but has yet to be examined from a public health perspective in other regions. Evidence is emerging for maternal valaciclovir therapy to prevent fetal infection after a maternal primary CMV infection in the first trimester of pregnancy. For those infants who are born with symptomatic cCMV, a 6-month course of valganciclovir, started within the first 4 weeks of life, and possibly up to 13 weeks of life, is the current recommended therapy. However, there is unclear evidence for the benefit of treatment for asymptomatic cCMV and cCMV with isolated hearing loss. Research to identify more effective antivirals and an effective CMV vaccine continues. More research is needed to determine the region-specific applicability of the new European recommendations for routine CMV screening in pregnancy. Areas of uncertainty in postnatal management include timing of initiation, duration of treatment and identifying pediatric subgroups that benefit from modification of the standard treatment recommendations.

Assessment of blood viral load in asymptomatic and symptomatic cases of congenital cytomegalovirus infection.

This study aimed to retrospectively evaluate the baseline and follow-up viral loads and viral clearance times in cases followed for asymptomatic and symptomatic congenital cytomegalovirus (cCMV) infection between August 2010 and August 2022. Among 93 cases, they had asymptomatic (n: 55) and symptomatic (n: 38). The median baseline blood viral load detected in the symptomatic cCMV (ScCMV) infection (13 054 IU/mL) was significantly higher than that of asymptomatic cCMV (AcCMV) infection (4636 IU/mL) (p < 0.013). There was no difference in median viral clearance times (75 and 90 days, respectively) in baseline viremic cases in the ScCMV and AcCMV infection groups. There were no differences in median baseline blood viral load (6930 IU/mL and 14 268 IU/mL, respectively) and median viral clearance times (75 and 85 days, respectively) between the 6-week and 6-month antiviral treatment group. No correlation was found between baseline blood viral load, clinical severity, and the number of systems involved. However, in initial viremic cases, the viral load threshold for a symptomatic case was 8856 IU/mL, with 85.7% sensitivity and 54.5% specificity.

What are the neurodevelopmental outcomes of children with asymptomatic congenital cytomegalovirus infection at birth? A systematic literature review.

Congenital cytomegalovirus (cCMV) is among the most common congenital infections globally. Of 85%-90% cCMV-infected infants without symptoms at birth, 10%-15% develop sequelae, most commonly sensorineural hearing loss (SNHL); their childhood neurodevelopmental outcomes are less well understood. Embase and MEDLINE were searched for publications from 16th September 2016 to 9th February 2024 to identify studies reporting primary data on neurodevelopmental outcomes in children with asymptomatic cCMV (AcCMV), measured using assessment tools or as evaluated by the study investigators, clinicians, educators, or parents. The Newcastle-Ottawa scale was applied to studies to assess risk of bias. Of 28 studies from 18 mostly high-income countries, there were 5-109 children with AcCMV per study and 6/28 had a mean or median age at last follow-up of ≥5years. Children with AcCMV had better neurodevelopmental outcomes than children with symptomatic cCMV in 16/19 studies. Of 9/28 studies comparing AcCMV with CMV-uninfected children, six reported similar outcomes whilst three reported differences limited to measures of full-scale intelligence and receptive vocabulary among children with AcCMV and SNHL, or more generally in motor impairment. Common limitations of studies for our question were a lack of cCMV-uninfected controls, heterogeneous definitions of AcCMV, lack of focus on neurodevelopment, selection bias and inadequate follow-up. There was little evidence of children with AcCMV having worse neurodevelopmental outcomes than CMV-uninfected children, but this conclusion is limited by study characteristics and quality; findings highlight the need for well-designed and standardised approaches to investigate long-term sequelae.

Neurobehavioral outcomes of neonatal asymptomatic congenital cytomegalovirus infection at 12-months

BackgroundCongenital cytomegalovirus (cCMV) is the most common congenital viral infection in the United States. Symptomatic infections can cause severe hearing loss and neurological disability, although ~ 90% of cCMV infections are asymptomatic at birth. Despite its prevalence, the long-term neurobehavioral risks of asymptomatic cCMV infections are not fully understood. The objective of this work was to evaluate for potential long-term neurobehavioral sequelae in infants with asymptomatic cCMV.MethodsInfants with cCMV were identified from a universal newborn cCMV screening study in a metropolitan area in the midwestern United States. Asymptomatic infants with cCMV were enrolled in a longitudinal neurodevelopmental study (N = 29). Age- and sex-matched healthy control infants (N = 193) were identified from the Baby Connectome Project (BCP), a longitudinal study of brain and behavioral development. The BCP sample supplemented an additional group of healthy control infants (N = 30), recruited from the same participant registry as the BCP specifically for comparison with infants with asymptomatic cCMV. Neurobehavioral assessments and parent questionnaires, including the Mullen Scales of Early Learning, the Repetitive Behavior Scales for Early Childhood (RBS-EC), and the Infant Toddler Social Emotional Assessment (ITSEA) were administered at 12 months of age. Neurobehavioral scores were compared between infants with asymptomatic cCMV and all identified healthy control infants.ResultsInfants with asymptomatic cCMV performed equivalently compared to healthy control infants on the neurobehavioral measures tested at 12 months of age.ConclusionsThese results indicate that at 12 months of age, infants with asymptomatic cCMV are not statistically different from controls in a number of neurobehavioral domains. Although follow-up is ongoing, these observations provide reassurance about neurobehavioral outcomes for infants with asymptomatic cCMV and inform the ongoing discussion around universal screening. Additional follow-up will be necessary to understand the longer-term outcomes of these children.

MicroRNA expression profiling of urine exosomes in children with congenital cytomegalovirus infection

Congenital cytomegalovirus (cCMV) infection can damage the central nervous system in infants; however, its prognosis cannot be predicted from clinical evaluations at the time of birth. Urinary exosomes can be used to analyze neuronal damage in neuronal diseases. To investigate the extent of neuronal damage in patients with cCMV, exosomal miRNA expression in the urine was investigated in cCMV-infected infants and controls. Microarray analysis of miRNA was performed in a cohort of 30 infants, including 11 symptomatic cCMV (ScCMV), 7 asymptomatic cCMV (AScCMV), and one late-onset ScCMV cases, and 11 healthy controls (HC). Hierarchical clustering analysis revealed the distinct expression profile of ScCMV. The patient with late-onset ScCMV was grouped into the ScCMV cluster. Pathway enrichment analysis of the target mRNAs differed significantly between the ScCMV and HC groups; this analysis also revealed that pathways related to brain development were linked to upregulated pathways. Six miRNAs that significantly different between groups (ScCMV vs. HC and ScCMV vs. AScCMV) were selected for digital PCR in another cohort for further validation. Although these six miRNAs seemed insufficient for predicting ScCMV, expression profiles of urine exosomal miRNAs can reveal neurological damage in patients with ScCMV compared to those with AcCMV or healthy infants.

1620. Identification of plasma biomarkers of neurological complications in patients with congenital cytomegalovirus infection by proteome analysis

Abstract Background Congenital cytomegalovirus infection (cCMV) is the leading cause of non-hereditary sensorineural hearing loss and can cause other long-term neurodevelopmental disabilities. To consider antiviral treatment, it is important to differentiate between symptomatic and asymptomatic patients by early infancy. However, it is difficult to identify neurological complications in some cases. This study aimed to identify candidate plasma biomarkers for neurological complications of cCMV during the neonatal period using proteome analysis. Methods This study retrospectively enrolled five patients with asymptomatic cCMV and nine patients with symptomatic cCMV, including those with hearing loss and/or abnormal brain imaging. Plasma samples were obtained during the neonatal period. After extraction of 14 high-abundant proteins from the plasma, proteins were digested by trypsin. The peptides were analyzed by liquid chromatography–mass spectrometry using an Orbitrap Fusion mass spectrometer. Protein quantification was performed using Proteome Discoverer. Levels of differently expressed proteins were validated by enzyme-linked immunosorbent assay. Results In total, 456 proteins were identified and quantified. Levels of 65 proteins were significantly higher in patients with symptomatic cCMV than in those with asymptomatic cCMV. The top two enriched categories for these proteins according to pathway enrichment analysis were “complement and coagulation cascade” and “inflammatory response.” In contrast, levels of 30 proteins were significantly higher in patients with abnormal brain imaging. Plasma levels of fms-related receptor tyrosine kinase 4 (FLT4) were significantly higher in patients with symptomatic cCMV than in those with asymptomatic cCMV. Moreover, levels of plasma peptidylprolyl isomerase A (PPIA) were significantly higher in patients with abnormal brain imaging than in those without. Conclusion Proteome analysis showed that the proteins related to inflammatory response pathways were upregulated in patients with symptomatic cCMV. FLT4 and PPIA can be used as novel diagnostic biomarkers for neurological complications of cCMV to enable early therapeutic intervention with antiviral agents. Disclosures All Authors: No reported disclosures

Proteomic Analysis Reveals Novel Plasma Biomarkers for Neurological Complications in Patients With Congenital Cytomegalovirus Infection.

Congenital cytomegalovirus (cCMV) infection is a leading cause of nonhereditary neurological complications. When considering antiviral treatment, it is important to differentiate between symptomatic and asymptomatic patients. This study aimed to identify candidate plasma biomarkers for neurological complications of cCMV infection using proteomic analysis. This study retrospectively enrolled five patients with symptomatic cCMV infection, four with asymptomatic cCMV infection with isolated sensorineural hearing loss (SNHL), and five with asymptomatic cCMV infection. The plasma samples were collected during neonatal period. The peptides were analyzed using liquid chromatography-mass spectrometry. The concentrations of differentially expressed proteins were validated using an enzyme-linked immunosorbent assay. A total of 456 proteins were identified and quantified. The levels of 80 proteins were significantly different between patients with and without cCMV-related symptoms including isolated SNHL. The levels of 31 proteins were significantly different between patients with and without neuroimaging abnormalities. The plasma concentrations of Fms-related receptor tyrosine kinase 4 in patients with cCMV-related symptoms were significantly higher than those in patients with asymptomatic cCMV infection. Moreover, plasma peptidylprolyl isomerase A levels were significantly higher in patients with neuroimaging abnormalities than in those without. Proteomic analysis of patients with cCMV infection showed that Fms-related receptor tyrosine kinase 4 and peptidylprolyl isomerase A could be novel diagnostic biomarkers for neurological complications of cCMV infection.

Neurodevelopmental outcomes of children with congenital cytomegalovirus: a systematic scoping review.

With the emergence of newborn congenital cytomegalovirus (cCMV) screening programs, more infants are being diagnosed and require long-term follow-up. The objective of the study was to summarize the literature to date on neurodevelopmental outcomes in children with cCMV with attention to study-specific definitions of disease severity (symptomatic vs. asymptomatic). This systematic scoping review included studies of children with cCMV (≤18 years-old) measuring neurodevelopment in ≥1 domain: global, gross motor, fine motor, speech/language, and intellectual/cognitive. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. PubMed, PsychInfo, and Embase databases were searched. 33 studies met inclusion criteria. Global development most frequently measured (n = 21), followed by cognitive/intellectual (n = 16) and speech/language (n = 8). Most (31/33) studies differentiated children by cCMV severity (symptomatic vs. asymptomatic), definitions of which ranged broadly. 15/21 studies described global development categorically (e.g., normal vs. abnormal). Across studies and domains, children with cCMV generally had equivalent or lower scores (vs. controls or normed measures). Variation in definitions of cCMV severity and blunt categorical outcomes may limit the generalizability of findings. Future studies should utilize standardized definitions of disease severity and in-depth measurement and reporting of neurodevelopmental outcomes in children with cCMV. Neurodevelopmental delays are common among children with cCMV, although gaps in the literature to have made quantification of such delays challenging. Variation in definitions of asymptomatic and symptomatic cCMV as well as the use of categorical outcomes of neurodevelopment (e.g., normal vs. abnormal) limits the generalizability and clinical utility of findings.

Neurodevelopmental outcome in children with congenital cytomegalovirus infection: A prospective multicenter cohort study

BackgroundCongenital cytomegalovirus infection (cCMV) is the most common congenital infection worldwide and is a major cause of neurodevelopmental impairment in children. At this point there are insufficient data on neurodevelopmental outcome of children with cCMV, both symptomatic and asymptomatic. AimThis study aimed to describe the neurodevelopmental outcome in a large prospective cohort of children with cCMV. MethodsAll children with cCMV, included in the Flemish cCMV register, were eligible for this study. Data on neurodevelopmental outcome was available in 753 children. Data on neuromotor, cognitive, behavioral, audiological and ophthalmological outcome were analyzed. ResultsNeurodevelopmental outcome was normal in 530/753 (70,4 %) at any age of last follow-up. Mild, moderate and severe neurodevelopmental impairment was found in 128/753 (16,9 %), 56/753 (7,4 %) and 39/753 (5,2 %), respectively. Adverse outcome is found both in the symptomatic and asymptomatic children (53,5 % versus 17,8 %). Autism spectrum disorder (ASD) was diagnosed more often than in the general population in Flanders (2,5 % versus 0,7 %). Speech and language impairment was found in 2 %, even in absence of hearing loss. ConclusionBoth symptomatic and asymptomatic cCMV children are at risk of sequelae, with higher risk in case of first trimester infection. During follow-up of this population, special attention should be given to the audiological follow-up, the presence of hypotonia at young age, the possible higher risk of ASD and the risk of speech and language impairment even in absence of hearing loss. Our results emphasize the need for multidisciplinary neurodevelopmental follow-up of all cCMV infected children.

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.

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.

Early neurodevelopmental outcomes in children with asymptomatic congenital CMV infection

BackgroundApproximately 85–90% of congenital cytomegalovirus infections (cCMV) are asymptomatic. Few studies have investigated early and long-term neurodevelopmental outcomes in children with asymptomatic cCMV (acCMV), and the data is contradictory. In the present study, we did investigate the effect of cCMV asymptomatic infection on neurological outcomes and in cognitive, language and motor development at 6 months of age.MethodsFifty-six children with cCMV asymptomatic infection were followed for 6 months, as part of a long-term surveillance program, examining their neurological and developmental outcomes. Neurological examination and Bayley-III Scales were performed.ResultsClinical evaluation revealed that early neurological outcomes were essentially normal, with minor neurological deficits (i.e., tone abnormalities) in a subgroup of patients. Bayley-III scores were substantially in the normal range, with 14% showing a score less than 85 (-1SD) in the Motor Scale. Children's neurological and neurodevelopmental outcomes at 6 months of age did not differ according to the trimester of infection.ConclusionsSome infants with cCMV asymptomatic infection may present minor neurological abnormalities in early stages of life. It seems useful to monitor this population for early and late neurodevelopmental sequelae.

2126. Disorders of Childhood Development in Congenital Cytomegalovirus

Abstract Background The spectrum of disease in congenital cytomegalovirus (cCMV) is broad. The widespread adoption of Electronic Medical Records (EMRs) at large academic centers suggests that high-throughput informatics approaches would be a reasonable means to extract relevant information to describe long term outcomes in cCMV. Database queries were used to extract records directly from EMR which describe progression of developmental and sensory disorders in cCMV. Methods SlicerDicerTM, a reporting tool in our Epic® EMR, was used to identify patients seen in our cCMV Clinic at Texas Children’s Hospital in Houston, Texas, between years 2008 and 2020, with a diagnosis of congenital cytomegalovirus (CMV) infection. ICD-10 diagnoses and encounters were extracted from our EMR with a series of generalizable Structured Query Language (SQL) queries. Using SAS V9.4 (Cary, N.C.), we parsed this information into relational databases and categorized ICD-10 codes by semantic terms associated with sensory and developmental disabilities guided by SNOMED-CT®. Results Data acquisition took seconds to complete and included over 55,000 unique encounters (Figure 1), 11,000 provider encounters, and 48,000 billing diagnoses. Of 152 patients with an ICD-10 diagnosis of cCMV, 112 were born after 1/1/2008 (when records were reliably found in our EMR). 76/112 (68%) had symptomatic cCMV (ScCMV), 36/112 (32%) had asymptomatic cCMV (AcCMV). 60 (79%) of ScCMV had at least one disorder of development noted in EMR compared with 20 (56%) of AcCMV (ChiSq: p&amp;lt; 0.05). The average age of first diagnosis of a disorder of development was 1.9 +/- 1.6 years (median 1.6 years) (Figure 2). Of the 48,000 billing diagnoses recorded for these children, only 3,751 (8%) pertained to disorders of development, of which “Mixed receptive-expressive language disorder: F80.2” (n=713, 19%) was most frequent (Table 1). Unique Encounters Across our Healthcare System by Department Stacked bar plot of all encounters for patients with cCMV within our EMR, colored by the department in which the encounter occurred. For visualization, we have binned data along the x-axis on the basis of the listed age ranges. Abbreviations: Texas Children’s Hospital (TCH), Texas Children’s Pediatric Associates (TCPA) Whisker Plot of Earliest Age that Deficits in Development are First Noted in cCMV A whisker plot of the age (years) at which ICD-10 codes specific to developmental disorders are first noted in the EMR. The age at which a diagnosis was first noted is the difference in the first occurrence of an ICD-10 code in a chart reported and the patient’s date of birth. The horizontal box plots have been sorted by the ascending mean age at which problems were noted. ICD-10 codes occurring less frequently than in 5% of the sample have been suppressed. Table of the Most Frequent Developmental Disorder ICD-10 Codes Billed for Patients with cCMV List of ICD-10 billing diagnoses pertinent to disorders of development, which were associated with all encounters for children with cCMV across our healthcare system. This cohort comprised 771 person-years of follow up, with a mean of 6.9 years of follow-up per patient. Conclusion Both ScCMV and AcCMV are associated with sensory and developmental disabilities, most of which manifest in the first 2 years of life. EMR gives us the potential to study the many facets of cCMV in finer detail (e.g hearing loss) to identify rates of systems-based disease progression throughout time (Figure 3), and provide help with anticipatory guidance and generate cost-models for the true economic impact of cCMV. Whisker Plot of Earliest Age that Hearing Deficits are Noted for Patients with cCMV A whisker plot of the age (years) at which ICD-10 codes specific to hearing problems are first noted in the EMR. The age at which a diagnosis was first noted is the difference in the first occurrence of an ICD-10 code in a chart reported and the patient’s date of birth. Repeated measures across the cohort have been mitigated by keeping only the first time a code was noted in the patient’s chart. The horizontal box plots have been sorted by the ascending mean age at which problems were noted. Disclosures Ryan H. Rochat, MD, PhD, MS, Merck Sharpe &amp; Dohme: Grant/Research Support 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.

#22 Does Cranial Ultrasound Differentiate Asymptomatic Congenital CMV (cCMV) Infection from cCMV with Central Nervous System Disease in Infants? Results from a Universal Screening Study in Minnesota, USA

Abstract Background Congenital cytomegalovirus (cCMV) is the most common infectious cause of neurodevelopmental deficits, including sensorineural hearing loss (SNHL). With the passage of a universal cCMV screening bill by the Minnesota legislature in 2021, it is imperative to define the optimal diagnostic approach for identified cases, particularly for asymptomatic infants. Cerebral ultrasound (US) is a safe, non-invasive technique to examine neonatal brains, and has been advocated by an international consensus panel as a modality for cCMV disease classification. This analysis described clinical manifestations of cCMV in infants identified by universal screening and characterized cranial US findings obtained during diagnostic evaluation. We correlated viral load in the newborn CMV screening saliva samples with clinical and US findings. Method Newborns were screened for cCMV at six Twin Cities nurseries by PCR of dried blood spots (DBS) obtained for routine newborn screening, and saliva collected 1-2 days after birth. Screen-positive infants had a confirmatory urine PCR test within 3 weeks of birth, and clinical evaluation that included cranial US. Results Through September 1, 2021, 19,017 newborns were screened for cCMV. 76 cases were identified (prevalence of 0.4%) by saliva or DBS, confirmed by urine CMV PCR testing. 76% (58/76) had asymptomatic cCMV; the remaining 24% were infants with cCMV disease. Nine had congenital or delayed-onset SNHL, of which 7 had abnormal US; 1 had normal US, and 1 did not have US performed. Median saliva viral load differed between infants with cCMV disease (3.3×104 IU/ml) and asymptomatic infants (8.6×106 IU/ml; p&amp;lt; 0.05, Fig. 1). Cranial US exams were available for 68 infants (51 asymptomatic, 17 with cCMV disease). 50 (74%) infants had normal US; 18 infants had abnormal US (Table 1). Of the 17 infants with cCMV disease, 12 had abnormal US, of which 4 showed cCMV disease-defining lesions. Of 51 asymptomatic infants, 6 had abnormal, and 45 normal, cranial US. Saliva viral loads did not vary between infants with normal vs. abnormal US (p=0.7). Conclusion PCR of newborn DBS and/or saliva revealed a prevalence of 4.0 per 1000 in a universal cCMV screening study. Surprisingly, an inverse relationship was observed between saliva viral load at birth and cCMV disease classification. Among babies with cCMV, the majority had normal cranial US, and most abnormalities were not pathognomonic for cCMV disease. Clarification is needed regarding which cranial US findings require detailed follow-up, including MRI, as universal cCMV screening programs move forward in clinical practice.

Amniotic fluid biomarkers predict the severity of congenital cytomegalovirus infection.

BACKGROUNDCytomegalovirus (CMV) is the most common intrauterine infection, leading to infant brain damage. Prognostic assessment of CMV-infected fetuses has remained an ongoing challenge in prenatal care, in the absence of established prenatal biomarkers of congenital CMV (cCMV) infection severity. We aimed to identify prognostic biomarkers of cCMV-related fetal brain injury.METHODSWe performed global proteome analysis of mid-gestation amniotic fluid samples, comparing amniotic fluid of fetuses with severe cCMV with that of asymptomatic CMV-infected fetuses. The levels of selected differentially excreted proteins were further determined by specific immunoassays.RESULTSUsing unbiased proteome analysis in a discovery cohort, we identified amniotic fluid proteins related to inflammation and neurological disease pathways, which demonstrated distinct abundance in fetuses with severe cCMV. Amniotic fluid levels of 2 of these proteins — the immunomodulatory proteins retinoic acid receptor responder 2 (chemerin) and galectin-3–binding protein (Gal-3BP) — were highly predictive of the severity of cCMV in an independent validation cohort, differentiating between fetuses with severe (n = 17) and asymptomatic (n = 26) cCMV, with 100%–93.8% positive predictive value, and 92.9%–92.6% negative predictive value (for chemerin and Gal-3BP, respectively). CONCLUSIONAnalysis of chemerin and Gal-3BP levels in mid-gestation amniotic fluids could be used in the clinical setting to profoundly improve the prognostic assessment of CMV-infected fetuses.FUNDINGIsrael Science Foundation (530/18 and IPMP 3432/19); Research Fund – Hadassah Medical Organization.

Vestibular and balance dysfunction in children with congenital CMV: a systematic review

ObjectiveThis systematic review evaluates vestibular and balance dysfunction in children with congenital cytomegalovirus (cCMV), makes recommendations for clinical practice and informs future research priorities.DesignMEDLINE, Embase, EMCARE, BMJ Best Practice, Cochrane...

Long-term ocular and visual outcomes following symptomatic and asymptomatic congenital CMV infection: a systematic review protocol

IntroductionCytomegalovirus (CMV) is one of the most common congenitally acquired infections worldwide. Visual impairment is a common outcome for symptomatic infants, with long-term ophthalmic surveillance often recommended. However, there are...

Congenital Cytomegalovirus

Congenital Cytomegalovirus

Cytomegalovirus infection in a single-centre Australian neonatal cohort.

Congenital cytomegalovirus (cCMV) is the most common infectious cause of congenital malformation, non-genetic sensorineural hearing loss and neurodevelopmental sequelae in childhood. The primary aim of this retrospective cohort study was to identify the birth and neurodevelopmental outcomes of neonates diagnosed with symptomatic and asymptomatic cCMV in a large regional tertiary referral hospital. This was a retrospective cohort study of laboratory-based cCMV diagnoses in neonates born at a single study centre between January 2005 and January 2020. Audit of medical records was undertaken to evaluate maternal characteristics, symptom patterns, radiological and neurodevelopmental outcomes of neonates meeting the laboratory diagnostic criteria during the first 24 months. There were 45 neonates with proven CMV infection and 27 mothers with proven infection with an associated pregnancy outcome. Nineteen neonates were born at term (>37 weeks). Of these, 32 (71.1%) neonates had a significant intercurrent comorbidity and 22 (48.9%) neonates were reported to have a degree of delay in one or more developmental domains. A large proportion (77.3%) of the symptomatic untreated neonates had an unknown history of maternal infection compared to the asymptomatic (10.0%) and symptomatic treated (53.8%) neonates (P= 0.001). Up to half of the neonates with cCMV were at risk of developing a degree of developmental delay at our centre. Whether these outcomes are related primarily to CMV infection or are confounded by the co-existence of prematurity is unclear and needs further evaluation in prospective studies.