Implications of dried blood spot testing for congenital CMV on management of children with hearing loss: A preliminary report.

INTRODUCTION: Non-genetic, congenital sensorineural hearing loss (cSNHL) is commonly caused by congenital CMV infection (cCMV). Hearing loss related to cCMV is variable in degree, often progressive, and can affect one or both ears. OBJECTIVES: We sought to examine the outcomes of DBS testing in California, and the hearing outcomes of cCMV-positive children. METHODS: This is a retrospective study of patients with SNHL of unknown etiology aged 6 months to 17 years old presenting to a tertiary care pediatric center and evaluated for cCMV by DBS testing. RESULTS: 114 children (228 ears) with SNHL of unknown origin were included. 6/114 (5.3%) tested positive for cCMV versus 108/114 (94.7%), who tested negative. None of the cCMV-positive children had symmetric bilateral hearing loss, compared with 56.5% (61/108) of cCMV-negative children (p < 0.05). cCMV-positive children were more likely to have profound SNHL in the worse-hearing ear (5/6 (83%) vs 16/108 (14.9%) of cCMV-negative children, p < 0.001). 86% (5/6) exhibited progressive hearing loss, including progression or new-onset hearing loss in the previously better hearing ear. 3 of the 6 children with cCMV underwent CI. CONCLUSION: A small proportion of patients presenting with SNHL tested positive on DBS. Of cCMV-positive children, most presented with profound hearing loss in the worse-hearing ear, and 50% of cCMV-positive children developed progressive hearing loss in the initially better-hearing ear. Prognostic information afforded by etiologic confirmation of cCMV infection informed decision-making concerning cochlear implantation in these cases.

Recognition, treatment, and sequelae of congenital cytomegalovirus in Australia: An observational study.

BACKGROUND AND OBJECTIVES: Australian national surveillance data was used to assess recognition, sequelae, and antiviral therapy for congenital cytomegalovirus (CMV) cases. STUDY DESIGN: Data from congenital CMV cases reported through the Australian Paediatric Surveillance Unit born January 1999 to December 2016 were described and Chi-square tests used to characterise trends and associations in case reporting, maternal CMV serology testing, and antiviral therapy. Descriptive analyses for hearing loss and developmental delay were reported for cases born ≥2004, following introduction of universal neonatal hearing screening. RESULTS: There were 302 congenital CMV cases (214 symptomatic, 88 asymptomatic). Congenital CMV was suspected in 70.6% by 30 days of age, with no differences across birth cohorts. Maternal CMV serology testing was associated with maternal illness during pregnancy but not birth cohort. There was increasing antiviral use for symptomatic cases, being used in 14% born 1999-2004, 19.6% born 2005-2010, and 44.4% born 2011-2016 (p < 0.001). For those born ≥2004, hearing loss was reported in 42.1% of symptomatic and 26.6% of asymptomatic cases; while developmental delay was reported in 16.9% of symptomatic and 1.3% of asymptomatic cases. CONCLUSION: There appears to be under-reporting and under-recognition of congenital CMV despite increasing use of antiviral therapy. Universal newborn CMV screening should be considered to facilitate follow-up of affected children and targeted linkage into hearing and developmental services, and to provide population-level infant CMV epidemiology to support research and evaluation of antiviral and adjunctive therapies.

Outcomes of cochlear implantations for mumps deafness: A report of four pediatric cases.

Mumps virus occasionally causes bilateral hearing loss. We report 4 cases of bilateral mumps deafness in whom cochlear implantations (CI) were performed. The age at the onset of hearing loss was 1-9 years. CI surgery was performed within 6 months from the onset of hearing loss in 3 cases and after 9 years in the other case, showing good speech perception in the early intervention cases and a poor outcome after later implantation. Early CI surgery is highly recommended in sudden onset deafness by mumps in childhood.

Neonates with congenital Cytomegalovirus and hearing loss identified via the universal newborn hearing screening program.

BACKGROUND: Congenital cytomegalovirus (CMV) is the most common non-genetic cause of sensorineural hearing loss. Currently, there are no universal CMV screening programs for newborns or routine CMV testing of neonates with hearing loss in Australia, or elsewhere. OBJECTIVES: This study was undertaken to determine the prevalence of congenital CMV infection in infants with hearing loss identified using routine resources via the Australian universal neonatal hearing screening (UNHS) program. STUDY DESIGN: Infants who failed UNHS, referred for audiological testing and found to have permanent hearing loss were screened for CMV via PCR of urine and saliva. Congenital CMV was diagnosed if CMV was detected in infants ≤30 days of age, or using retrospective testing on stored new born screening cards, retrospective testing, or using clinical criteria if >30 days of age. The cohort was analyzed for time of testing and prevalence of congenital CMV determined. RESULTS: The Audiology Department reviewed 1669 infants who failed UNHS between 2009 and 2016. Thirty percent (502/1669) had permanent hearing loss confirmed, of whom 336/502 were offered CMV testing. A definite (n = 11) or probable (n = 8) diagnosis of congenital CMV occurred in 19/323 (5.9%), of whom definite diagnoses were made in 4/19 on tests positive prior to 21 days of life, in 5/19 who were positive on neonatal blood screening card (NBSC) testing, in 2/19 who were positive on placental testing. In 8/19 probable diagnoses were made based on positive testing between ages 23-42 days and a consistent clinical syndrome in the absence of another cause for hearing loss after genetic and other testing. CMV testing mirrored the timing of audiological testing, with ∼40% completing audiology and CMV testing by 21 days, and 64% by 30 days. CONCLUSION: This program, utilizing existing clinical services identified probable congenital CMV in ∼6% of a large cohort failing UNHS with permanent hearing loss, of whom more than half were definite diagnoses. No additional assets were required to those already existing in this tertiary referral pediatric centre, whilst providing useful and timely data for clinical and audiological management.

Management and outcomes of cochlear implantation in patients with congenital cytomegalovirus (cCMV)-related deafness.

OBJECTIVE: Congenital Cytomegalovirus (cCMV) is a well-defined cause for neonatal mortality and morbidity, particularly sensorineural hearing loss and other neurodevelopmental disruption. We present a retrospective study which provides an overview of the assessment and preoperative work-up for patients diagnosed with cCMV and their cochlear implant (CI) outcomes. METHOD: This was a retrospective case series study of all children with a confirmed diagnosis of cCMV who underwent cochlear implantation at St Thomas' Hospital from 2003 to 2015. Data were collected on the preoperative audiology, imaging findings, and neurological assessment. CI outcomes were measured using the Speech Intelligibility Rating (SIR), Category of Auditory Performance (CAP), and Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS). RESULTS: Eleven patients underwent cochlear implantation, 45% had severe-to-profound hearing loss, and 55% had bilateral profound hearing loss. The mean age at initial assessment was 2.1 years (median 1.7, range 0.6-7.5) and the mean age of implantation was 4.0 years (median 2.5, range 0.9-11.8). The mean length of follow-up was 4.8 years (median 2.3, range 1.5-14). Six patients had bilateral simultaneous implantation (55%), four bilateral sequential (36%), and one unilateral (9%). Nine patients had white matter changes on magnetic resonance imaging, largely in the periventricular and cortical regions. Of the 11 patients, 4 (36%) had associated neurological comorbidities and 3 (27%) had additional neurocognitive developmental delay of varying severity. The majority of patients showed improvement in auditory outcomes. No statistically significant correlation was found between age of implantation, neurocognitive, and neurological comorbidities or length of follow-up and hearing outcomes. CONCLUSION: While the overall outcomes were mixed, most children in our cohort were found to benefit from cochlear implantation. Our data also highlight the significant neurodevelopmental comorbidities associated with cCMV and their negative impact on CI outcomes. With the recent advances in medical treatment, this underlines the importance of multidisciplinary management of these patients.

Hearing Loss in Children With Asymptomatic Congenital Cytomegalovirus Infection.

OBJECTIVES: To assess the prevalence, characteristics, and risk of sensorineural hearing loss (SNHL) in children with congenital cytomegalovirus infection identified through hospital-based newborn screening who were asymptomatic at birth compared with uninfected children. METHODS: We included 92 case-patients and 51 controls assessed by using auditory brainstem response and behavioral audiometry. We used Kaplan-Meier survival analysis to estimate the prevalence of SNHL, defined as ≥25 dB hearing level at any frequency and Cox proportional hazards regression analyses to compare SNHL risk between groups. RESULTS: At age 18 years, SNHL prevalence was 25% (95% confidence interval [CI]: 17%-36%) among case-patients and 8% (95% CI: 3%-22%) in controls (hazard ratio [HR]: 4.0; 95% CI: 1.2-14.5; P = .02). Among children without SNHL by age 5 years, the risk of delayed-onset SNHL was not significantly greater for case-patients than for controls (HR: 1.6; 95% CI: 0.4-6.1; P = .5). Among case-patients, the risk of delayed-onset SNHL was significantly greater among those with unilateral congenital/early-onset hearing loss than those without (HR: 6.9; 95% CI: 2.5-19.1; P < .01). The prevalence of severe to profound bilateral SNHL among case-patients was 2% (95% CI: 1%-9%). CONCLUSIONS: Delayed-onset and progression of SNHL among children with asymptomatic congenital cytomegalovirus infection continued to occur throughout adolescence. However, the risk of developing SNHL after age 5 years among case-patients was not different than in uninfected children. Overall, 2% of case-patients developed SNHL that was severe enough for them to be candidates for cochlear implantation.

Cytomegalovirus DNA detection in dried blood spots and perilymphatic fluids from pediatric and adult cochlear implant recipients with prelingual deafness.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is the leading cause of non-genetic congenital hearing loss. The contribution of congenital CMV to prelingual deafness and the pathophysiology is largely unknown. OBJECTIVE: (1) To analyze the prevalence of congenital CMV among cochlear implant (CI) recipients with prelingual deafness. (2) To genotype CMV present in dried blood spots (DBS) and in the inner ear years after birth. STUDY DESIGN: Children and adults with prelingual deafness who received a CI in 2010-2011 were included prospectively. Perilymphatic fluids were collected during CI surgery and, in the pediatric cases, DBS were retrieved for CMV DNA detection. Furthermore, a cohort of children with prelingual deafness who received a CI between 2003 and 2008 were included retrospectively. CMV detection in DBS and perilymph was followed by gB and gH genotyping. RESULTS: Seventysix pediatric CI recipients were included. Seventy DBS were tested for CMV DNA, resulting in a prevalence of congenital CMV of 14% (10/70). Perilymphatic fluid was available from 29 pediatric CI recipients. One perilymph fluid, of a 21-month old girl with congenital CMV, asymptomatic at birth, was CMV DNA positive. The CMV strain in the perilymph was genotypically identical to the strain present in her DBS (gB1/gH2). Perilymph samples from 21 adult CI recipients were CMV DNA negative. CONCLUSIONS: Our study stresses the important contribution of congenital CMV among pediatric CI recipients. Furthermore, our genotyping data support the hypothesis that CMV-related hearing loss is associated with ongoing viral replication in the inner ear up to years after birth.

Long-term follow-up of implanted children with cytomegalovirus-related deafness.

OBJECTIVE: To evaluate, with a long-term follow-up, the speech perception and language development in children with cytomegalovirus (CMV)-related deafness after cochlear implantation. STUDY DESIGN: A retrospective study on CMV-related profound deafness and cochlear implantation was performed from 1995 to 2010. Six children with an average follow-up of 10 years were included in this research. Medical history, imaging, cognitive delay, speech perception and production data were reviewed. RESULTS: Two of the 6 patients developed a functional language with the use of phrases and word sequences based on morphological and syntactic rules; the others demonstrated the development of a preverbal or transitional language with the use of single words only. CONCLUSION: Patients with CMV-related deafness benefit from cochlear implantation; however, the expectations of the parents must be evaluated in a series of counseling efforts prior to the surgery.

Clinical profile of hearing loss in children with congenital cytomegalovirus (CMV) infection: CMV DNA diagnosis using preserved umbilical cord.

CONCLUSIONS: Congenital cytomegalovirus (CMV) infection is a major cause of bilateral and unilateral sensorineural hearing loss (SNHL) in children, accounting for 9.0% of SNHL cases. The diagnostic rate using combined genetic deafness test and CMV DNA detection test was determined to be 46.4% in bilateral profound SNHL. OBJECTIVES: The present study investigated the prevalence of congenital CMV infection diagnosed retrospectively by detection of CMV DNA in dried umbilical cord specimens from children with unilateral or bilateral SNHL up to the age of 12 years. METHODS: Preserved dried umbilical cords were collected from 134 children with bilateral (46 children) or unilateral (88 children) SNHL. DNA was extracted from the dried umbilical cords and CMV DNA was detected by quantitative PCR. Genetic deafness tests based on the invader assay were performed in children with bilateral SNHL. RESULTS: CMV DNA from the dried umbilical cords was detected in 8.7% of the bilateral SNHL and 9.1% of unilateral SNHL. Deafness gene mutations were identified in 21.7% (10/46) of children with bilateral SNHL.

Cytomegalovirus DNA retrieval in the inner ear fluids of a congenitally deaf child one month after primary infection: a case report.

In the present article we report cytomegalovirus (CMV) DNA localization in the inner ear of a 15-month-old deaf boy 1 month after a virologically documented primary infection. CMV DNA retrieval was possible thanks to polymerase chain reaction analysis of the perilymph collected at cochlear implant surgery. To the authors' knowledge this is the first demonstration of CMV persistence in the cochlea of an immunocompetent subject after an acquired infection.

Implementing neonatal screening for congenital cytomegalovirus: addressing the deafness of policy makers.

Congenital cytomegalovirus (CMV) infection is an important public health problem with approximately 7 in 1,000 newborns infected and consequently at risk for hearing impairment. Newborn hearing screening will fail to detect this hearing impairment in approximately half of the cases because late onset hearing loss is frequent. Hearing impairment has profound impact on cognitive and social development of children and their families, determining most of the disease burden of congenital CMV infection. The potential value of newborn screening for congenital CMV is increasingly discussed. To date, many experts acknowledge the benefit of antiviral treatment in the prevention of hearing deterioration in newborns with neurological symptoms, and the benefit of early identification of late-onset hearing impairment by means of extensive audiological follow up of infected infants. These opinions imply that the potential of newborn screening for CMV would lie in the identification of the large proportion of asymptomatic congenitally infected newborns at risk for developing late-onset hearing loss. Experience with postnatal antiviral treatment of symptomatic newborns is encouraging, but has not been studied in asymptomatic congenitally infected newborns. A large-scale study on the safety and effectiveness of combined screening and antiviral therapy for congenital CMV infection is the necessary next step to take and should not be delayed.

Multiple viral genome search in endolabyrinthic fluids of profoundly deaf patients: possible cytomegalovirus intracochlear reactivation.

BACKGROUND: The cause of about 30% of bilateral sensorineural hearing loss (SNHL) is still unknown. A viral etiology is among the most frequently proposed ones and the supposed diagnosis is only based upon few clinical and laboratory data. The detection of viral presence within a damaged compartment may represent a way to supply interesting data for confirmation of viral etiology and to explain pathogenic mechanisms. OBJECTIVES: The aim of our study was to identify the possible presence of pathogenic viruses in the inner ear extracellular compartment in patients with bilateral severe sensorineural deafness of unknown etiology who underwent cochlear implant surgery. METHODS: 4 patients, aged from 2 to 7 years and affected by SNHL underwent cochlear implantation surgery and, at the same time, endolabyrinthine fluid sampling. The samples were subsequently sent for viral nucleic acid extraction and polymerase chain reaction (PCR) treatment: multiplex PCR and realtime-PCR were used. In each endolabyrinthine fluid sample, cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus type 1 and 2 (HSV-1, HSV-2) and enterovirus genomes were searched for. RESULTS: One patient was positive for intracochlear CMV, as confirmed by another base-pair segment PCR. EBV, VZV, HSV and enterovirus were detected in none of the 4 patients. CONCLUSIONS: Our finding of CMV genome within the cochlea of a deaf patient without any evidence of acute and prenatal CMV infection suggests its possible role in postnatal inner ear injury through reactivation of latent virus within the cochlea. This hypothesis could also be considered valid for some patients with anti-CMV-IgG-positive serology and absence of endolabyrinthine viral genome since viruses can be in an inactive state at the time of fluid collection. PCR has proved to be a very useful tool in order to investigate infectious causes of deafness even for more than one virus type at a time and in a limited quantity of sample, such as the small volume of endolabyrinthine liquid collected from children during cochlear implant surgery.

A 41-year-old HIV-positive man with acute onset of quadriplegia after West Nile virus infection.

Most cases of West Nile encephalitis virus (WNV) infection are asymptomatic. In cases where WNV is symptomatic, patients usually experience high fever of sudden onset, myalgia, headache, and gastrointestinal symptoms, accompanied by a macular erythematous rash in a quarter to half of cases. More severe infections manifest as a poliomyelitis. Immunocompromise and immune senescence confer an increased risk of severe central nervous system (CNS) infection. Patients with human immunodeficiency virus (HIV) infection are therefore more susceptible, but, because the symptoms of WNV infection may be attributed to other CNS syndromes common in HIV patients, it is likely that the presence of WNV infection is underdiagnosed and underreported. We present a patient with severe WNV infection who was found to be HIV positive, who also suffered hearing loss. Several key differences in the presentation of WNV infection and Guillain-Barré syndrome that have treatment implications are discussed.

Macrophage inflammatory proteins in cytomegalovirus-related inner ear injury.

OBJECTIVE: Inner ear inflammation triggered by CMV infection may play a role in CMV-related auditory pathogenesis. The purpose of the study was to determine if a virally encoded macrophage inflammatory protein played a role in CMV-related hearing loss. DESIGN: Mutagenesis was performed with deletion of a guinea pig CMV macrophage inflammatory protein. Intracochlear inoculations were performed on three groups of animals (n = 18). Group 1 received sterile viral media, Group 2 received wild-type CMV virus, and Group 3 received "knockout" (KO) virus with a deleted immunomodulation gene. Baseline and postinoculation ABRs were obtained. ELISA and PCR were performed and temporal bones examined. SUBJECTS: Eighteen guinea pigs. RESULTS: The KO group had significantly better hearing than the WT group. There were no significant differences between the KO and sham groups. The WT group had significant hearing loss at all frequencies. Inflammation and fibrosis were noted in the WT temporal bones only. CONCLUSIONS: Virally encoded macrophage inflammatory proteins appear to play a significant role in CMV-related hearing loss.

Epidemiological study of mumps deafness in Japan.

In Japan, mumps vaccination is optional and the mumps were increased accompanied with prevalent waves according to the Infections Agents Surveillance Report (IASR). The aim of this study was to clarify that there was relevance for increase of mumps epidemic and mumps deafness. The Acute Profound Deafness Research Committee of the Japanese Ministry of Health and Welfare (reorganized to the Ministry of Health, Labour and Welfare in 2001) conducted a nationwide epidemiological survey to determine the number of patients treated for mumps deafness in 1987, 1993 and 2001. Based on its findings, the annual numbers of mumps deafness cases was estimated to be 300 in 1987, 400 in 1993 and 650 in 2001, which correlated with the overall incidence of mumps in those years. Because the majority of cases exhibited severe or profound sensorineural hearing loss that usually did not recover, rapid improvement of mumps vaccine coverage is strongly recommended.

Cochlear implantation in children deafened by cytomegalovirus: speech perception and speech intelligibility outcomes.

BACKGROUND: Concerns have been expressed with regard to suitability for cochlear implantation of children deafened by cytomegalovirus because of possible coexisting central disorders/learning difficulties. The aim of the current study was to assess speech perception and intelligibility of speech produced by children deafened by cytomegalovirus and compare their progress with that of congenitally deaf children after cochlear implantation. METHODS: The study assessed 16 implanted children who were deafened by cytomegalovirus, using the Iowa Closed Sentence Test and Speech Intelligibility Rating. The results were compared with those of a group of 131 children who had undergone implantation who were congenitally deaf but did not have cytomegalovirus as the cause of deafness. The mean age at implantation was 3.9 years for the cytomegalovirus group (median, 3.5 years) and 4.1 years (median, 4 years) for the congenitally deaf children. They all received the Nucleus multichannel cochlear implant system. The follow-up period ranged from 1 to 5 years after implantation for both groups. RESULTS: After cochlear implantation, the intelligibility of speech produced by children deafened by cytomegalovirus had a wide range, varying from unintelligible speech to connected speech intelligible to all listeners. Relative to the median score for the control group at the last evaluation interval, 3 of the 16 children with cytomegalovirus (19%) performed better, 8 children (50%) performed more poorly, and 5 (31%) performed the same. The difference between the two groups was not statistically significant (p > 0.05). With regard to speech perception Iowa Sentence Test (Level B), relative to the median score for the control group at the last evaluation interval, 5 of the 16 children with cytomegalovirus (31%) performed better, 3 children (19%) performed more poorly, and 8 (50%) performed the same. The difference between the two groups was not statistically significant (p > 0.05). With regard to Level A and relative to the median score for the control group at the last evaluation interval, 1 of the 16 children with cytomegalovirus (6%) performed better, 6 children (38%) performed more poorly, and 9 (56%) performed the same. The difference between the two groups was statistically significant (p = 0.04). CONCLUSION: The results of the current study showed that cytomegalovirus alone, as a cause of deafness, is not a contraindication for cochlear implantation. Parents should be informed about the wide range of linguistic outcomes after implantation and that these children may need more specific or intensive rehabilitation. Although additional problems are common and outcomes may, on average, be poorer, cochlear implantation can provide useful auditory input to these children. Further research is needed to identify factors associated with cytomegalovirus that may influence the outcomes.