Anna H. Messner

A Phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies

tgAAVCF, an adeno-associated cystic fibrosis transmembrane conductance regulator (CFTR) viral vector/gene construct, was administered to 23 patients in a Phase II, double-blind, randomized, placebo-controlled clinical trial. For each patient, a dose of 100,000 replication units of tgAAVCF was administered to one maxillary sinus, while the contralateral maxillary sinus received a placebo treatment, thereby establishing an inpatient control. Neither the primary efficacy endpoint, defined as the rate of relapse of clinically defined, endoscopically diagnosed recurrent sinusitis, nor several secondary endpoints (sinus transepithelial potential difference [TEPD], histopathology, sinus fluid interleukin [IL]-8 measurements) achieved statistical significance when comparing treated to control sinuses within patients. One secondary endpoint, measurements of the anti-inflammatory cytokine IL-10 in sinus fluid, was significantly (p < 0.03) increased in the tgAAVCF-treated sinus relative to the placebo-treated sinus at day 90 after vector instillation. The tgAAVCF administration was well tolerated, without adverse respiratory events, and there was no evidence of enhanced inflammation in sinus histopathology or alterations in serum-neutralizing antibody titer to adeno-associated virus (AAV) capsid protein after vector administration. In summary, this Phase II trial confirms the safety of tgAAVCF but provides little support of its efficacy in the within-patient controlled sinus study. Various potentially confounding factors are discussed.

Safety and Biological Efficacy of an Adeno‐Associated Virus Vector–Cystic Fibrosis Transmembrane Regulator (AAV‐CFTR) in the Cystic Fibrosis Maxillary Sinus

Objective: The host immune response and low vector efficiency have been key impediments to effective cystic fibrosis transmembrane regulator (CFTR) gene transfer for cystic fibrosis (CF). An adeno‐associated virus vector (AAV‐CFTR) was used in a phase I dose‐escalation study to transfer CFTR cDNA into respiratory epithelial cells of the maxillary sinus of 10 CF patients. Study Design: A prospective, randomized, unblinded, dose‐escalation, within‐subjects, phase I clinical trial of AAV‐CFTR was conducted. Patients: Ten patients with previous bilateral maxillary antrostomies were treated. Main Outcome Measures: Safety, gene transfer as measured by semiquantitative polymerase chain reaction (PCR), and sinus transepithelial potential difference (TEPD) were measured. Results: The highest level of gene transfer was observed in the range of 0.1–1 AAV‐CFTR vector copy per cell in biopsy specimens obtained 2 weeks after treatment. When tested, persistence was observed in one patient for 41 days and in another for 10 weeks. Dose‐dependent changes in TEPD responses to pharmacologic intervention were observed following treatments. Little or no inflammatory or immune responses were observed. Conclusion: AAV‐CFTR administration to the maxillary sinus results in successful, dose‐dependent gene transfer to the maxillary sinus and alterations in sinus TEPD suggestive of a functional effect, with little or no cytopathic or host immune response. Further study is warranted for AAV vectors as they may prove useful for CFTR gene transfer and other in vivo gene transfer therapies. A prospective, randomized, double‐blind, placebo‐controlled, within‐subjects, phase II clinical trial of the effect AAV‐CFTR on clinical recurrence of sinusitis will determine the clinical efficacy of AAV gene therapy for CF.

Ankyloglossia: controversies in management☆

PURPOSE To determine current beliefs regarding ankyloglossia and its treatment. DESIGN Anonymous written survey. PARTICIPANTS Otolaryngologists (OTO, n=423), pediatricians (PD, n=425), speech pathologists (SP, n=400), and lactation consultants (LC, n=350) were randomly selected from professional membership lists, with a response rate of 209 (49%), 235 (55%), 150 (37.5%), and 203 (58%), respectively. CLINICAL FINDINGS Sixty-nine percent of LCs, but a minority of physician respondents, believe tongue-tie is frequently associated with feeding problems. Sixty percent of OTOs, 50% of SPs, but only 23% of PDs believe tongue-tie is at least sometimes associated with speech difficulties. Sixty-seven percent of OTOs versus 21% of PDs believe tongue-tie is at least sometimes associated with social/mechanical issues. Surgery is recommended at least sometimes for feeding, speech, and social/mechanical issues by 53, 74, and 69% of OTOs, respectively, but by only 21%, 29%, and 19% of PDs. CONCLUSION The significance of ankyloglossia in children remains controversial, both within, and between, specialty groups.

Acetaminophen versus acetaminophen with codeine after pediatric tonsillectomy.

Objective To compare the effectiveness of acetaminophen versus acetaminophen with codeine after pediatric tonsillectomy and adenoidectomy.

Retropharyngeal abscess management in children: Current practices

Retropharyngeal abscesses (RAs) in children are uncommon in the modern antibiotic era. As a result, there are few large series outlining the management of these infections in contemporary literature. The goal of this study is to determine the current standard of care for RA. The membership of the American Society of Pediatric Otolaryngology was surveyed, and the response rate was 77.5%. Seventy-two percent of practitioners reported that CT is their preferred diagnostic method. Nearly two thirds recommended a trial of intravenous antibiotics at least occasionally for suspected RA before operative drainage was considered; 51% of respondents indicated that 20% to 40% of RA may resolve with antibiotics alone. Intraoral incision and drainage is the surgical technique preferred by 83% of respondents. Tracheotomy and short-term intubation (24 to 72 hours) are rarely required. This study defines current management practices for RA in children among pediatric otolaryngologists. Results are compared with those in the existing literature.

Pediatric vocal fold paralysis after cardiac surgery : Rate of recovery and sequelae

Objective To determine the rate of recovery of pediatric vocal fold paralysis (VFP) after cardiac surgery. Study Design and Setting Retrospective case series from January 2000 to 2005 at 4 tertiary care pediatric hospitals. Results A total of 109 children with VFP were identified. Of 80 patients with follow-up >3 months, 28 (35%) recovered vocal fold function with a median time to diagnosis of recovery of 6.6 months. Fifty-two (65%) patients had persistent vocal fold paralysis with a median follow-up time of 16.4 months. Twenty-five (45%) of 55 patients demonstrated aspiration or laryngeal penetration with modified barium swallow. Twenty-nine (27%) of the 109 patients underwent surgical intervention for their airway, feeding, or voice. Conclusions Pediatric VFP is not an uncommon complication after cardiac surgery and can result in serious sequelae. This study demonstrates a 35% rate of recovery, 45% rate of aspiration, and 27% rate of complications that require surgical intervention.

The Effect of Ankyloglossia on Speech in Children

OBJECTIVE: We wanted to determine whether ankyloglossia is associated with articulation problems and the effect of frenuloplasty on speech and tongue mobility. STUDY DESIGN: We conducted a prospective study of 30 children aged 1 to 12 years with ankyloglossia undergoing frenuloplasty. Outcomes were assessed by measurements of tongue mobility, speech evaluation, and parent questionnaires. RESULTS: Mean tongue protrusion improved from 14.2 mm preoperatively to 25.8 mm postoperatively (P < 0.01). Similarly, mean tongue elevation improved from 5.2 to 22 mm (P < 0.01). Preoperative speech pathology evaluation documented articulation problems thought due to ankyloglossia in 15 of 21 children. Postoperative evaluation in 15 of these children showed improvement in articulation in 9, no change in 4 who had normal speech preoperatively, and an ongoing articulation disorder in 2. Parent perception of speech intelligibility on a scale of 1 to 5 improved from 3.4 to 4.2 (P < 0.01). CONCLUSION: Tongue mobility and speech improve significantly after frenuloplasty in children with ankyloglossia who have articulation problems.

Ankyloglossia: does it matter?

Ankyloglossia is an uncommon oral anomaly that can cause difficulty with breast-feeding, speech articulation, and mechanical tasks such as licking the lips and kissing. For many years the subject of ankyloglossia has been controversial, with practitioners of many specialties having widely different views regarding its significance. In many children, ankyloglossia is asymptomatic; the condition may resolve spontaneously, or affected children may learn to compensate adequately for their decreased lingual mobility. Some children, however, benefit from surgical intervention (frenotomy or frenuloplasty) for their tongue-tie. Parents should be educated about the possible long-term effects of tongue-tie while their child is young (< 1 year of age), so that they may make an informed choice regarding possible therapy.

Simultaneous Multigene Mutation Detection in Patients With Sensorineural Hearing Loss Through a Novel Diagnostic Microarray: A New Approach for Newborn Screening Follow-up

OBJECTIVE. The advent of universal newborn hearing screening in the United States and other countries, together with the identification of genes involved in the process of hearing, have led to an increase in both the need and opportunity for accurate molecular diagnosis of patients with hearing loss. Deafness and hearing impairment have a genetic cause in at least half the cases. The molecular genetic basis for the majority of these patients remains obscure, however, because of the absence of associated clinical features in ∼70% (ie, nonsyndromic hearing loss) of patients, genetic heterogeneity, and the lack of molecular genetic tests that can evaluate a large number of mutations across multiple genes. DESIGN. We report on the development of a diagnostic panel with 198 mutations underlying sensorineural (mostly nonsyndromic) hearing loss. This panel, developed on a microarray, is capable of simultaneous evaluation of multiple mutations in 8 genes (GJB2, GJB6, GJB3, GJA1, SLC26A4, SLC26A5 and the mitochondrial genes encoding 12S rRNA and tRNA-Ser[UCN]). RESULTS. The arrayed primer extension array for sensorineural hearing loss is based on a versatile platform technology and is a robust, cost-effective, and easily modifiable assay. Because hearing loss is a major public health concern and common at all ages, this test is suitable for follow-up after newborn hearing screening and for the detection of a genetic etiology in older children and adults. CONCLUSIONS. Comprehensive and relatively inexpensive genetic testing for sensorineural hearing loss will improve medical management for affected individuals and genetic counseling for their families.

Pediatric laryngeal dimensions: an age-based analysis.

BACKGROUND: In children, the cricoid is considered the narrowest portion of the “funnel-shaped” airway. Growth and development lead to a transition to the more cylindrical adult airway. A number of airway decisions in pediatric airway practice are based on this transition from the pediatric to the adult airway. Our primary aim in this study was to measure airway dimensions in children of various ages. The measures of the glottis and cricoid regions were used to determine whether a transition from the funnel-shaped pediatric airway to the cylindrical adult airway could be identified based on images obtained from video bronchoscopy. METHODS: One hundred thirty-five children (ASA physical status 1 or 2) aged 6 mo to 13 yr were enrolled for measurement of laryngeal dimensions, including cross-sectional area (G-CSA), anteroposterior and transverse diameters at the level of the glottis and the cricoid (C-CSA), using the video bronchoscopic technique under general anesthesia. RESULTS: Of the 135 children enrolled in the study, seven patients were excluded from the analysis mainly because of poor image quality. Of the 128 children studied (79 boys and 49 girls), mean values (±standard deviation) for the demographic data were age 5.9 (±3.3) yr, height 113.5 (±22.2) cm and weight 23.5 (±13) kg. Overall, the mean C-CSA was larger than the G-CSA (48.9 ± 15.5 mm2 vs 30 ± 16.5 mm2, respectively). This relationship was maintained throughout the study population starting from 6 mo of age (P < 0.001, r = 0.45, power = 1). The mean ratio for C-CSA: G-CSA was 2.1 ± 1.2. There was a positive correlation between G- and the C-CSA versus age (r = 0.36, P < 0.001; r = 0.27, P = 0.001, respectively), height (r = 0.34, P < 0.001; r = 0.29, P < 0.001, respectively), and weight (r = 0.35, P < 0.001; r = 0.25, P = 0.003, respectively). No significant gender differences in the mean values of the studied variables were observed. CONCLUSION: In this study of infants and children, the glottis rather than cricoid was the narrowest portion of the pediatric airway. Similar to adults, the pediatric airway is more cylindrical than funnel shaped based on these video bronchoscopic images. Further studies are needed to determine whether these static airway measurements in anesthetized and paralyzed children reflect the dynamic characteristics of the glottis and cricoid in children.