Valganciclovir for symptomatic congenital cytomegalovirus disease.

BACKGROUND: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. METHODS: We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. RESULTS: A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). CONCLUSIONS: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).

Tympanostomy tubes and developmental outcomes at 9 to 11 years of age.

BACKGROUND: Developmental impairments in children have been attributed to persistent middle-ear effusion in their early years of life. Previously, we reported that among children younger than 3 years of age with persistent middle-ear effusion, prompt as compared with delayed insertion of tympanostomy tubes did not result in improved cognitive, language, speech, or psychosocial development at 3, 4, or 6 years of age. However, other important components of development could not be assessed until the children were older. METHODS: We enrolled 6350 infants soon after birth and evaluated them regularly for middle-ear effusion. Before 3 years of age, 429 children with persistent effusion were randomly assigned to undergo the insertion of tympanostomy tubes either promptly or up to 9 months later if effusion persisted. We assessed literacy, attention, social skills, and academic achievement in 391 of these children at 9 to 11 years of age. RESULTS: Mean (+/-SD) scores on 48 developmental measures in the group of children who were assigned to undergo early insertion of tympanostomy tubes did not differ significantly from the scores in the group that was assigned to undergo delayed insertion. These measures included the Passage Comprehension subtest of the Woodcock Reading Mastery Tests (mean score, 98+/-12 in the early-treatment group and 99+/-12 in the delayed-treatment group); the Spelling, Writing Samples, and Calculation subtests of the Woodcock-Johnson III Tests of Achievement (96+/-13 and 97+/-16; 104+/-14 and 105+/-15; and 99+/-13 and 99+/-13, respectively); and inattention ratings on visual and auditory continuous performance tests. CONCLUSIONS: In otherwise healthy young children who have persistent middle-ear effusion, as defined in our study, prompt insertion of tympanostomy tubes does not improve developmental outcomes up to 9 to 11 years of age. (ClinicalTrials.gov number, NCT00365092 [ClinicalTrials.gov].).

Developmental outcomes after early or delayed insertion of tympanostomy tubes.

BACKGROUND: To prevent later developmental impairments, myringotomy with the insertion of tympanostomy tubes has often been undertaken in young children who have persistent otitis media with effusion. We previously reported that prompt as compared with delayed insertion of tympanostomy tubes in children with persistent effusion who were younger than three years of age did not result in improved developmental outcomes at three or four years of age. However, the effect on the outcomes of school-age children is unknown. METHODS: We enrolled 6350 healthy infants younger than 62 days of age and evaluated them regularly for middle-ear effusion. Before three years of age, 429 children with persistent middle-ear effusion were randomly assigned to have tympanostomy tubes inserted either promptly or up to nine months later if effusion persisted. We assessed developmental outcomes in 395 of these children at six years of age. RESULTS: At six years of age, 85 percent of children in the early-treatment group and 41 percent in the delayed-treatment group had received tympanostomy tubes. There were no significant differences in mean (+/-SD) scores favoring early versus delayed treatment on any of 30 measures, including the Wechsler Full-Scale Intelligence Quotient (98+/-13 vs. 98+/-14); Number of Different Words test, a measure of word diversity (183+/-36 vs. 175+/-36); Percentage of Consonants Correct-Revised test, a measure of speech-sound production (96+/-2 vs. 96+/-3); the SCAN test, a measure of central auditory processing (95+/-15 vs. 96+/-14); and several measures of behavior and emotion. CONCLUSIONS: In otherwise healthy children younger than three years of age who have persistent middle-ear effusion within the duration of effusion that we studied, prompt insertion of tympanostomy tubes does not improve developmental outcomes at six years of age.

A Targeted Approach for Congenital Cytomegalovirus Screening Within Newborn Hearing Screening.

BACKGROUND AND OBJECTIVE: Congenital cytomegalovirus (cCMV) infection remains a leading cause of childhood hearing loss. Currently universal CMV screening at birth does not exist in the United States. An alternative approach could be testing infants who do not pass their newborn hearing screening (NHS) for cCMV. This study was undertaken to evaluate whether a targeted approach will identify infants with CMV-related sensorineural hearing loss (SNHL). METHODS: Infants born at 7 US medical centers received NHS and were also screened for cCMV while in the newborn nursery. Infants who tested positive for CMV received further diagnostic audiologic evaluations to identify or confirm hearing loss. RESULTS: Between 2007 and 2012, 99 945 newborns were screened for both hearing impairment and cCMV. Overall, 7.0% of CMV-positive infants did not pass NHS compared with 0.9% of CMV-negative infants (P < .0001). Among the cCMV infants who failed NHS, diagnostic testing confirmed that 65% had SNHL. In addition, 3.6% of CMV-infected infants who passed their NHS had SNHL confirmed by further evaluation during early infancy. NHS in this cohort identified 57% of all CMV-related SNHL that occurred in the neonatal period. CONCLUSIONS: A targeted CMV approach that tests newborns who fail their NHS identified the majority of infants with CMV-related SNHL at birth. However, 43% of the infants with CMV-related SNHL in the neonatal period and cCMV infants who are at risk for late onset SNHL were not identified by NHS.

Hearing Loss Detection in Schools and Early Child Care Settings: An Overview of School-Age Hearing Screening Practices.

The school nurse is the key figure in successful school screening programs. A student with unidentified and unmet health care needs is unlikely to perform at their full potential, both academically and socially. The purpose of the article is to serve as a resource, providing guidance, strategies, and a discussion of available equipment to assist with successful screening programs.

Treatment of children with congenital cytomegalovirus infection with ganciclovir.

BACKGROUND: Congenital cytomegalovirus (CMV) infection affects approximately 1% of live births in the US. Ten percent of these infants have symptoms at birth and another 10 to 15% acquire hearing loss or developmental problems. Congenital CMV is the most common cause of nonhereditary sensorineural hearing loss in children, and progressive hearing loss is common. To arrest the natural progression of congenital CMV, children referred to our center were treated with a prolonged course of ganciclovir. METHODS: Medical records of children with congenital CMV who were treated with ganciclovir were reviewed to tabulate their presenting symptoms, duration of treatment, audiologic and developmental assessments and complications. RESULTS: We treated nine children with symptomatic CMV with iv ganciclovir at a median age of 10 days (range, 3 days to 11 months). Findings at diagnosis included microcephaly (five of nine); petechiae (five of nine); thrombocytopenia (seven of nine); and intracranial calcifications (six of eight). Hearing loss was noted before therapy in five of nine. The median duration of iv and subsequent oral ganciclovir was 1 year and 0.83 year, respectively. Median follow-up was 2 years (range, 1 to 7 years). No child had progression of hearing loss; improvement occurred in two. Seven children had at least one complication of ganciclovir therapy: central venous catheter/site infection (six); catheter malfunction (three); and neutropenia (one). CONCLUSION: Of nine children none treated with ganciclovir for congenital CMV had detectable progressive hearing loss. Complications associated with iv therapy occurred frequently. Currently available oral analogues of ganciclovir may facilitate earlier and more prolonged therapy for children with symptomatic congenital CMV and should be subjected to randomized controlled trials.

Early versus delayed insertion of tympanostomy tubes for persistent otitis media: developmental outcomes at the age of three years in relation to prerandomization illness patterns and hearing levels.

BACKGROUND: Whether prompt insertion of tympanostomy tubes in children with persistent early life otitis media prevents or minimizes subsequent developmental impairment has been the subject of conflicting opinions and differing approaches to management. METHODS: We randomly assigned 429 children with persistent middle ear effusion (MEE) before the age of 3 years to have tympanostomy tubes inserted either as soon as possible or up to 9 months later if MEE persisted. In 402 of these children, we found no significant differences at age 3 years between the 2 treatment groups in mean scores on any measure of speech, language and cognition and in 401 of the children no significant differences in measures of psychosocial development. We then examined outcomes within subgroups of children who might have been the most severely affected, namely those who had been randomized on the basis of bilateral, continuous MEE rather than unilateral and/or discontinuous MEE and those who had the greatest degrees of hearing loss. RESULTS: In none of the subgroups we considered were scores on any outcome measure significantly more favorable in children in the early treatment group than in children in the late treatment group. CONCLUSIONS: In otherwise normal children who have MEE, during the first 3 years of life within the durations we studied, prompt insertion of tympanostomy tubes does not measurably improve developmental outcomes at age 3 years, irrespective of whether MEE has been continuous or discontinuous and unilateral or bilateral and whether or not MEE has been accompanied by mild to moderate hearing loss.

Call for calibration standard for newborn screening using auditory brainstem responses.

The mode of stimulation employed in newborn screening of the auditory brainstem response has evolved from the clinically standardized supraaural earphone to the tubal insert earphone, to most recently a circumaural earphone developed for this test. Considered here is the need to develop a standard for calibration of such devices for newborn screening applications, in particular. At risk is the prospect of missing the milder degrees of hearing loss, assuming a goal of detecting all clinically-significant congenital hearing losses. Two commercially manufactured test instruments for automated newborn screening were scrutinized via bench testing of sound output from their respective transducers, using a variety of measurements. By convention or design, none of the measurement approaches involved a model of the newborn ear, per se. While it was concluded that the manufacturers' method shows promise, namely as a relatively simple and potentially reliable method of calibration, concerns arose regarding output levels when measured according to both the manufacturers' and the authors' methods. Further work is needed to critically assess calibration methods and to establish, to the extent possible, appropriate norms and validation studies in newborns to provide a better understanding of the actual sound pressure level of the screening stimulus.

Reliability of electric response audiometry using 80 Hz auditory steady-state responses.

The reliability of the Auditory Steady State Response (ASSR) has not been thoroughly evaluated despite its recent application as a clinical tool for threshold estimation. The purpose of this study was to examine test-retest (TR) reliability of ASSR threshold estimates in an empirical research design. The ASSR, tested using modulation frequencies approximately 80 Hz and above, was evaluated against pure tone audiometry (PTA), and the slow vertex potential (SVP, N1-P2). Sixteen normal-hearing young female adults were tested twice, one week apart. Varying degrees of sensorineural hearing loss of a notched configuration were simulated with filtered masking noise. Test-retest reliability was assessed using Pearson-product moment correlation analysis, supplemented by other post-hoc analyses. Results demonstrated moderately strong TR reliability for ASSR at 1000, 2000 and 4000 Hz (r = 0.83-0.93); however, the reliability of ASSR at 500 Hz was weaker (r = 0.75). Results suggest that ASSR-ERA is a reliable test at mid-high frequencies, at least with the configuration and degrees of simulated sensorineural hearing loss examined in this study.

Validity and accuracy of electric response audiometry using the auditory steady-state response: evaluation in an empirical design.

The validity and accuracy of the application of the auditory steady-state response (ASSR) to electric response audiometry (ERA) was tested further in a study permitting subjects to be their own controls for hearing loss. Simulated sensorineural hearing loss (SSHL) of complex configuration and varying degrees was effected using filtered masking noise. Thresholds estimated via ASSR-ERA were compared to those measured via conventional pure-tone audiometry. Further, the slow vertex potential N1-P2 was recorded to permit a comparison with an evoked-response test of common content validity and known accuracy. Results in a homogeneous subject sample demonstrated strong interest correlation and agreement within 10 dB at 1000 to 4000 Hz (on average), but not at 500 Hz. The configurations determined by ASSR-ERA followed behavioral audiometric patterns well, except for the mildest degree of SSHL tested. Consequently, limitations of ERA remain, although ASSR-ERA appears to be quite valid overall and promises (justifiably) broad clinical applicability.

Tympanometric findings and the probability of middle-ear effusion in 3686 infants and young children.

OBJECTIVE: We examined relationships between tympanometric findings and the presence or absence of middle-ear effusion in a population-based sample of children under the age of 3 years. METHODS: In a study of children's development in relation to early-life otitis media, we enrolled 6350 infants soon after birth and evaluated them regularly for the presence of middle-ear effusion. In 3686 of the children, we compared tympanometric findings with otoscopic diagnoses. We categorized tympanograms according to varying combinations of tympanometric peak height, peak pressure, and width, and calculated for each resulting category the percentage of the associated ears diagnosed as having effusion. Using these findings we developed algorithms for estimating the probability of middle-ear effusion associated with tympanograms of any configuration. RESULTS: For tympanograms generally, the lower their height and the greater their width, the greater was the probability of associated middle-ear effusion; the probability also was greater when peak pressure was negative rather than positive. Among children > or = 6 months of age, effusion was diagnosed in only 2.7% of ears with tympanometric height > or = 0.6 mL, but in 80.2% of ears with flat tympanograms. Relationships among younger infants were similar but less consistent. In both age groups, the tympanographic configurations most commonly encountered were associated with either a relatively low probability (<30%) or a relatively high probability (>70%) of the presence of middle-ear effusion. The receiver operating characteristic curve we generated using the algorithm we developed for children > or = 6 months of age gave an area under the curve of 0.84. The algorithm performed equally well when applied to a separate group of children, suggesting that it is generalizable to other unselected populations. CONCLUSIONS: The present report offers two alternative methods for estimating the probability of middle-ear effusion in children aged 6 through 35 months, given any combination of tympanometric values.

Hearing levels in infants and young children in relation to testing technique, age group, and the presence or absence of middle-ear effusion.

OBJECTIVE: As part of a prospective study of possible effects of early-life otitis media on speech, language, cognition, and psychosocial development, we evaluated hearing both during episodes of middle-ear effusion (MEE) and when MEE was not present. The objective of this report is to describe age-specific hearing threshold levels in relation to the presence or absence of MEE in a large sample of young children. DESIGN: Participants were 1,055 children drawn from a sample of 6,350 children who were enrolled in the larger study by 2 mo of age. Otologic evaluation of each child was conducted at least monthly. The protocol of the larger study called for hearing evaluations 1) after 8 wk of continuous unilateral or bilateral MEE and every 4 wk thereafter until one test had been conducted when MEE was no longer present; 2) immediately before developmental testing; and 3) in a sample of children without MEE to obtain age-specific normative data. RESULTS: Results are presented by testing technique, age group, and middle-ear condition. In general, hearing threshold levels were highest in the youngest children tested with visual reinforcement audiometry and lowest in the oldest children tested with conventional audiometry. In general also, thresholds were lowest in children with normal middle-ear status, intermediate in children with unilateral MEE, and highest in children with bilateral MEE. On average, the presence of bilateral MEE was associated with hearing threshold levels 10 to 15 dB higher than the normative values for the corresponding age group. CONCLUSIONS: In infants and young children, audiometric results are influenced by testing technique, age group, and the presence or absence of effusion in each ear.

Development of f2/f1 ratio functions in humans.

Otoacoustic emissions (OAEs) presumably represent active processes within the cochlea fundamental to frequency-selectivity in peripheral auditory function. Maturation of the cochlear amplifier, vis-a-vis frequency encoding or selectivity, has yet to be fully characterized in humans. The purpose of this study was to further investigate the maturation of features of the f2/f1 frequency ratio (Distortion Product OAE amplitude X f2/f1 ratio) presumed to reflect cochlear frequency selectivity. A cross-sectional, multivariate study was completed comparing three age groups: pre-term infants, term infants and young adult subjects. Frequency ratio functions were analyzed at three f2 frequencies--2000, 4000 and 6000 Hz. An analysis included an estimation of the optimal ratio (OR) and a bandwidth-like measure (Q3). Analysis revealed significant interactions of age x frequency x gender for optimal ratio and a significant interaction of age x frequency for Q3. Consistent and statistically significant differences for both OR and Q3 were found in female subjects and when f2 = 2 or 6 kHz. This supports research by others [Abdala, J. Acoust. Soc. Am. 114, 3239-3250 (2003)] suggesting that the development of cochlear active mechanisms may still be somewhat in flux at least through term birth. Furthermore, OAEs appear to demonstrate gender differences in the course of such maturational changes.

Risk factors for speech delay of unknown origin in 3-year-old children.

One hundred 3-year-olds with speech delay of unknown origin and 539 same-age peers were compared with respect to 6 variables linked to speech disorders: male sex, family history of developmental communication disorder, low maternal education, low socioeconomic status (indexed by Medicaid health insurance), African American race, and prolonged otitis media. Abnormal hearing was also examined in a subset of 279 children who had at least 2 hearing evaluations between 6 and 18 months of age. Significant odds ratios were found only for low maternal education, male sex, and positive family history; a child with all 3 factors was 7.71 times as likely to have a speech delay as a child without any of these factors.

Otitis media and tympanostomy tube insertion during the first three years of life: developmental outcomes at the age of four years.

OBJECTIVE: In a long-term, prospective study, we set out to determine whether otitis media in the first 3 years of life persisting for periods currently considered developmentally threatening actually results in later impairments of children's cognitive, language, speech, or psychosocial development; whether prompt insertion of tympanostomy tubes prevents or lessens any such impairments; and whether, irrespective of causality, associations exist between persistent early-life otitis media and later developmental impairments. This report describes findings in study participants at the age of 4 years. METHODS: We enrolled 6350 healthy infants from 2 to 61 days of age at urban hospitals and 2 small-town/rural and 4 suburban private pediatric practices. We regularly evaluated the children for the presence of middle-ear effusion (MEE) throughout their first 3 years of life by pneumatic otoscopy, supplemented by tympanometry; we monitored the validity of the otoscopic observations on an ongoing basis; and we treated children for otitis media according to specified guidelines. In the clinical trial component of the study, we randomly assigned 429 children who met specified minimum criteria regarding the persistence of MEE to undergo tympanostomy tube insertion either promptly or after a defined extended period if MEE remained present. In the associational component of the study, we selected a representative sample of 241 children who ranged from having no MEE to having MEE the cumulative duration of which fell just short of meeting randomization criteria for the clinical trial. In 397 (92.5%) of the children in the clinical trial and in 234 (97.1%) of the children in the representative sample, we assessed cognitive, language, speech, and psychosocial development at the age of 4 years, using formal tests, conversational samples, and parent questionnaires. RESULTS: In children in the randomized clinical trial, there were no statistically significant differences in mean (+/-standard deviation) scores (higher denotes more favorable) favoring the early-treatment group over the late-treatment group on the General Cognitive Index of the McCarthy Scales of Children's Abilities (97 +/- 14 and 98 +/- 14, respectively); the Peabody Picture Vocabulary Test-Revised, a measure of receptive language (90 +/- 15 vs 92 +/- 16); the Nonword Repetition Test, a measure of phonological memory (66 +/- 12 vs 70 +/- 12); the Number of Different Words, a measure of word diversity (150 +/- 34 vs 150 +/- 31); the Mean Length of Utterance in Morphemes, a measure of sentence length and grammatical complexity (3.4 +/- 0.8 vs 3.4 +/- 0.7); or the Percentage of Consonants Correct-Revised, a measure of speech-sound production (92 +/- 5 vs 93 +/- 5). There were also no significant differences in ratings (higher denotes less favorable) on the Parenting Stress Index-Short Form (Total Stress scores: 68 +/- 18 vs 65 +/- 17) or the Child Behavior Checklist (Total Problem T scores: 50 +/- 10 vs 49 +/- 10). In the associational component of the study, correlations between the children's durations of MEE and their developmental outcomes were generally weak and, in most instances, nonsignificant. Exceptions, after adjustment for sociodemographic variables and for hearing thresholds at the time of developmental testing, consisted of a significant negative correlation between children's cumulative durations of MEE in their first 3 years of life and scores on the McCarthy Verbal subscale, and significant positive correlations between durations of MEE and scores on 2 measures of parent-child stress. The percentage of variance in these scores explained by time with MEE beyond that explained by sociodemographic variables ranged from 1.6% to 3.3%. In both the randomized clinical trial and the associational component, sociodemographic variables seemed to be the most important factors influencing developmental outcomes, and in both components, the results at 4 years of age were consistent with the results that had been obtained at 3 years of age. CONCLUSIONS: In otherwise healthy children who are younger than 3 years and have persistent MEE within the duration limits that we studied, prompt insertion of tympanostomy tubes does not measurably improve developmental outcomes at 4 years of age. In such children, persistent MEE within the duration limits that we studied is negligibly associated with and probably does not affect developmental outcomes at 4 years of age.