Congenital Cytomegalovirus Testing Outcomes From the ValEAR Trial.

OBJECTIVE: To determine the positivity rate of congenital cytomegalovirus (cCMV) testing among universal, hearing-targeted CMV testing (HT-cCMV) and delayed targeted dried blood spot (DBS) testing newborn screening programs, and to examine the characteristics of successful HT-cCMV testing programs. STUDY DESIGN: Prospective survey of birth hospitals performing early CMV testing. SETTING: Multiple institutions. METHODS: Birth hospitals participating in the National Institutes of Health ValEAR clinical trial were surveyed to determine the rates of cCMV positivity associated with 3 different testing approaches: universal testing, HT-cCMV, and DBS testing. A mixed methods model was created to determine associations between successful HT-cCMV screening and specific screening protocols. RESULTS: Eighty-two birth hospitals were surveyed from February 2019 to December 2021. Seven thousand six hundred seventy infants underwent universal screening, 9017 infants HT-cCMV and 535 infants delayed DBS testing. The rates of cCMV positivity were 0.5%, 1.5%, and 7.3%, respectively. The positivity rate for universal CMV screening was less during the COVID-19 pandemic than that reported prior to the pandemic. There were no statistically significant drops in positivity for any approach during the pandemic. For HT-cCMV testing, unique order sets and rigorous posttesting protocols were associated with successful screening programs. CONCLUSION: Rates of cCMV positivity differed among the 3 approaches. The rates are comparable to cohort studies reported in the literature. Universal CMV prevalence decreased during the pandemic but not significantly. Institutions with specific order set for CMV testing where the primary care physician orders the test and the nurse facilitates the testing process exhibited higher rates of HT-cCMV testing.

Update on injection augmentation pharyngoplasty in the treatment of velopharyngeal insufficiency.

PURPOSE OF REVIEW: Velopharyngeal insufficiency (VPI) refers to a structural defect resulting in incomplete closure between the soft palate and posterior pharyngeal wall, leading to inadequate speech and deglutition. Traditional surgical options for VPI include sphincter pharyngoplasty, pharyngeal flaps and palatoplasty. Although these procedures have been successfully used over the past several decades, they are associated with complications such as pain, bleeding, infection and obstructive sleep apnoea. They also require postoperative admission. Injection augmentation pharyngoplasty (IAP) is increasingly being viewed as a viable, less invasive surgical option for patients with mild to moderate VPI. RECENT FINDINGS: Both autologous fat and alloplastic synthetics have been used as injectable materials, with low morbidity and good speech outcomes. However, given the overall lack of standardization across studies, no single material has shown clear superiority. SUMMARY: IAP is a promising alternative to more invasive surgeries in the treatment of patients with mild to moderate VPI. The purpose of this review is to provide an overview of this approach, with an emphasis on its safety and efficacy.

HSV-2 triggers upregulation of MALAT1 in CD4+ T cells and promotes HIV latency reversal.

Herpes simplex virus type 2 (HSV-2) coinfection is associated with increased HIV-1 viral loads and expanded tissue reservoirs, but the mechanisms are not well defined. HSV-2 recurrences result in an influx of activated CD4+ T cells to sites of viral replication and an increase in activated CD4+ T cells in peripheral blood. We hypothesized that HSV-2 induces changes in these cells that facilitate HIV-1 reactivation and replication and tested this hypothesis in human CD4+ T cells and 2D10 cells, a model of HIV-1 latency. HSV-2 promoted latency reversal in HSV-2-infected and bystander 2D10 cells. Bulk and single-cell RNA-Seq studies of activated primary human CD4+ T cells identified decreased expression of HIV-1 restriction factors and increased expression of transcripts including MALAT1 that could drive HIV replication in both the HSV-2-infected and bystander cells. Transfection of 2D10 cells with VP16, an HSV-2 protein that regulates transcription, significantly upregulated MALAT1 expression, decreased trimethylation of lysine 27 on histone H3 protein, and triggered HIV latency reversal. Knockout of MALAT1 from 2D10 cells abrogated the response to VP16 and reduced the response to HSV-2 infection. These results demonstrate that HSV-2 contributes to HIV-1 reactivation through diverse mechanisms, including upregulation of MALAT1 to release epigenetic silencing.

A Validated 3D Printed Laryngeal Suturing Simulator for Endoscopic Laryngeal Cleft Repair.

OBJECTIVES: Endoscopic laryngeal cleft repair (ELCR) with endolaryngeal suturing is an advanced surgical skill. This study objective was to assess the validity of 3-dimensionally (3D) printed laryngeal suturing simulator for ELCR. STUDY DESIGN: Development and validation of a simulator for ELCR. METHODS: An ELCR model was developed using 3D printed and readily available materials. Participants were surveyed before and after a simulation session using five-point Likert scale questions. Performance data was assessed using blinded expert video review and rated using a novel objective structured assessment of technical skills (OSATS) for endoscopic laryngeal suturing. RESULTS: Twenty-one participants ranging from residents to attendings completed the simulation session. Survey respondents reported on a five-point Likert scale that the model was "easy to use" and "quite realistic" (both mean of 4). Confidence improved significantly in 86% of participants (p < 0.01). Overall OSATS scores (out of a total of 55) showed a median improvement in technical skills of 11.7 points (p = 0.004). OSATS demonstrated good intra-rater (κ = 0.689 and 0.677) and moderate inter-rater (κ = 0.573) reliability. Completion times improved from the first to the last suture by a median time of 512 to 350 s (decrease of 202 s, p = 0.002). Participants with no prior ELCR experience improved more than those with in vivo experience. CONCLUSION: This study demonstrates the validity of a simulator utilizing 3D printed larynges for ELCR. A novel OSATS for endoscopic laryngeal suturing was successfully implemented. Confidence, technical skills, and completion times improved with the use of the model across a variety of participants. Laryngoscope, 133:785-791, 2023.

A Modified Laryngeal Stent for Glotto-Subglottic Stenosis: A Novel Stent for Better Outcomes.

Management of laryngotracheal stenosis is challenging and laryngotracheal stenosis is generally managed with laryngotracheal reconstruction. Stents are often used as part of the reconstructive surgery. Although most stents adequately stabilize the reconstruction during healing, they often do a poor job of mimicking glottic anatomy, particularly the anterior glottis. Here, we present a modified suprastomal stent designed to stabilize reconstruction after laryngotracheal reconstruction while also improving postoperative glottic anatomy and function. The case of a 15-year-old tracheostomy-dependent patient with glotto-subglottic stenosis who underwent laryngotracheal reconstruction using this modified stent is described. The patient had an excellent outcome with decannulation of her tracheostomy and significant improvement in voice.

Early Extended Neonatal Screening for Congenital Cytomegalovirus Infection: A Quality Improvement Initiative.

BACKGROUND: Identification of congenital cytomegalovirus (cCMV) infection in neonates is important for early diagnosis of sensorineural hearing loss. Therefore, a quality improvement project was designed with an aim to improve newborn CMV screening by 25% from a baseline rate of 22%. METHODS: This project was conducted across two hospital sites at one medical center with two tertiary care newborn nurseries and neonatal intensive care units. Symptomatic neonates with suggestive findings of cCMV, who had failed the newborn hearing screen, who had not had a hearing screen performed by 10 days of age, or who were infants of HIV-positive mothers were screened for cCMV. Serial interventions (formalized teaching sessions using an algorithm and involving a nurse educator, creation of electronic medical record order sets, huddle board reminders, and regular audits) were conducted, and statistical process control p-charts were used to identify any signals and to determine if there was any special cause variation. RESULTS: Of 5,817 infants born in 2018, 903 were eligible for screening. Small for gestational age (46%) was the most common indication for screening. After multiple interventions, the median screening rate increased from a baseline of 22% in 2016 to 74% during the one-year study period. Four infants had positive CMV screen and received appropriate treatment as a result of these interventions. CONCLUSION: Multidisciplinary quality improvement initiatives can improve newborn screening for cCMV infection in a tertiary care environment.

Ex utero intrapartum treatment (EXIT) for fetal neck masses: A tertiary center experience and literature review.

OBJECTIVE: Currently no established criteria exist to guide use of ex utero intrapartum treatment (EXIT) for fetal neck mass management. This study aims to correlate prenatal radiographic findings with incidence of ex utero intrapartum treatment and necessity of airway intervention at delivery. METHODS: We reviewed our EXIT experience between 2012 and 17. Furthermore, we performed a literature review of articles reporting incidences of fetal neck masses considered for EXIT. Articles that were included (1) discussed prenatal radiographic findings such as size, features, and evidence of compression and (2) reported extractable data on delivery outcomes and airway status. RESULTS: Ten cases at our institution were reviewed. Another 137 cases across 81 studies met inclusion criteria. These studies showed aerodigestive tract compression to be significantly associated with neck masses undergoing EXIT. Additionally, there was significantly higher incidence of airway intervention in cases where polyhydramnios, anatomic compression, and solid masses were seen on prenatal diagnostic imaging, while mass location and size did not correlate with airway intervention. CONCLUSION: With this data, we propose that any neck mass with anatomic compression on fetal imaging in the 3rd trimester should be considered for EXIT. When radiographic findings do not show compression but do display polyhydramnios or a solid neck mass (regardless of polyhydramnios), an airway surgeon should be available for perinatal airway assistance.

Chondrodysplasia punctata presenting with tracheal obstruction.

Chondrodysplasia punctata is a group of congenital bone and cartilage disorders characterized by erratic calcification during development. Laryngeal and tracheal calcification and subsequent stenosis, while being reported in several cases of chondrodysplasia punctata, are not frequent findings and there are no proposed management techniques. We describe here a case of an infant with chondrodysplasia punctata associated to tracheal stenosis that was successfully treated with balloon dilation, and with long term follow-up.

Swallowing function in pediatric patients with bilateral vocal fold immobility.

INTRODUCTION: Infants with bilateral vocal fold immobility (BVFI) often have poor swallow function in addition to potential airway compromise. While there are several reports on BVFI and its effect on patients' airway status, little is known about long term swallow function. OBJECTIVES: We aim to characterize the swallowing function over time in pediatric patients with bilateral vocal fold immobility. METHODS: A retrospective review of medical records of infants diagnosed with BVFI at a tertiary care children's hospital between 2005 and 2014 was conducted. Patient demographics, nature and etiology of immobility, laryngoscopy findings, comorbidities, and swallow outcomes at diagnosis and follow-up were recorded. Swallowing outcomes as measured by presence or absence of a gastrostomy tube were compared by etiology, vocal fold status, and normal or developmentally delay using the Fisher's exact test. RESULTS: 110 patients with a diagnosis of vocal fold immobility were identified. Twenty-nine (26%) had BVFI and twenty-three had complete medical records. Etiologies of vocal fold immobility include cardiac related in 13% (3/23), idiopathic in 30% (7/23) prolonged intubation in 26% (6/23) central neurologic in 22% (5/23), trauma in 4% (1/23), and infection in 4% (1/23). Average follow-up time was 44 months (range 5-94 months). Ten patients (56.5%) required a gastrostomy tube at time of diagnosis. Of this cohort who received gastrostomy tubes, three (30%) ultimately transitioned to complete oral feeds. Return of vocal fold mobility did not correlate with swallow function. In those with non-neurologic etiologies, the need for gastrostomy tube at end of follow up was unlikely. There was a statistically significant difference in the percentage of gastrostomy tube-free children at most recent follow up in patients who were normally developed (86%) versus those who were developmentally delayed (33%) (p = 0.02). CONCLUSION: We characterized the swallowing function of 23 pediatric patients with BVFI. Comorbidities are significant predictors of long term swallow function in patients with BVFI while return of vocal fold function is not.

Etiology and long-term functional swallow outcomes in pediatric unilateral vocal fold immobility.

OBJECTIVE: Unilateral vocal fold immobility (UVFI) results in deficits in phonatory, respiratory, and swallow function of the pediatric patient. Little is known about long-term functional swallow outcomes. METHODS: Medical records of children diagnosed with UVFI between 2005 and 2014 at a tertiary children's hospital were retrospectively reviewed. Etiology, laryngoscopy findings, and swallow status at diagnosis and follow-up were recorded. Swallow outcomes were compared by etiology using Fisher's exact test. McNemar's test was used to identify correlations between return of mobility and swallow recovery. Rates of pneumonia were compared with initial swallow evaluation results using a two-tailed t-test. RESULTS: Eighty-eight patients with UVFI were identified and 73 patients (47% female, mean age 14.4 months, standard deviation (SD) 26.7 months) had complete medical records. Mean follow up time was 52.7 months (SD 36.8 months). Etiologies included cardiothoracic surgery (68.5%), idiopathic (12.3%), prolonged intubation (11.0%), central nervous system (CNS) abnormality (5.5%), and non-cardiac iatrogenic injury to the recurrent laryngeal nerve (2.7%). Forty-seven patients underwent a follow up laryngoscopy, and recovery of vocal fold (VF) mobility was documented in 42.6% (20/47). At diagnosis, 31.5% fed orally, compared with 79.5% at follow-up. Direct correlation between recovery of VF mobility and swallow recovery was not demonstrated. Cardiac etiologies demonstrated higher rates of swallow recovery than CNS abnormalities (p = 0.0393). Twenty-five children aspirated on initial modified barium swallow (MBS) and 10 children developed pneumonias at some point during the follow up period. There was no significant difference in rates of pneumonia in patients with and without aspiration on MBS. CONCLUSION: Recovery of swallow in children with UVFI does not directly parallel return of VF mobility. Long-term swallow outcome is favorable in this population. Initial MBS does not indicate ultimate swallow outcome.

Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is the leading infectious cause of birth defects, mental retardation and non-genetic sensorineural hearing loss. Murine models have been developed in order to understand the pathophysiological mechanisms underlying these lesions. These models are being proposed for the validation of therapeutic protocols for clinical use. The aim of this preclinical study was to assess the pharmacokinetics of the reference antiviral molecule, ganciclovir, in order to optimize these protocols and confirm the diffusion of the molecule to the appropriate target zones. METHODS: Transplacental and intracochlear diffusion of ganciclovir was evaluated in mice and rats. Pharmacokinetics was assessed in adult mice and pups after 5 consecutive days of intraperitoneal injection of ganciclovir. The occurrence of hematological side effects of ganciclovir was evaluated in the different blood cell lineages. RESULTS: In adult rats, the intracochlear diffusion of ganciclovir was shown to achieve the same concentration as in blood. In gestating mice, transplacental diffusion was observed, with a fetal-to-maternal blood ratio of 0.5. In newborn mice, the plasma concentration profile of ganciclovir showed a peak at 2 h followed by a gradual decrease. In adult mice, the concentration peaked at 1 h, but became undetectable by 2 h after injection. Counts of white blood cells, red blood cells and platelets decreased significantly in ganciclovir-treated newborn mice. CONCLUSION: Our data provide evidence for the intracochlear diffusion of the molecule, which may be relevant for the treatment of sensorineural hearing loss in congenitally-infected children.

Combination therapies using an intratympanic polymer gel delivery system in the guinea pig animal model: A safety study.

OBJECTIVES: High dose antivirals have been shown to cause hearing loss when applied via the intratympanic route. The aim of this study was to determine if a combination therapy using dexamethasone (DXA) with either Cidofovir (CDV) or Ganciclovir (GCV), in solution or in PLGA-PEG-PLGA (PPP) hydrogel, is innocuous to the inner ear. METHODS: Cytomegalovirus (CMV)-free guinea pigs were separated into four principal study groups and treated via intratympanic injection (IT) of CDV/DXA solution, CDV/DXA Hydrogel, GCV/DXA solution and GCV/DXA hydrogel. Hearing thresholds were evaluated with pretreatment ABR and post injection weekly ABRs for a total follow up of 28 days. Temporal bone tissue was harvested and stained with Hematoxylin and Eosin for histologic analysis. RESULTS: ABR analysis revealed that GCV/DXA in solution and in hydrogel led to a mild hearing loss at days 7-21 but returned to baseline by day 28 When administered via PPP hydrogel, CDV/DXA demonstrated mild persistent hearing loss at 32kHz at 28 days. An inflammatory response was identified in the cochlear specimen of the CDV/DXA/PPP hydrogel group, in concert with mild hearing loss, at days 21 and 28. CONCLUSION: Results of this study support the safe intratympanic use of higher concentrations of antivirals when combined with DXA, both in solution and when applied via PPP hydrogel.

High-dose sublesional bevacizumab (avastin) for pediatric recurrent respiratory papillomatosis.

OBJECTIVES: We review and report the use of high-dose bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP) in pediatric patients. METHODS: We included all patients with pediatric-onset RRP who underwent bevacizumab (25 mg/mL) injections by a single practitioner. A series of 5 consecutive subepithelial injections were administered at 4- to 6-week intervals with concomitant 532 nm KTP laser ablation. The lesions were staged according to the Derkay staging system. The outcomes included pretreatment and posttreatment Derkay scores, the time interval between procedures, and voice outcomes. The demographic data extracted included sex, age at diagnosis, and current age. RESULTS: Nine patients were included in this study, with 1 patient lost to follow-up; their median age was 8 years (range, 3 to 21 years). The mean bevacizumab dose was 14.25 mg (range, 5 to 45 mg). There was a median Derkay score of 11.5 (range, 4 to 23) at the time of diagnosis and a median 58% improvement following therapy. All patients demonstrated an increased time interval between injections, for a median improvement of 2.05× (range, 1.6× to 3.25×). CONCLUSIONS: Evidence exists in support of vascular endothelial growth factor as an important factor in the development of RRP. Although some variability in response is demonstrated by this study, high-dose bevacizumab appears to yield promising results for pediatric patients with RRP.

Safety of cidofovir by intratympanic delivery technique.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is one of the most common infectious causes of congenital sensorineural hearing loss. To date, a safe and effective therapy for CMV-induced hearing loss does not exist. We hypothesize that the antiviral cidofovir (CDV) can be delivered to the inner ear via intratympanic (IT) injections to safely and effectively mitigate CMV-induced hearing loss. METHODS: To evaluate the safety of CDV IT injections, weanling guinea pigs with normal hearing were injected intratympanically with 3 mg or 5 mg concentrations of CDV and compared to control animals injected with sterile saline. A separate group of weanling guinea pigs were inoculated with CMV and a subset of this group was treated with CDV following inoculation. RESULTS: The 3 mg/ml and 5 mg/ml CDV concentrations resulted in hearing loss following IT injection into uninfected animals. No signs of inflammation or toxicity were noted on histologic analysis and there was no evidence of systemic toxicity in serology. Hearing loss induced as a result of guinea pig CMV infection recovered by day 21 in animals treated with IT injections of 5 mg/ml CDV. CONCLUSIONS: We provide promising evidence demonstrating both the efficacy and safety of IT CDV in the guinea pig animal model. This research further establishes a sound framework upon which ongoing investigations into drug delivery mechanisms for CMV-induced hearing loss will be based.

Hypoplastic epiglottis in a non-syndromic child: a rare anomaly with serious consequences.

Hypoplasia of the epiglottis is a rarely reported anomaly. These patients may have complex malformations or are totally asymptomatic. We herewith present the case of a 26-month-old infant who was repeatedly treated for severe aspiration pneumonias that didn't resolve with gastrostomy. The role of epiglottis in protecting the airway is an unsolved question. The long-term evolution of hypoplasic epiglottis cases is also not known. The presentation and the evolution in cases of epiglottic anomalies vary a lot to deduce a trend. Close specialized follow-up is needed to answer these questions and to optimize these patients' prognosis.

Management of postintubation tracheal stenosis: appropriate indications make outcome differences.

BACKGROUND: Laryngotracheal stenosis is difficult to treat and its etiologies are multiple; nowadays, the most common ones are postintubation or posttracheostomy stenoses. OBJECTIVE: To provide an algorithm for the management of postintubation laryngotracheal stenoses (PILTS) based on the experience of a tertiary care referral center. METHODS: A retrospective study was conducted on all patients treated for PILTS over a 10-year period. Patients were divided into a surgically and an endoscopically treated group according to predefined criteria. The characteristics of the two groups were analyzed and the outcomes compared. RESULTS: Thirty-three consecutive patients were included in the study: 14 in the surgically treated group and 19 in the endoscopically treated group. Our candidates for airway surgery were healthy patients presenting with complex tracheal stenoses, subglottic involvement or associated tracheomalacia. The endoscopic candidates were chronically ill patients presenting with simple, strictly tracheal stenoses not exceeding 4 cm in length. Stents were placed if the stenosis was associated with tracheomalacia or exceeded 2 cm in total length. In the surgically treated group, 2/14 patients needed more than one procedure versus 8/19 patients in the endoscopically treated group. At the end of the intervention, 50% of the patients were decannulated in the surgically treated group versus 84.2% in the endoscopically treated group (p = 0.03). However, the decannulation rates at 6 months and the symptomatology at rest and on exertion on the last follow-up visit were comparable in the two groups. CONCLUSION: Our experience in the management of PILTS demonstrates that both surgery and endoscopy yield excellent functional outcomes if the treatment strategy is based on clear, predefined objective criteria.