Anesthesia for laryngotracheal reconstruction in children: A narrative review.

Laryngotracheal stenosis, congenital or acquired, is a common cause of pediatric airway obstruction. Acquired subglottic stenosis frequently results from prolonged neonatal intubation. The clinical presentation of subglottic stenosis is variable, ranging from biphasic stridor and frequent upper respiratory infections to acute airway compromise. Optimal patient care requires clinical coordination within a multidisciplinary subspecialty team. Medical management includes optimizing respiratory status, gastroesophageal reflux, speech, feeding, nutrition therapies, and providing psychosocial support. If surgical intervention is required, the otolaryngologist, anesthesiologist, and perioperative team must collaborate closely to ensure successful operative outcomes. This narrative review of laryngotracheal stenosis will discuss the pathophysiology, clinical evaluation, medical management, and surgical interventions, and focus on the perioperative anesthetic considerations for children undergoing laryngotracheal reconstruction.

FUT2 Variants Confer Susceptibility to Familial Otitis Media.

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154∗) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202∗) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10-5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154∗) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10-7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154∗, and p.Arg202∗-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.

A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.

APOBR Is Downregulated in EBV+ Tonsils of Children with Obstructive Sleep-Disordered Breathing.

Background: Obstructive sleep-disordered breathing (oSDB) is a heterogeneous phenotype that is increasing in prevalence worldwide and has many potential comorbidities that could severely affect quality of life. There is a need to identify biomarkers for oSDB and its comorbidities to improve clinical management, particularly in children. Methods: We performed bulk mRNA-sequencing, differential expression analysis, and qPCR replication of selected differentially expressed genes (DEGs) using RNA samples extracted from tonsils of children with oSDB. Two variables were used as classifier, namely, detection of Epstein-Barr virus (EBV) in tonsils and need for continuous positive airway pressure (CPAP) treatment. Standard statistical tests were used to determine associations across clinical, EBV, and DEG variables. Results: Nineteen genes were dysregulated in tonsils that are EBV+ or from children needing CPAP. Of these genes, APOBR was downregulated in both EBV+ and CPAP+ tonsils, and this downregulation was replicated by qPCR in an independent set of pediatric samples. In the tonsils of adult patients with oSDB, APOBR was positively correlated with age, and potentially with diastolic blood pressure. Conclusions: Taken together, APOBR and DEGs in tonsillar tissues may be useful as potential biomarkers of oSDB severity and comorbidity across the lifespan, with APOBR levels being dependent on latent EBV infection.

Otitis Media in Children with Down Syndrome Is Associated with Shifts in the Nasopharyngeal and Middle Ear Microbiotas.

Background: Otitis media (OM) is defined as middle ear (ME) inflammation that is usually due to infection. Globally, OM is a leading cause of hearing loss and is the most frequently diagnosed disease in young children. For OM, pediatric patients with Down syndrome (DS) demonstrate higher incidence rates, greater severity, and poorer outcomes. However, to date, no studies have investigated the bacterial profiles of children with DS and OM. Method: We aimed to determine if there are differences in composition of bacterial profiles or the relative abundance of individual taxa within the ME and nasopharyngeal (NP) microbiotas of pediatric OM patients with DS (n = 11) compared with those without DS (n = 84). We sequenced the 16S rRNA genes and analyzed the sequence data for diversity indices and relative abundance of individual taxa. Results: Individuals with DS demonstrated increased biodiversity in their ME and NP microbiotas. In children with OM, DS was associated with increased biodiversity and higher relative abundance of specific taxa in the ME. Conclusion: Our findings suggest that dysbioses in the NP of DS children contributes to their increased susceptibility to OM compared with controls. These findings suggest that DS influences regulation of the mucosal microbiota and contributes to OM pathology.

Cytokine responses in the common cold and otitis media.

Cytokines are a group of diverse molecules that influence the function of every organ system. They are most well studied in their effects on the immune system and their integral role in mediating inflammation. The common cold and otitis media are two such disease states, and much has been learned about the various effects of cytokines in each disease. Most often the viruses isolated include rhinovirus (RV), respiratory syncytial virus (RSV), adenovirus, coronavirus, and picornavirus. Otitis media, sinusitis, bronchiolitis, pneumonia, and asthma exacerbation are commonly accepted as complications of viral upper respiratory tract infections. Furthermore, otitis media and upper respiratory infections are inextricably linked in that the majority (>70 %) of cases of acute otitis media occur as complications of the common cold. Cytokine polymorphisms have been associated with the severity of colds as well as the frequency of otitis media. This article attempts to update the reader on various studies that have recently been published regarding the role of cytokines in these two disease entities.

Posterior tracheopexy for preterm infants with severe bronchopulmonary dysplasia and severe tracheobronchomalacia: A case series.

We report a series of four patients with severe bronchopulmonary dysplasia (BPD) who underwent posterior tracheopexy for severe tracheomalacia (TM). While posterior tracheopexy is an established surgical treatment for TM associated with tracheoesophageal fistula, it has not been previously described in TM associated with BPD. There were no significant intraoperative or postoperative complications from the surgeries. Three of the four patients required tracheostomy and mechanical ventilation, which may reflect the degree of lung disease and other multisystem comorbidities in these patients. More investigation is needed to determine whether posterior tracheopexy is an effective surgical option for TM related to BPD.

The risks of polytetrafluoroethylene pledget use in tracheopexy.

Posterior tracheopexy, performed most often for intrinsic tracheomalacia, is a procedure that is gaining in popularity and application. In this procedure, pledgeted sutures are placed between the trachea and a more fixed structure, in order to provide the airway with greater patency. Polytetrafluoroethylene pledgets are readily available but risk migration into adjacent structures over time. We present a case of a pledget migrating in to the airway and presenting as an obstructing lesion that has required multiple repeat interventions. Given that bioabsorbable materials are available, surgeons should consider alternative pledgets for these patients.

The FUT2 Variant c.461G>A (p.Trp154*) Is Associated With Differentially Expressed Genes and Nasopharyngeal Microbiota Shifts in Patients With Otitis Media.

Otitis media (OM) is a leading cause of childhood hearing loss. Variants in FUT2, which encodes alpha-(1,2)-fucosyltransferase, were identified to increase susceptibility to OM, potentially through shifts in the middle ear (ME) or nasopharyngeal (NP) microbiotas as mediated by transcriptional changes. Greater knowledge of differences in relative abundance of otopathogens in carriers of pathogenic variants can help determine risk for OM in patients. In order to determine the downstream effects of FUT2 variation, we examined gene expression in relation to carriage of a common pathogenic FUT2 c.461G>A (p.Trp154*) variant using RNA-sequence data from saliva samples from 28 patients with OM. Differential gene expression was also examined in bulk mRNA and single-cell RNA-sequence data from wildtype mouse ME mucosa after inoculation with non-typeable Haemophilus influenzae (NTHi). In addition, microbiotas were profiled from ME and NP samples of 65 OM patients using 16S rRNA gene sequencing. In human carriers of the FUT2 variant, FN1, KMT2D, MUC16 and NBPF20 were downregulated while MTAP was upregulated. Post-infectious expression in the mouse ME recapitulated these transcriptional differences, with the exception of Fn1 upregulation after NTHi-inoculation. In the NP, Candidate Division TM7 was associated with wildtype genotype (FDR-adj-p=0.009). Overall, the FUT2 c.461G>A variant was associated with transcriptional changes in processes related to response to infection and with increased load of potential otopathogens in the ME and decreased commensals in the NP. These findings provide increased understanding of how FUT2 variants influence gene transcription and the mucosal microbiota, and thus contribute to the pathology of OM.

The role of CDHR3 in susceptibility to otitis media.

Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility. KEY MESSAGES: • Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media. • Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media. • CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens. • Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear. • Cdhr3 was downregulated 3 h after infection of mouse middle ear.

The Generalizability of the Clinical Assessment Score-15 for Pediatric Sleep-Disordered Breathing.

OBJECTIVE: The Clinical Assessment Score-15 (CAS-15) has been validated as an office-based assessment for pediatric sleep-disordered breathing in otherwise healthy children. Our objective was to determine the generalizability of the CAS-15 in a multi-institutional fashion. METHODS: Five hundred and thirty children from 13 sites with suspected sleep-disordered breathing were recruited, and the investigators completed the CAS-15. Based on decisions made in the course of clinical care, investigators recommended overnight polysomnography, observation, medical therapy, and/or surgery. Two hundred and forty-seven subjects had a follow-up CAS-15. RESULTS: Mean age was 5.1 (2.6) years; 54.2% were male; 39.1% were white; and 37.0% were African American. Initial mean (standard deviation [SD]) CAS-15 was 37.3 (12.7), n = 508. Spearman correlation between the initial CAS-15 and the initial apnea-hypopnea index (AHI) was 0.41 (95% confidence interval [CI], 0.29, 0.51), n = 212, P < .001. A receiver-operating characteristic curve predicting positive polysomnography (AHI > 2) had an area under the curve of 0.71 (95% CI, 0.63, 0.80). A score ≥ 32 had a sensitivity of 69.0% (95% CI, 61.7, 75.5), a specificity of 63.4% (95% CI, 47.9, 76.6), a positive predictive value of 88.7% (95% CI, 82.1, 93.1), and a negative predictive value of 32.9% (95% CI, 23.5, 44.0) in predicting positive polysomnography. Among children who underwent surgery, the mean change (SD) score was 30.5 (12.6), n = 201, t = 36.85, P < .001, effect size = 3.1. CONCLUSION: This study establishes the generalizability of the CAS-15 as a useful office tool for the evaluation of pediatric sleep-disordered breathing. LEVEL OF EVIDENCE: 2B Laryngoscope, 130:2256-2262, 2020.

Multi-omic studies on missense PLG variants in families with otitis media.

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.

Pediatric tracheocutaneous fistula closure following tracheostomy decannulation.

OBJECTIVE: To determine the frequency and risk factors that lead to the development of persistent TCF (tracheocutaneous fistula) formation in children following tracheostomy decannulation at our institution. METHODS: A retrospective chart review of all pediatric patients at Children's Hospital Colorado who underwent tracheostomy decannulation and were being followed between January 1, 2007 and December 31, 2013. TCF was defined as a persistent fistula six months following decannulation. We determined patient demographics, age at tracheotomy, primary indication for tracheotomy, tracheostomy-tube size, medical comorbidities, age at decannulation, date of TCF closure, and method of TCF closure. RESULTS: One hundred twenty-nine patients ranging from 51 days to 19 years of age underwent tracheostomy decannulation. 63 (49%) patients underwent surgical closure of TCF. Compared to those with spontaneous closure by multivariable analysis, those with surgical closure were younger at tracheostomy placement (p = 0.0002), had a tracheostomy for a longer duration (p = 0.0025), and were diagnosed with tracheobronchomalacia (p = 0.0051). The likelihood of spontaneous closure decreased over time. Tracheostomy tube internal diameter correlated with age (R = 0.64, p < 0.0001). CONCLUSIONS: Approximately 50% of pediatric tracheostomy stoma sites will close spontaneously. Development of a persistent TCF was associated with younger age at placement, longer duration of tracheostomy, and the presence of tracheobronchomalacia. These observations may help clinicians anticipate outcomes following tracheostomy decannulation in children.

Infection of the spheno-occipital synchondrosis: A morbid complication following adenoidectomy.

Two 2-year-old males presented post-operatively following adenoidectomy with persistent fever and neck stiffness. After multiple office visits, both patients were admitted and found to have a widened spheno-occipital synchondrosis and other imaging findings indicative of skull base osteomyelitis. Treatment with antibiotics allowed for recovery with good long-term outcomes. Infection involving the spheno-occiptal synchondrosis is rare and its circuitous presentation of these two children no doubt led to delayed diagnosis.

Secondary Reverse Slide Tracheoplasty for Airway Rescue.

Slide tracheoplasty is used in cases of tracheal stenosis or injury. With expanding indications for its use at tertiary centers, salvage techniques for dehiscence or restenosis after slide tracheoplasty are increasingly relevant. We present a case in which slide tracheoplasty was augmented with an anterior costochondral graft that stenosed again and ultimately failed. We salvaged this airway emergency by performing a secondary reverse slide tracheoplasty. Using this technique, we were able to establish a safe and durable airway using only native airway tissue.

Congenital nasal pyriform aperture stenosis: is there a role for nasal dilation?

IMPORTANCE: Congenital nasal pyriform aperture stenosis (CNPAS) may require sublabial drill-out of the pyriform aperture when symptoms are severe or refractory to medical therapy. Less invasive nasal dilation decreases potential morbidity to neonates with severe CNPAS. OBJECTIVE: To determine the outcome of patients with CNPAS who underwent nasal dilation alone without other surgical therapy. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case series at a tertiary pediatric hospital involving neonates with CNPAS. INTERVENTIONS: Nasal dilation using Hegar cervical dilators in neonates with severe CNPAS. MAIN OUTCOMES AND MEASURES: Avoidance of sublabial pyriform aperture drill-out and length of stay in the hospital after treatment. RESULTS: Four patients (median age, 15 days) had respiratory distress and feeding difficulties. Nasal stenosis was suspected, and maxillofacial computed tomography scans revealed a mean pyriform aperture width of 4.5 mm. Medical therapy was initiated, but symptoms persisted. Direct laryngoscopy, rigid bronchoscopy, and nasal endoscopy with nasal dilation to at least 4 mm were performed in 4 patients without postoperative stenting. Mean length of stay after treatment was 4 days. Two patients underwent repeat nasal dilation on postoperative days 18 and 23. All 4 patients remained free of nasal disease in a median follow-up of 4.5 months. CONCLUSIONS AND RELEVANCE: Four patients with severe CNPAS were successfully treated with nasal dilation without pyriform aperture bone removal or nasal stenting. This series, while small, suggests that nasal dilation may be a therapeutic option for severe CNPAS that decreases the risks of open surgery and subsequent stent use.

Comparison of 2 techniques of tracheocutaneous fistula closure: analysis of outcomes and health care use.

IMPORTANCE: Tracheocutaneous fistula (TCF) can be repaired using various techniques. This research is an outcomes and health care use comparative analysis of 2 commonly used techniques to repair TCF. OBJECTIVES: To compare outcomes and health care use for 2 techniques of TCF repair. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at a tertiary care children's hospital. The study population comprised 50 consecutive patients aged 11 to 216 months who underwent surgical treatment for persistent TCF between January 2007 and August 2012. INTERVENTIONS: Tracheocutaneous fistula closure was achieved using excision of the TCF alone and healing by secondary intent or excision of the TCF plus primary closure over a drain. MAIN OUTCOMES AND MEASURES: Differences in perioperative and postoperative outcomes. RESULTS: In total, 30 patients underwent excision of a TCF plus primary closure over a drain (closure group), and 20 patients underwent excision of a TCF alone and healing by secondary intent (excision group). Statistically, the closure and excision groups were not significantly different regarding gestational age, age at tracheotomy, duration between decannulation and TCF repair, and duration of tracheostomy. The mean (SD) procedure durations were 9.7 (3.7) minutes for the excision group and 37.4 (25.1) minutes for the closure group (P < .001). The mean (SD) lengths of hospital stay were 0.3 (0.5) day for the excision group and 1.1 (0.9) days for the closure group (P = .001). The mean (SD) lengths of intensive care unit stay were 0.0 (0.0) day for the excision group and 1.0 (1.5) day for the closure group (P = .001). Closure success rates were 20 of 22 for the excision group and 30 of 30 for the closure group (P = .17). Complication rates were 0 of 22 for the excision group and 2 of 30 for the closure group (P = .50). CONCLUSIONS AND RELEVANCE: The rates of success and complications were not significantly different between TCF closure and excision groups. Excision of a TCF alone with healing by secondary intent requires less operating room time and shorter hospital stay, which may suggest more efficient health care use.

Pediatric transoral robotic surgery for oropharyngeal malignancy: a case report.

The treatment of oropharyngeal malignancy is associated with numerous functional morbidities. Transoral robotic surgery has been used with increased frequency in adult oropharyngeal malignancy. The benefits include decreased surgical morbidity and improved functional outcomes. Use of transoral robotic has been limited in children. This case represents our experience with a 17-month old child who was diagnosed with a high-grade undifferentiated sarcoma of the soft palate. She was able to be successfully treated with transoral robotic surgery as a part of her multimodal therapy, representing the first case of transoral robotic surgery for an oropharyngeal malignancy in a young child.

Aortopexy for innominate artery tracheal compression in children.

OBJECTIVES: (1) Evaluate the presentation, diagnostic workup, and outcomes of contemporary surgical intervention for airway obstruction from innominate artery tracheal compression in children. (2) Assess the significance of synchronous airway lesions in the treatment of innominate artery tracheal compression. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care children's hospital. METHODS: This study is a retrospective medical record review of 26 consecutive children who underwent aortopexy for innominate artery tracheal compression at a tertiary care children's hospital. Presenting symptoms, diagnostic workup, presence of synchronous airway lesions, length of hospitalization, and treatment outcomes were examined. RESULTS: Twenty-six patients (17 male, 65%) were included in the study. All were diagnosed with bronchoscopy and confirmed with radiographic imaging. Median age at diagnosis and surgery was 9.7 and 10.0 months, respectively. Presenting symptoms included noisy breathing (93%), cough (78%), dyspnea (44%), apnea (44%), cyanosis (19%), and recurrent respiratory infections (15%). Average degree of tracheal compression was 71% (SD, 12%). Fifteen of 26 (58%) patients had synchronous airway lesions, including mild laryngomalacia and subglottic stenosis. Median length of stay was 2 days. Median follow-up was 10 months. Subjective improvement occurred in all 21 patients for whom follow-up information was available. CONCLUSION: Anterior tracheal vascular compression can cause a variety of airway symptoms. Mild synchronous airway lesions are common and do not prevent successful aortopexy. Aortopexy is a viable treatment option for symptomatic anterior tracheal vascular compression from the innominate artery.