Inflammatory molecular endotypes of nasal polyps derived from White and Japanese populations.

BACKGROUND: Emerging evidence suggests that chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with disparate inflammatory characteristics between different racial groups and geographies. Currently, little is known about possible underlying distinguishing factors between these inflammatory differences. OBJECTIVE: Our aim was to interrogate differences in CRSwNP disease between White/non-Asian patients and Japanese patients by using whole transcriptome and single-cell RNA gene expression profiling of nasal polyps (NPs). METHODS: We performed whole transcriptome RNA sequencing with endotype stratification of NPs from 8 White patients (residing in the United States) and 9 Japanese patients (residing in Japan). Reproducibility was confirmed by quantitative PCR in an independent validation set of 46 White and 31 Japanese patients. Single-cell RNA sequencing (scRNAseq) was used to stratify key cell types for contributory transcriptional signatures. RESULTS: Unsupervised clustering analysis identified 2 major endotypes that were present within both cohorts of patients with NPs and had previously been reported at the cytokine level: (1) type 2 endotype and (2) non-type 2 endotype. Importantly, there was a statistically significant difference in the proportion of these endotypes between these geographically distinct subgroups with NPs (P = .03). Droplet-based single-cell RNA sequencing further identified prominent type 2 inflammatory transcript expression: C-C motif chemokine ligand 13 (CCL13) and CCL18 in M2 macrophages, as well as cystatin SN (CST1) and CCL26 in basal, suprabasal, and secretory epithelial cells. CONCLUSION: NPs from both racial groups harbor the same 2 major endotypes, which we have determined to be present in differing ratios between each cohort with CRSwNP disease. Distinct inflammatory and epithelial cells contribute to the type 2 inflammatory profiles observed.

Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers.

Understanding viral tropism is an essential step toward reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, decreasing mortality from coronavirus disease 2019 (COVID-19) and limiting opportunities for mutant strains to arise. Currently, little is known about the extent to which distinct tissue sites in the human head and neck region and proximal respiratory tract selectively permit SARS-CoV-2 infection and replication. In this translational study, we discover key variabilities in expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential SARS-CoV-2 entry factors, among the mucosal tissues of the human proximal airways. We show that SARS-CoV-2 infection is present in all examined head and neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. Finally, we uncover an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in interferon (IFN)-ß1 levels between smokers and non-smokers.

Long-Term Outcomes of Inferior Meatus Augmentation Procedure to Treat Empty Nose Syndrome.

OBJECTIVES/HYPOTHESIS: We sought to report the long-term, symptom-focused, prospective outcomes in empty nose syndrome (ENS) patients after undergoing inferior meatus augmentation procedure (IMAP) through use of four validated questionnaires: Empty Nose Syndrome 6-Item Questionnaire (ENS6Q), 22-item Sino-Nasal Outcome Test (SNOT-22), Generalized Anxiety Disorder 7-Item Scale (GAD-7), and Patient Health Questionnaire-9 (PHQ-9). STUDY DESIGN: Prospective case series. METHODS: A single-center prospective case series was performed for patients diagnosed with ENS who underwent IMAP between July 2017 and February 2020. Diagnosis of ENS was based on the following criteria: 1) reported discomfort with nasal breathing and/or paradoxical nasal obstruction after inferior turbinate reduction, 2) a positive ENS6Q score of at least 11, and 3) a positive cotton test. Questionnaire responses were recorded prior to surgery as well as 1, 3, 6, and 12 months postoperatively. RESULTS: Seventeen eligible patients were included. Mean ENS6Q scores were significantly reduced at all postoperative time points (p < .0001, p < .0001, p < .0001, p = .0003). Of the six ENS6Q subdomains, five (suffocation, dryness, sense of diminished airflow, nasal crusting, and nasal burning) were significantly reduced 1-year postoperatively (p < .0001, p = .0004, p = .0136, p = .0114, p = .0080, respectively). SNOT-22 scores were significantly reduced at all time points (p = .0021, p = .0227, p = .0004, and p = .0025). Of the SNOT-22 subdomains, the sleep subdomain was significantly reduced 1-year postoperatively (p = .0432). Low baseline GAD-7 and PHQ-9 scores were recorded at 7 and 9.4, respectively, and although scores at all postoperative time points were reduced, there was no statistical significance. CONCLUSION: IMAP via implant of cadaveric rib cartilage provides significant, long-term improvements in ENS-specific and general sinonasal symptoms. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2736-E2741, 2021.

Inferior meatus augmentation procedure (IMAP) normalizes nasal airflow patterns in empty nose syndrome patients via computational fluid dynamics (CFD) modeling.

BACKGROUND: Empty nose syndrome (ENS) is a controversial upper airway disorder most commonly associated with tissue loss from the inferior turbinates. The inferior meatus augmentation procedure (IMAP) has been shown to effectively reduce ENS symptoms in a durable manner, but the precise mechanisms that may govern this symptomatic improvement remain unknown. METHODS: Five patients with ENS who underwent bilateral IMAP via submucosal costal cartilage implant were assessed. Pre-implant and 6 months post-implant computed tomography (CT) imaging for each ENS patient was analyzed in a blinded fashion using computational fluid dynamics (CFD) modeling to investigate intrapatient changes in airflow parameters. RESULTS: Following surgery, ENS patients have significantly improved symptoms as indexed by Empty Nose Syndrome 6-Item Questionnaire (ENS6Q) scoring (pre-implant: 14.00 ± 4.06 [mean ± standard deviation]; 95% confidence interval [CI], 10.44 to 17.56; post-implant: 4.8 ± 2.77; 95% CI, 2.37 to 7.23; Cohen's d = 2.64; p = 0.02). Using CFD, a significant shift in nasal airflow patterns was observed, where airflow deviates away from the middle meatus upon hitting the implant (pre-implant: 67.13% ± 11.14%; 95% CI, 60.22% to 74.04%; post-implant: 46.18% ± 12.81%; 95% CI, 38.23% to 54.12%; d = 1.74; p < 0.05) toward the inferior meatus (pre-implant: 30.55% ± 11.29%; 95% CI, 23.55% to 37.55%; post-implant: 42.59% ± 9.60%; 95% CI, 36.63 to 48.54%; d = 1.14; p < 0.05). No significant changes were found in nasal resistance (pre-implant: 0.102 ± 0.015; 95% CI, 0.092 to 0.112 Pa*s/mL; post-implant: 0.105 ± 0.041; 95% CI, 0.081 to 0.130 Pa*s/mL). In addition, the improvement of ENS6Q scoring significantly correlated with percent reduction in aberrant airflow through the middle meatus (R2 = 0.60, p = 0.04). CONCLUSION: This study supports our prior working hypothesis that disordered vectors of nasal airflow congregate in the middle meatus contribute to ENS symptoms, not nasal resistance. Moreover, these data illuminate a paradoxical, but consistent, restoration of nasal airflow to the inferior meatus following the replacement of turbinate tissue volume in the inferior meatus via IMAP surgery, potentially due to the Coanda effect.

ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs.

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.

Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers.

We investigated the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of healthy human donors. We detected ACE2 protein expression within the cilia organelle of ciliated airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during respiratory transmission. We further determined whether ACE2 expression in the cilia of upper respiratory cells was influenced by patient demographics, clinical characteristics, co-morbidities, or medication use, and found no evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) increases ACE2 protein expression.

Nasal vestibular body treatment for recalcitrant nasal obstruction.

BACKGROUND: The nasal vestibular body (NVB) is a recently reported dynamic swell body present in the inferolateral internal nasal valve. The contribution of NVB presence to persistent nasal obstruction, and effects of NVB treatment, are undefined. METHODS: Thirty-five patients with recalcitrant nasal obstruction and NVB presence were retrospectively reviewed between 2013 and 2019, including 25 patients (48 sides) who had NVBs reduced via radiofrequency ablation (RFA) and 10 patients (20 sides) who had untreated NVBs. Posttreatment healing and complications were reviewed at early (<1 month) and late (mean, 7.3 months) time-points after RFA of the NVB. A subset of the NVB-treatment patients (18 of 25 patients) were compared with 10 NVB-control patients for pre-/posttreatment outcomes using 22-item Sino-Nasal Outcome Test (SNOT-22) and subdomain scoring. RESULTS: NVBs were successfully reduced in 100% of cases (48 of 48 sides) over both time-points. Early sequelae of NVB treatment, such as local crusting (22 of 23, 95.6%) and bone exposure (4 of 23, 17.3%), resolved by the late time-point, with complete remucosalization (23 of 23, 100%) of all NVB treatment sites. No persistent pain, sensory loss, or pyriform aperture stenosis was noted from any patient/side. Significant reductions between mean pre- and postoperative SNOT-22 (-24, p = 0.001) and individual subdomain (-2, p = 002) scores were seen in the NVB-treatment patients compared to the reductions in NVB-controls (-8 and -1, respectively, both p > 0.001). CONCLUSION: NVB treatment using RFA is safe and highly effective, providing complete swell body reduction with only transient local morbidity. NVB presence contributes to persistent/recalcitrant nasal obstruction, with significant improvement in nasal airway function noted after NVB soft tissue reduction.

Inferior Meatus Augmentation Procedure (IMAP) to Treat Empty Nose Syndrome: A Pilot Study.

Our understanding of empty nose syndrome (ENS) continues to evolve. Prior studies evaluating airway augmentation to treat ENS did not use validated disease-specific questionnaires, making the true impact of these surgeries unclear. We present a case series of 10 patients with ENS (11 procedures) who underwent the inferior meatus augmentation procedure (IMAP) between September 2014 and May 2017. Subjective outcomes of IMAP included comparisons of preoperative and postoperative assessments (1 week, 1 month, 3 months, 6 months) using the Empty Nose Syndrome 6-item Questionnaire (ENS6Q), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7-item Scale (GAD-7), and Sino-Nasal Outcome Test-22 (SNOT-22). The decrement in ENS6Q scores observed maintained statistical significance at 6 months (P ≤ .001). Similar results were achieved with PHQ-9, GAD-7, and SNOT-22 (P ≤ .01, P ≤ .01, P ≤ .001, respectively). IMAP can dramatically improve the quality of life of ENS patients regarding both ENS-specific symptoms and psychological well-being.

The cotton test redistributes nasal airflow in patients with empty nose syndrome.

BACKGROUND: Empty nose syndrome (ENS) remains a controversial disease primarily associated with inferior turbinate tissue loss. Cotton placement into the inferior meatus often alleviates ENS symptoms within minutes, but the physiologic explanation for this phenomenon is unknown. Computational fluid dynamics (CFD) was employed to evaluate the mechanisms of altered nasal airflow conferred by cotton testing. METHODS: Six ENS patients (12 sides) with pre-existing sinus computed tomography (CT) imaging were enrolled after marked symptomatic improvement (decrease in score on the Empty Nose Syndrome 6-Item Questionnaire [ENS6Q] of >7 points) with office-based cotton testing. The fashioned cotton plug was labeled in situ with iohexol contrast spray, and sinus CT was immediately obtained to detect cotton contouring in the inferior meatus. CT imaging from pre- and post-cotton placement was analyzed using comparative CFD techniques. RESULTS: After cotton placement, significant symptomatic improvement and reduced ENS6Q scores (16.8 ± 4.1 to 3.1 ± 2.4; p < 0.001) were recorded. Using CFD, cotton placement produced an expected 21% increase in upper airway resistance (p < 0.05). However, a significant shift in the nasal airflow distribution was also detected, with a transition of airflow vectors away from a middle meatus jetstream (-41%; p < 0.002). CONCLUSION: Objective CFD assessment confirmed that the cotton test not only increases nasal resistance, but also restores airflow distribution to the inferior meatus in symptomatic ENS patients. These results highlight the potential efficacy of cotton test in ENS patients and further bolster the utility of this tool in identifying appropriate candidates for the inferior meatus augmentation procedure.

The effect of topical epinephrine 1:1000 with and without infiltration of 1% lidocaine with epinephrine 1:100,000 on endoscopic surgical field visualization: a double-blind randomized controlled study.

BACKGROUND: The objective of this study is to determine whether the infiltration of 1% lidocaine with 1:100,000 epinephrine in addition to topical application of 1:1000 epinephrine significantly improves surgical field grading scale score over topical 1:1000 epinephrine alone. METHODS: A prospective, double-blind, randomized, controlled study was performed of 40 patients undergoing bilateral endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS). Patients were enrolled and randomly assigned to receive infiltration with 1% lidocaine with 1:100,000 epinephrine on 1 side of the nasal cavity vs plain saline on the other side in preparation for ESS. Both groups received topical application of 1:1000 epinephrine. Surgical videos were recorded and Wormald surgical field grading scale was assigned by 2 blinded reviewers. The number of extra 1:1000 epinephrine pledgets used during the surgery, estimated blood loss, and surgical duration were also recorded. RESULTS: There were no statistically significant differences in Wormald surgical field grading scale, number of extra pledgets used, or estimated blood loss between the nasal cavity side infiltrated with 1% lidocaine with 1:100,000 epinephrine in comparison to infiltration with saline. The side infiltrated with 1% lidocaine with 1:100,000 epinephrine had a reduced operative time compared to the side infiltrated with saline (p = 0.002). There were no differences in postoperative bleeding from questionnaire completed by patient at the first postoperative visit. CONCLUSION: Addition of infiltration of 1% lidocaine with epinephrine 1:100,000 to topical application of epinephrine 1:1000 for preparation of ESS does not significantly improve surgical field of view compared to topical epinephrine alone.

The Sternocleidomastoid Myocutaneous Flap: A Laryngeal Preservation Option for Total Hypopharyngoesophageal Stenosis.

Complete hypopharyngoesophageal (HPE) stenosis is rare and a challenging condition to treat. When endoscopic therapy fails, total laryngectomy with or without pharyngeal reconstruction is usually performed. We present a retrospective case series involving 3 patients with complete HPE stenosis who failed endoscopic repair and were gastrostomy dependent. All were managed successfully with the sternocleidomastoid myocutaneous (SCM) flap. A temporary fistula occurred in 1 patient. Hospitalization ranged from 5 to 15 days, patients resumed oral intake from 21 to 82 days postoperatively, and their gastrostomy tubes were removed from 28 to 165 days postoperatively. We suggest that the SCM flap is a laryngeal preservation option for reconstruction of complete HPE stenosis when endoscopic techniques fail. This flap allows HPE repair and reconstruction within the same surgical field, imposes no significant donor site morbidity, and affords good functional and cosmetic outcomes.

Rates of symptomatology are lower in recurrent sinonasal malignancy than in other recurrent cancers of the head and neck: a multi-institutional study.

BACKGROUND: Sinonasal malignancies are a rare subset of head and neck tumors, and surveillance strategies after definitive tumor treatment are often generalized from those for overall head and neck cancer outcomes data. However, recent literature suggests that the posttreatment period in sinonasal cancer is fundamentally different and a more tailored surveillance approach may be beneficial. Although rates of symptomatology are high in head and neck cancer recurrence and patient-driven follow-up is common, rates of symptomatology are unknown in sinonasal cancer specifically. METHODS: Patients with recurrence of sinonasal malignancy were identified at 3 academic rhinology and skull base surgery centers. Demographic, tumor, and treatment data were collected. Rates of symptomatology at presentation were tabulated and examined in the context of several other variables. RESULTS: Fifty-five patients had recurrence of sinonasal malignancy after definitive treatment. Fifty-one percent of patients had no suspicious symptoms at the time of tumor recurrence, with an average time to recurrence of 33 months. Male patients and patients with stage IVA or lower disease were significantly more likely to be asymptomatic at the time of recurrence (p < 0.05). CONCLUSION: Patients with sinonasal malignancy have a much lower rate of symptomatology during tumor recurrence than that observed in head and neck cancer overall. Furthermore, time to recurrence is substantially longer, as a majority of head and neck cancer recurrences occur in the first 12 months after treatment. These differences highlight the need for more tailored surveillance paradigms in asymptomatic patients with a history of a definitively treated sinonasal neoplasm.

Use of intranasal submucosal fillers as a transient implant to alter upper airway aerodynamics: implications for the assessment of empty nose syndrome.

BACKGROUND: Empty nose syndrome (ENS) is a debilitating condition associated with inferior turbinate tissue loss. Surgical augmentation of the inferior meatus has been proposed to treat ENS, although efficacy data with validated, disease-specific questionnaires is limited. Instead we evaluated submucosal injection of a transient, resorbable filler into the inferior meatus to favorably alter nasal aerodynamics in ENS patients. METHODS: Patients with a history of inferior turbinate reduction, diagnosed with ENS via Empty Nose Syndrome 6-Item Questionnaire (ENS6Q) and cotton testing, were enrolled and underwent submucosal injection of carboxymethylcellulose/glycerin gel (Prolaryn®) into the inferior meatuses between July 2014 and May 2018. This material likely resorbs over several months. Outcomes included comparisons of preinjection and postinjection symptoms at 1 week, 1 month, and 3 months using the ENS6Q, 22-item Sino-Nasal Outcome Test (SNOT-22), Generalized Anxiety Disorder 7-item scale (GAD-7), and Patient Health Questionnaire-9 (PHQ-9). RESULTS: Fourteen patients underwent injections. Mean ENS6Q scores significantly decreased from baseline at 1 week (20.8 vs 10.5; p < 0.0001), and remained reduced but upward-trending at 1 month (13.7, p = 0.002) and 3 months (15.5, p > 0.05) following injections. Mean SNOT-22 scores significantly decreased at 1 week (p = 0.01) and 1 month (p = 0.04), mean GAD-7 at 1 month (p = 0.02) and 3 months (p = 0.02), and mean PHQ-9 at 1 week (p = 0.01) and 1 month (p = 0.004) postinjection. CONCLUSION: Transient, focal airway bulking via submucosal filler injection at sites of inferior turbinate tissue loss markedly benefits ENS patients, suggesting that aberrant nasal aerodynamics from inferior turbinate tissue loss contributes to (potentially reversible) ENS symptoms.

Microcurrent technology for rapid relief of sinus pain: a randomized, placebo-controlled, double-blinded clinical trial.

BACKGROUND: Transcutaneous electrical nerve stimulation has proven to be effective in alleviating chronic pain from facial myalgias. We evaluated the efficacy of a novel handheld microcurrent-emitting device in short-term, office-based treatment of patients with sinus pain. This device, which is U.S. Food and Drug Administration (FDA)-cleared, detects and treats regions corresponding to nerve fibers. METHODS: Randomized, double-blinded, placebo-controlled trial. Seventy-one participants with facial pain attributed to self-reported nasal/sinus disease were recruited from a tertiary rhinologic practice and the surrounding community and randomly assigned to either office-based use of an active (n = 38) or placebo (n = 33) microcurrent emitter. The study device was repetitively applied by each patient to the bilateral periorbital areas for 5 minutes. A visual analogue scale (VAS) for pain severity was administered before, and 10 minutes after, treatment. RESULTS: Active microcurrent-treated patients had a reduction in mean pain score from 5.63 pretreatment to 3.97 posttreatment (mean difference, 1.66; 95% confidence interval [CI], 1.20 to 2.12). Patients using the sham device also reported sinus pain reductions (mean difference, 0.91; 95% CI, 0.61 to 1.21). However, the active device demonstrated a significantly greater reduction in pain compared to sham (0.75-point difference, p = 0.007). Notably, 23.7% of patients using the active device had a reduction of 3 or more points by VAS compared to 0% of sham device patients (p = 0.003). One minor occurrence of transient facial skin erythema was noted. CONCLUSION: This trial suggests that treatment of rhinologic facial pain using this noninvasive microcurrent device is safe and effective in providing rapid relief of nasal/sinus pain. Additional studies with longer term follow-up are warranted.

Precision medicine: why surgeons deviate from "appropriateness criteria" in the management of chronic rhinosinusitis and effects on outcomes.

BACKGROUND: In uncomplicated chronic rhinosinusitis (CRS), a consensus regarding appropriate medical therapy (AMT) before surgical intervention has been published in the form of "appropriateness criteria" for endoscopic sinus surgery (ESS). We sought to determine why tertiary surgeons may deviate from the suggested criteria and evaluated whether those deviations result in change in outcomes. METHODS: Patients with uncomplicated CRS were prospectively enrolled over the course of 1 year. The 22-item Sino-Nasal Outcomes Test (SNOT-22), a general health outcome out of 100, and a physician form, indicating management pathway and decision making, was completed at each visit over a 6-month follow-up period. A descriptive analysis was used to quantify reasons for veering from the "appropriateness criteria," and repeated linear regression modeling was used to measure whether compliance impacted SNOT-22, general health, and Lund-Kennedy (LK) scores over the period of study. RESULTS: One hundred fifty-five patients were enrolled. Sixty-eight percent followed the appropriate management pathway based on their presentation and the suggested criteria. Disparate reasons were documented for deviation in the other 32%, and, despite establishing several predictive categories, "other" was the most common reason, with various explanations well documented. SNOT-22, general health, and LK scores were not statistically impacted by compliancy status (p > 0.05). CONCLUSION: The suggested "appropriateness criteria" predict a management pathway for the majority of CRS patients. However, in a tertiary sinus center, surgeons may deviate from that model with a significant minority of their patients, for multiple reasons, without causing a change in outcomes.

Evidence for a 'preinvasive' variant of fungal sinusitis: Tissue invasion without angioinvasion.

Clinical experience has suggested the existence of an intermediate form of fungal sinusitis between the categories of non-invasive fungal sinusitis (non-IFS) and invasive fungal sinusitis (IFS). This fungal sinusitis variant demonstrates unhealthy mucosa by endoscopy with fungal invasion, but lacks angioinvasion microscopically, representing what clinically behaves as a 'pre-invasive' subtype of fungal sinusitis. Unlike non-IFS disease, patients with pre-invasive fungal sinusitis were still felt to require anti-fungal medications due to histologic presence of invasive fungus. While sharing some clinical features of IFS, these 'intermediate' patients were successfully spared extended and repeated surgical debridements given the microscopic findings, and have been successfully treated with shorter courses of antifungal therapy. These select patients have had favorable outcomes when managed in a judicious and semi-aggressive manner, in an undefined zone between the treatments for routine fungal ball and aggressive IFS.