IL-13-associated epithelial remodeling correlates with clinical severity in nasal polyposis.

BACKGROUND: Epithelial remodeling is a histopathologic feature of chronic inflammatory airway diseases including chronic rhinosinusitis (CRS). Cell-type shifts and their relationship to CRS endotypes and severity are incompletely described. OBJECTIVE: We sought to understand the relationship of epithelial cell remodeling to inflammatory endotypes and disease outcomes in CRS. METHODS: Using cell-type transcriptional signatures derived from epithelial single-cell sequencing, we analyzed bulk RNA-sequencing data from sinus epithelial brushings obtained from patients with CRS with and without nasal polyps in comparison to healthy controls. RESULTS: The airway epithelium in nasal polyposis displayed increased tuft cell transcripts and decreased ciliated cell transcripts along with an IL-13 activation signature. In contrast, CRS without polyps showed an IL-17 activation signature. IL-13 activation scores were associated with increased tuft cell, goblet cell, and mast cell scores and decreased ciliated cell scores. Furthermore, the IL-13 score was strongly associated with a previously reported activated ("polyp") tuft cell score and a prostaglandin E2 activation signature. The Lund-Mackay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, prostaglandin E2, and IL-13 signatures and negatively with ciliated cell transcriptional signatures. CONCLUSIONS: These results demonstrate that cell-type alterations and prostaglandin E2 stimulation are key components of IL-13-induced epithelial remodeling in nasal polyposis, whereas IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13-driven epithelial remodeling.

Use of Real-Time Superior Hypophyseal Artery Indocyanine Green Angiogram During Endoscopic Resection of a Third Ventricular Craniopharyngioma: 2-Dimensional Operative Video.

The endoscopic endonasal approach for resection of craniopharyngiomas has gained popularity because of its minimal need for retraction and superior visualization of and access to the optic chiasm.1-4 Despite these advantages, the proximity of craniopharyngiomas to the optic apparatus still challenges the preservation of visual function.5-10 Indocyanine green (ICG) angiography can evaluate the perfusion of the chiasm and can predict visual outcomes after endonasal approaches, in addition to known uses of the dye.3 ICG angiography may therefore hold promise in the real-time assessment of optic chiasm perfusion during resection of craniopharyngiomas by delineating details of the superior hypophyseal artery (SHA) system. Here, we present a case in which ICG angiogram was used to assess the perfusion of the chiasm before, during, and after tumor resection. This technique signaled thrombosis of the left principal SHA during tumor resection that was compensated by the anastomotic SHA system from the right. The case shows an endoscopic endonasal approach for the resection of a third ventricular craniopharyngioma in a 21-year-old woman presenting with unremitting headaches, endocrine dysfunction, and vision loss. Postoperatively, the patient's neurological examination remained unchanged and visual function improved within 2 weeks. This case underscores the potential for real-time intraoperative ICG angiography to assist in the careful resection of craniopharyngiomas while improving visual outcomes. Institutional review board approval was not required; the patient consented to the procedure and to publishing of the operative video.

In office sampling of eosinophil peroxidase to diagnose eosinophilic chronic rhinosinusitis.

BACKGROUND: Practical biomarkers for endotypic characterization of chronic rhinosinusitis (CRS) remain elusive, hindering clinical utility. Eosinophil peroxidase (EPX) is an enzyme released by activated eosinophils. The objective of this study was to evaluate a clinic EPX assay as a marker of eosinophilic CRS. METHODS: Subjects with and without CRS presenting to a tertiary care rhinology clinic were prospectively enrolled, and nasal cytology brushings were collected from the middle meatus during in-clinic nasal endoscopy. ELISA assay was used to quantify EPX levels, and a customized multiplex immunoassay was used to quantify inflammatory cytokine mediators. Findings were correlated with clinical data. RESULTS: Forty-two subjects were enrolled, including 31 CRS subjects and 11 controls. Median EPX levels were 125.0 ng/mL (standard deviation [SD] 1745.8) and 6.5 ng/mL (SD 99.0) for CRS group and controls, respectively (p = 0.003). EPX levels were associated with history of asthma (p = 0.015), allergies (p = 0.028), polyps (p = 0.0006), smell loss (p = 0.006), and systemic eosinophilia or elevated immunoglobulin E (p ≤ 0.0001). Twenty-eight subjects from both the CRS and control groups had prior pathology for comparison, with histologic confirmation of local tissue eosinophilia (>10 eosinophils/hpf) in 11 subjects. This subgroup had a median EPX level of 967.5 ng/mL compared to 10.6 ng/mL in 17 subjects without local tissue eosinophilia (p = 0.0008). EPX levels were positively correlated to interleukin-5 levels (p = 0.0005). CONCLUSION: EPX levels can be measured via well-tolerated in-clinic collection of nasal mucus. EPX levels are associated with clinical markers of type 2 inflammation and tissue eosinophilia and may provide a valuable diagnostic tool to delineate eosinophilic CRS.

Formal Closure of Endoscopic Endonasal Skull Base Defects With a "Bow Tie" Tri-Layer Graft.

OBJECTIVE: Risk factors for a postoperative cerebrospinal fluid leak (CSF) after surgery include an intraoperative high flow of CSF, elevated body mass index, defect size, and defect site. In our prior series, a high postoperative CSF leak rate for tumors of the central skull base (planum, sella, and clivus) appeared to be due to graft migration. We changed our closure technique from a single layer of collagen +/- fat graft to a novel graft, termed a "Bow tie" (a tri-layer fat graft with two pieces of collagen matrix), and report our results in this study. METHODS: Retrospective temporal epoch study of a single otolaryngologist's experience of closing skull base defects in our skull base center from 2005 to 2017. RESULTS: One hundred and forty-nine patients met inclusion criteria in two time periods, pre- and post-introduction of the Bow tie technique. In epoch I, from 2005 to 2013, 79 patients had reconstruction with a single layer of dural graft (25 had additional free fat graft). In epoch II, from 2014 to 2017, 70 patients had reconstruction with the Bow tie. RESULTS: CSF leak rates were 8.7% overall: 15.2% in epoch I and 1.4% in epoch II (p = 0.01). After controlling the procedure, defects with a size greater than 2 cm had a 5.7 greater likelihood of failure. Epoch II had a lower incidence of major complications. CONCLUSION: Using a single surgeon's experience, the multilayer Bow tie has a significant reduction in postoperative CSF leak and associated major complications for defects of the central skull base. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1568-1575, 2023.

Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome.

Mutations in SLC26A4 cause nonsyndromic hearing loss associated with an enlarged vestibular aqueduct (EVA, also known as DFNB4) and Pendred syndrome (PS), the most common type of autosomal-recessive syndromic deafness. In many patients with an EVA/PS phenotype, mutation screening of SLC26A4 fails to identify two disease-causing allele variants. That a sizable fraction of patients carry only one SLC26A4 mutation suggests that EVA/PS is a complex disease involving other genetic factors. Here, we show that mutations in the inwardly rectifying K(+) channel gene KCNJ10 are associated with nonsyndromic hearing loss in carriers of SLC26A4 mutations with an EVA/PS phenotype. In probands from two families, we identified double heterozygosity in affected individuals. These persons carried single mutations in both SLC26A4 and KCNJ10. The identified SLC26A4 mutations have been previously implicated in EVA/PS, and the KCNJ10 mutations reduce K(+) conductance activity, which is critical for generating and maintaining the endocochlear potential. In addition, we show that haploinsufficiency of Slc26a4 in the Slc26a4(+/-) mouse mutant results in reduced protein expression of Kcnj10 in the stria vascularis of the inner ear. Our results link KCNJ10 mutations with EVA/PS and provide further support for the model of EVA/PS as a multigenic complex disease.

IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function.

Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single-cell RNA sequencing of airway epithelium and mouse modeling, we found that IL-13 expanded and programmed airway tuft cells toward eicosanoid metabolism and that tuft cell deficiency led to a reduction in airway prostaglandin E2 (PGE2) concentration. Allergic airway epithelia bore a signature of PGE2 activation, and PGE2 activation led to cystic fibrosis transmembrane receptor-dependent ion and fluid secretion and accelerated mucociliary transport. These data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.

Short-term chemosensory distortions and phantoms in COVID-19.

Objective: To identify differentiation features of chemosensory dysfunction in COVID-19 infection and their primary drivers. Study Design: Cross-sectional cohort comparison. Methods: A national anonymous survey was used to query participants regarding nasal symptoms and chemosensory dysfunction including sensitivity levels, and presence or absence of distortions and phantoms within the 6-week time window surrounding their COVID-19 testing and survey completion. Results: Three-hundred and sixty-four respondents who reported COVID-19 positive (COVID+; n = 176) or COVID-19 negative (COVID-; n = 188) test results completed the survey. The COVID+ cohort had higher occurrence rates for: (a) chemosensory sensitivity impairments (67.0% vs 30.3%; P < .01), where the rate of complete loss of smell (anosmia) or taste (ageusia) was higher (35.8% vs 4.8%; P < .01), and (b) chemosensory distortions (39.8% vs 19.1%; P < .01), where the rate of anosmia or ageusia with distortions was also higher in the COVID+ cohort (19.9% vs 2.7%; P < .01). Occurrence rates in the two cohorts were similar for chemosensory phantoms (COVID+ 17.0%, COVID- 18.6%; P = .70) and nasal discharge or stuffiness in the presence of sensitivity impairment (COVID+ 63.6%, COVID- 52.6%; P = .17). Conclusion: Chemosensory dysfunction in COVID-19 is associated with higher rates of smell or taste sensitivity impairments and distortions. Higher rates of anosmia and ageusia drive these key findings. Chemosensory phantoms and nasal symptoms in the presence of sensitivity impairment occur at rates that should demand clinical attention, but they do not appear to be specific to COVID-19 positivity. Level of Evidence: 2b.

Septum submucosal glands exhibit aberrant morphology and reduced mucin production in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is characterized by significant accumulation and thickening of mucus in the sinonasal cavities. One contributor of aberrant mucus production and impaired mucociliary clearance (MCC) is altered function of the sinonasal submucosal glands (SMGs), yet contributions of SMGs to upper airway disease initiation and progression remain unknown. The objective of this study was to characterize the morphology and secretory cell identities of the nasal septum SMGs in both healthy and CRS adults. METHODS: Biopsies from adult participants with CRS without nasal polyps (CRSsNP, n = 4), CRS with nasal polyps (CRSwNP, n = 8), and non-CRS controls (n = 14) were collected from the posterior septum. Glandular morphology and mucus markers were investigated using histological techniques and high-resolution confocal microscopy. RESULTS: Analysis revealed a significant decrease in gland density in the posterior septum of CRSsNP (28% ± 6.15%) and CRSwNP (23% ± 3.09%) compared to control participants (53% ± 1.59%, p < 0.0001). Further analysis of the CRS SMG secretory function revealed an overall decrease in Mucin 5B+ gland mucus being produced. Dilated and cystic ductal structures filled with inspissated mucus were also common to CRS glands. CONCLUSION: Here, we describe a significant alteration in SMG structure and function in the adult CRS posterior septum suggesting reduced gland contribution to MCC. The SMGs of both the nose and sinuses may represent targets for future therapeutic approaches.

The impact of frailty on perioperative outcomes and resource utilization in sinonasal cancer surgery.

OBJECTIVES/HYPOTHESIS: Frailty is a measure of decreased physiologic reserve that has been associated with adverse outcomes in older surgical patients. We aimed to measure the association of preoperative frailty with outcomes in patients undergoing sinonasal cancer surgery. STUDY DESIGN: Retrospective cohort study. METHODS: We identified 5,346 patients in the Nationwide Readmissions Database undergoing sinonasal cancer surgery from 2010 to 2014. Frailty was defined using the Johns Hopkins Adjusted Clinical Groups frailty-defining diagnoses indicator. Multivariate regression was used to analyze the association of frailty with postoperative outcomes. RESULTS: Frailty was present in 7.4% of patients. Frailty was a significant independent predictor of intensive care unit-level complications (odds ratio [OR]: 4.83; 95% confidence interval [CI]: 2.95-7.93; P < .001) and nonhome discharge (OR: 3.07; 95% CI: 1.68-5.60; P < .001). Compared to nonfrail patients, frail patients had threefold longer median length of stay (12 days vs. 4 days; P < .001) and more than twofold higher median hospital costs ($44,408 vs. $18,660; P < .001). Frailty outperformed advanced comorbidity (defined as Charlson-Deyo score ≥3), age ≥80 years, and markers of surgical complexity (e.g., skull base/orbit involvement, flap reconstruction, neck dissection) in predicting serious complications, nonhome discharge, length of stay, and hospital costs. CONCLUSIONS: Frailty appears to have a stronger and more consistent association with adverse outcomes and increased resource utilization after sinonasal cancer surgery than age or comorbidity index. This information may be used in surgical risk stratification and can guide strategies to prevent or mitigate adverse events in this high-risk group. LEVEL OF EVIDENCE: NA Laryngoscope, 130:290-296, 2020.

Temporal Profile of Olfactory Dysfunction in COVID-19.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with olfactory dysfunction, but the evolution of the olfactory loss and timeline to recovery are largely unknown. This study examines changes in smell sensitivity in COVID-19-positive (COVID+) and COVID-19-negative (COVID-) viral illness during the initial weeks after infection. STUDY DESIGN: Cross-sectional cohort comparison. SETTING: National anonymous surveys. METHODS: Survey participants were queried about smell sensitivity and general health status at the time of COVID-19 testing and in the weeks that followed. RESULTS: In total, 375 (174 COVID+, 201 COVID-) participants completed the survey and 132 (62 COVID+, 70 COVID-) participants completed the 2-week follow-up survey. Normal smell in the COVID+ cohort was less frequent at the time of testing and at follow up (P < .05). Dynamic changes in smell sensitivity in the COVID+ cohort were more frequent in the initial weeks (P < .001). In those with normosmia at the start of infection, 38% of the COVID+ cohort reported worsening smell compared to only 8% in the COVID- cohort (P < .05). Recovery of overall health was associated with normosmia at the time of infection and improvement of smell sensitivity within weeks of infection. CONCLUSION: The COVID+ cohort showed greater dynamic change in smell sensitivity and a higher rate of persistent olfactory dysfunction in the weeks after infection. Normal smell at the time of COVID-19 infection may still worsen before recovery. Overall health recovery after viral illness is associated with improvement in smell sensitivity and the absence of initial anosmia or hyposmia.

Smell and taste symptom-based predictive model for COVID-19 diagnosis.

BACKGROUND: The presentation of coronavirus 2019 (COVID-19) overlaps with common influenza symptoms. There is limited data on whether a specific symptom or collection of symptoms may be useful to predict test positivity. METHODS: An anonymous electronic survey was publicized through social media to query participants with COVID-19 testing. Respondents were questioned regarding 10 presenting symptoms, demographic information, comorbidities, and COVID-19 test results. Stepwise logistic regression was used to identify predictors for COVID-19 positivity. Selected classifiers were assessed for prediction performance using receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 145 participants with positive COVID-19 testing and 157 with negative results were included. Participants had a mean age of 39 years, and 214 (72%) were female. Smell or taste change, fever, and body ache were associated with COVID-19 positivity, and shortness of breath and sore throat were associated with a negative test result (p < 0.05). A model using all 5 diagnostic symptoms had the highest accuracy with a predictive ability of 82% in discriminating between COVID-19 results. To maximize sensitivity and maintain fair diagnostic accuracy, a combination of 2 symptoms, change in sense of smell or taste and fever was found to have a sensitivity of 70% and overall discrimination accuracy of 75%. CONCLUSION: Smell or taste change is a strong predictor for a COVID-19-positive test result. Using the presence of smell or taste change with fever, this parsimonious classifier correctly predicts 75% of COVID-19 test results. A larger cohort of respondents will be necessary to refine classifier performance.

Endoscopic skull base and transoral surgery during COVID-19 pandemic: Minimizing droplet spread with negative-pressure otolaryngology viral isolation drape.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has raised concern of transmission of infectious organisms through aerosols formation in endonasal and transoral surgery. METHODS: Retrospective review. We introduce the negative-pressure otolaryngology viral isolation drape (NOVID) system to reduce the risk of aerosol. NOVID consists of a plastic drape suspended above the patient's head and surgical field with a smoke evacuator suction placed inside the chamber. RESULTS: Four patients underwent endonasal (4) and endo-oral surgery (1). Fluorescein was applied to the surgical field. Black light examination of fluorescein-treated operative fields revealed minimal contamination distant to the surgical field. In two prolonged cases with high-speed drilling, droplets were identified under the barrier and on the tip of the smoke evacuator. Instruments and cottonoids appeared to be a greater contributor to field contamination. CONCLUSIONS: Negative-pressure aspiration of air under a chamber barrier, which appears to successfully keep aerosol and droplet contamination to a minimum.

Immunoglobulin replacement therapy reduces chronic rhinosinusitis in patients with antibody deficiency.

BACKGROUND: Patients with primary antibody deficiencies have an increased frequency of sinonasal and pulmonary infections. Immunoglobulin (Ig) replacement is a standard therapy for common variable immunodeficiency (CVID) and other antibody deficiency diseases. Although there is convincing evidence that Ig replacement reduces pulmonary infections, there is little evidence that it reduces sinus infections or abates chronic rhinosinusitis (CRS). This study aims to identify the impact of Ig replacement on CRS in antibody deficiencies. METHODS: A single-center, retrospective chart review of adult patients from 1995 to 2015 was performed. Inclusion criteria were diagnosis of CVID or specific antibody deficiency (SAD), history of CRS requiring medical and/or surgical management within the year prior to presentation, treatment with Ig replacement therapy, and follow-up interval of at least 1 year after initiating Ig replacement. Patients with secondary immune deficiencies were excluded. Thirty-one patients met criteria. Data collected included pretreatment and posttreatment Lund-Mackay scores, and frequency of sinusitis and pulmonary infections requiring rescue antibiotics. Statistical analysis was performed using Wilcoxon signed-rank tests. RESULTS: A significant decline in the Lund-Mackay score was evidenced from pretreatment to posttreatment (p < 0.01). Treatment also resulted in significantly lower rates of sinusitis (p < 0.01) and pulmonary infections (p < 0.01). Additionally, 56% of patients who were on prophylactic antibiotics prior to Ig replacement were able to discontinue their use. CONCLUSION: We present objective evidence showing that Ig replacement therapy has a positive impact on the frequency of sinusitis and confirm its positive impact on pulmonary infections in adult patients with CVID and SAD.