Late-onset Hearing Loss From Congenital Cytomegalovirus Infection After Newborn Period in a Highly Immune Population in China.
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SUBMITTER: Wang C
PROVIDER: S-EPMC8383185 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Congenital cytomegalovirus (cCMV) is a common congenital infection and a leading nongenetic cause of sensorineural hearing loss (SNHL). CMV exhibits extensive genetic variability, and infection with multiple CMV strains (mixed infection) was shown to be common in congenital CMV. The role of mixed infections in disease and outcome remains to be defined. METHODS:Genotyping of envelope glycoproteins, UL55 (gB), UL73 (gN) and UL75 (gH), was performed on saliva specimens of 79 infants from the ongoing CMV and Hearing Multicenter Screening (CHIMES) Study and on blood and urine specimens of 52 infants who participated in natural history studies at the University of Alabama at Birmingham. Genotyping of UL144 and US28 was also performed in the CHIMES cohort. The association of individual genotypes and mixed infection with clinical findings at birth and SNHL was examined. RESULTS:Thirty-seven of 131 infants (28%) were symptomatic at birth and 26 (20%) had SNHL at birth. All known genotypes of UL55, UL75, UL73 and US28 were represented, and no particular genotype was associated with symptomatic infection or SNHL. UL144 subtype C was more common in symptomatic infants but not associated with SNHL. Mixed infection was observed in 59 infants (45%) and not associated with symptoms (P = 0.43) or SNHL at birth (P = 0.82). In the cohort of 52 infants with long-term hearing outcome, mixed infection at birth was not predictive of SNHL. CONCLUSIONS:Mixed infection is common in infants with congenital CMV but is neither associated with symptomatic infection nor associated with SNHL.
| S-EPMC3785554 | biostudies-literature
Project description:Cytomegalovirus (CMV) is the most common viral agent of congenital infections and a leading nongenetic cause of sensorineural hearing loss (SNHL). The host immunologic factors that render a developing foetus prone to intrauterine CMV infection and development of hearing loss are unknown. The aim of this study was to assess the potential associations between the polymorphisms within cytokine and cytokine receptors genes, and the risk of congenital CMV infection, and the hearing outcome. A panel of 11 candidate single nucleotide polymorphisms (SNPs): TNF rs1799964, TNF rs1800629, TNFRSF1A rs4149570, IL1B rs16944, IL1B rs1143634, IL10 rs1800896, IL10RA rs4252279, IL12B rs3212227, CCL2 rs1024611, CCL2 rs13900, CCR5 rs333 was genotyped in 470 infants (72 with confirmed intrauterine CMV infection and 398 uninfected controls), and related to congenital CMV infection, and the outcome. In multivariate analysis, the IL1B rs16944 TT and TNF rs1799964 TC genotypes were significantly associated with intrauterine CMV infection (aOR = 2.32; 95% CI, 1.11-4.89; p = 0.032, and aOR = 2.17, 95% CI, 1.25-3.77; p = 0.007, respectively). Twenty-two out of 72 congenitally infected newborns had confirmed SNHL. Carriers of CT or TT genotype of CCL2 rs13900 had increased risk of hearing loss at birth and at 6 months of age (aOR = 3.59; p = 0.028 and aOR = 4.10; p = 0.039, respectively). This is the first study to report an association between SNPs in IL1B, TNF, and CCL2, and susceptibility to congenital CMV infection (IL1B and TNF) and SNHL (CCL2).
| S-EPMC5602083 | biostudies-literature
Project description:ObjectiveTo describe the progression of sensorineural hearing loss (SNHL) in the better- and poorer-hearing ears in children with asymptomatic congenital cytomegalovirus (CMV) infection with isolated SNHL.Study designLongitudinal prospective cohort study.SettingTertiary medical center.Subjects and methodsWe analyzed hearing thresholds of the better- and poorer-hearing ears of 16 CMV-infected patients with isolated congenital/early-onset or delayed-onset SNHL identified through hospital-based CMV screening of >30,000 newborns from 1982 to 1992.ResultsBy 12 months of age, 4 of 7 patients with congenital/early-onset SNHL developed worsening thresholds in the poorer-hearing ear, and 1 had an improvement in the better-hearing ear. By 18 years of age, all 7 patients had worsening thresholds in the poorer-hearing ear and 3 patients had worsening thresholds in the better-hearing ear. Hearing loss first worsened at a mean age of 2 and 6 years in the poorer- and better-hearing ears, respectively. Nine patients were diagnosed with delayed-onset SNHL (mean age of 9 years vs 12 years for the poorer- and better-hearing ears), 6 of whom had worsening thresholds in the poorer-hearing ear and 1 in both ears.ConclusionIn most children with congenital CMV infection and isolated SNHL, the poorer-hearing ear worsened earlier and more precipitously than the better-hearing ear. This study suggests that monitoring individual hearing thresholds in both ears is important for appropriate interventions and future evaluation of efficacy of antiviral treatment.
| S-EPMC7274837 | biostudies-literature
Project description:BACKGROUND:This study was designed to determine whether elevated viral load in infants and young children is associated with congenital cytomegalovirus (CMV)-related hearing loss. METHODS:Blood samples were obtained from 135 children with congenital CMV infection. CMV DNA in the peripheral blood was quantitated with a real-time polymerase chain reaction assay. Viral load measurements were analyzed in 3 different age groups (<2 months, 2-12 months, 12-36 months). RESULTS:In children with symptomatic and asymptomatic infection, CMV DNA levels were not different between children with hearing deficit and those with normal hearing in all 3 age groups. In children with asymptomatic infection, the positive predictive value of a peripheral blood viral load >3500 genomic equivalents per milliliter (ge/mL) at <2 months and 2 to 12 months of age is 8%, and at 12 to 36 months of age is 11.8%. However, the negative predictive value of a viral load <3500 ge/mL is 94.4% at <2 months of age, and 100% at 2 to 36 months of age. CONCLUSIONS:Peripheral blood viral load is not associated with hearing loss in children with congenital CMV infection. However, a viral load of <3500 ge/mL is associated with a lower risk of hearing loss in children born with asymptomatic congenital infection.
| S-EPMC3033214 | biostudies-literature
Project description:Cytomegalovirus is the most common pathogen causing congenital infection and can result in significant neurodevelopmental adverse outcomes. For this reason, it is the standard of care in many regions to treat congenital cytomegalovirus infection involving the brain with six weeks of ganciclovir. There have been no reports in the published literature of significant cytomegalovirus neonatal infection in infants previously treated for congenital infection.A preterm male infant with congenital symptomatic cytomegalovirus infection was initially treated with over 8 weeks of ganciclovir between the ages of 3 and 14 weeks. At four months chronologic age, just prior to planned discharge, he developed an episode of life-threatening multisystem cytomegalovirus disease notable for severe pneumonitis, encephalitis, hepatitis, and disseminated intravascular coagulation. This disease resolved after re-treatment with a prolonged course of intravenous ganciclovir and oral valganciclovir.Clinicians should be aware of the possibility of recurrence of congenital cytomegalovirus infection, especially in preterm infants. Serial plasma cytomegalovirus viral load monitoring may have a role in the management of premature infants treated with ganciclovir; had the diagnosis of recrudescent cytomegalovirus infection been considered sooner, specific therapy might have been more quickly initiated and perhaps further morbidity would have been prevented.
| S-EPMC3847698 | biostudies-literature
Project description:Connexin26 (Cx26, GJB2) mutations account for >50% of nonsyndromic hearing loss. The deafness is not always congenital. A large group of these patients (∼30%) demonstrate a late-onset hearing loss, starting in childhood. They have normal hearing early in life and are therefore good candidates for applying protective and therapeutic interventions. However, the underlying deafness mechanism is unclear. In this study, we used a time-controlled, inducible gene knockout technique to knockout Cx26 expression in the cochlea after birth. We found that deletion of Cx26 after postnatal day 5 (P5) in mice could lead to late-onset hearing loss. Similar to clinical observations, the mice demonstrated progressive, mild to moderate hearing loss. The hearing loss initiated at high frequencies and then extended to the middle- and low-frequency range. The cochlea showed normal development and had no apparent hair cell loss. However, distortion product otoacoustic emission (DPOAE) was reduced. The reduction was also progressive and large at high-frequencies. Consistent with DPOAE reduction, we found that outer hair cell electromotility-associated nonlinear capacitance was shifted to the right and the slope of voltage dependence was reduced. The endocochlear potential was reduced in Cx26 conditional knockout (cKO) mice but the reduction was not associated with progressive hearing loss. These data suggest that Cx26 deficiency may impair active cochlear amplification leading to late-onset hearing loss. Our study also helps develop newer protective and therapeutic interventions to this common nonsyndromic hearing loss.
| S-EPMC4268423 | biostudies-literature
Project description:Diaphanous-related formin 1 (DIAPH1) is a formin homology F-actin elongating protein encoded by DIAPH1. Homozygous recessive variants resulting in the loss of DIAPH1 function cause seizures, cortical blindness, and microcephaly syndrome (SCBMS), but hearing loss has not been reported. In contrast, dominant variants of human DIAPH1 are associated with DFNA1 non-syndromic sensorineural hearing loss. The deafness phenotype is due partly to abnormal F-actin elongation activity caused by disruption of the DIAPH1 autoinhibitory mechanism. We report an elderly female heterozygous for the c.3145C>T: p.R1049X variant who showed late-onset sensorineural hearing loss in her fifth decade. p.R1049X lacks F-actin elongation activity because this variant truncates one-third of the FH2 domain, which is vital for DIAPH1 dimerization and processive F-actin elongation activity. Concordantly, no increase of F-actin or processive F-actin elongation activity was observed after overexpression of p.R1049X DIAPH1 in HeLa cells or by single-molecule microscopy using Xenopus XTC cells. However, overexpression of the p.R1049X variant impairs formation of cell-cell junctions and mitosis. We speculate that late-onset hearing loss is a long-term consequence of heterozygosity for the recessive p.R1049X variant, a phenotype that may have been overlooked among carriers of other recessive alleles of DIAPH1.
| S-EPMC8981108 | biostudies-literature
Project description:Importance: Congenital cytomegalovirus infection (cCMVi) is one of the most common infections associated with childhood hearing loss. Prevention and mitigation of cCMVi-related hearing loss will require an increase in newborn screening, which is not yet available in China.Objective: To estimate the cost-effectiveness of newborn screening strategies for cCMVi from the perspective of the Chinese health care system.Design, setting, and participants: A decision tree for a simulated cohort population of 15?000?000 live births was developed to compare the costs and health effects of 3 mutually exclusive interventions: (1) no screening, (2) targeted screening using CMV polymerase chain reaction assay for newborns who fail a universal hearing screening, and (3) universal screening for CMV among all newborns. Markov diagrams were used to evaluate the lifetime horizon (76 years).Main outcomes and measures: Cost, hearing-related health outcomes, and incremental cost-effectiveness ratios (ICERs) were estimated based on a direct medical costs perspective. Costs and ICERs were reported in 2018 US dollars.Results: Incidence of cCMVi among newborns was reported to be approximately 0.7% in China. Targeted screening was less costly but also less effective than universal screening, identifying 41% of cases needing antiviral treatment and preventing nearly half of less severe or profound hearing loss. To avoid 1 CMV-related severe or profound hearing loss, 13 and 16 newborns need to be treated by targeted and universal screening, respectively. The ICERs of targeted and universal screening vs no screening were $79 and $2087 per quality-adjusted life-year gained, respectively, at the discounted rate of 3.5%. Both screening options were cost-effective for the Chinese health care system based on the willingness-to-pay threshold of 3?×?gross domestic product per capita. The sensitivity analysis showed that the prevalence of cCMVi, as well as diagnosis and treatment costs, were key factors that may be associated with decision-making.Conclusions and relevance: To achieve cost-effectiveness and best health outcomes, universal screening could be considered for the Chinese population. While the results are specific to China, the model may easily be adapted for other countries.
| S-EPMC7718603 | biostudies-literature
Project description:Congenital hearing loss is a common chronic condition affecting children in both developed and developing nations. In many cases, congenital hearing loss is ultimately attributed to viral infection, most often by cytomegalovirus (CMV), but also in Congenital Zika Syndrome (CZS). The mechanisms by which CMV and ZIKV virus cause these cranial developmental defects have not been elucidated. Inner ear development has been particularly difficult to study, given the inaccessibility and scarcity of the tissue in animal models or on human autopsy; however, it is now possible to culture stem-cell derived otic progenitor cells (OPCs). Here we describe successful in-vitro infection of OPCs with either CMV or ZIKV. We find that ZIKV infection rapidly and strongly induces the expression of type I IFN and inflammatory genes, while simultaneously decreasing otic cell viability in culture that is at least in part attributable to apoptosis. In contrast, CMV infection did not appear to elicit either of these effects and instead demonstrated a clear dysregulation of the expression of many key genes and pathways associated with inner ear development and function, including Cochlin, NGFR, SOX11 and TGF-β signaling. These findings suggest that ZIKV and CMV infections cause congenital hearing loss through very different pathways; that is, by killing progenitor cells in the case of ZIKV infection, and via disruption of critical developmental pathways in the case of CMV infection. In addition to demonstrating differential hCMV and ZIKV pathogenesis mechanisms in OPCs, this study highlights the advantages of otic progenitor cell models for the study of congenital hearing loss induced by viral infection.
2024-01-18 | GSE234062 | GEO
Project description:Objectives To compare hearing trajectories among children with symptomatic and asymptomatic congenital cytomegalovirus infection through age 18 years and to identify brain abnormalities associated with sensorineural hearing loss (SNHL) in asymptomatic case patients. Study Design Longitudinal prospective cohort study. Setting Tertiary medical center. Subjects and Methods The study included 96 case patients (4 symptomatic and 92 asymptomatic) identified through hospital-based newborn cytomegalovirus screening from 1982 to 1992 and 72 symptomatic case patients identified through referrals from 1993 to 2005. We used growth curve modeling to analyze hearing thresholds (0.5-8 kHz) by ear with increasing age and Cox regression to determine abnormal findings on head computed tomography scan associated with SNHL (hearing threshold ?25 dB in any audiometric frequency) among asymptomatic case patients. Results Fifty-six (74%) symptomatic and 20 (22%) asymptomatic case patients had SNHL: congenital/early-onset SNHL was diagnosed in 78 (51%) and 10 (5%) ears, respectively, and delayed-onset SNHL in 25 (17%) and 20 (11%) ears; 49 (32%) and 154 (84%) ears had normal hearing. In affected ears, all frequency-specific hearing thresholds worsened with age. Congenital/early-onset SNHL was significantly worse (severe-profound range, >70 dB) than delayed-onset SNHL (mild-moderate range, 26-55 db). Frequency-specific hearing thresholds were significantly different between symptomatic and asymptomatic case patients at 0.5 to 1 kHz but not at higher frequencies (2-8 kHz). Among asymptomatic case patients, white matter lucency was significantly associated with SNHL by age 5 years (hazard ratio, 4.4; 95% CI, 1.3-15.6). Conclusion Congenital/early-onset SNHL frequently resulted in severe to profound loss in symptomatic and asymptomatic case patients. White matter lucency in asymptomatic case patients was significantly associated with SNHL by age 5 years.
| S-EPMC5880689 | biostudies-other