Immunological memory diversity in the human upper airway.

The upper airway is an important site of infection, but immune memory in the human upper airway is poorly understood, with implications for COVID-19 and many other human diseases1-4. Here we demonstrate that nasal and nasopharyngeal swabs can be used to obtain insights into these challenging problems, and define distinct immune cell populations, including antigen-specific memory B cells and T cells, in two adjacent anatomical sites in the upper airway. Upper airway immune cell populations seemed stable over time in healthy adults undergoing monthly swabs for more than 1 year, and prominent tissue resident memory T (TRM) cell and B (BRM) cell populations were defined. Unexpectedly, germinal centre cells were identified consistently in many nasopharyngeal swabs. In subjects with SARS-CoV-2 breakthrough infections, local virus-specific BRM cells, plasma cells and germinal centre B cells were identified, with evidence of local priming and an enrichment of IgA+ memory B cells in upper airway compartments compared with blood. Local plasma cell populations were identified with transcriptional profiles of longevity. Local virus-specific memory CD4+ TRM cells and CD8+ TRM cells were identified, with diverse additional virus-specific T cells. Age-dependent upper airway immunological shifts were observed. These findings provide new understanding of immune memory at a principal mucosal barrier tissue in humans.

Pro-inflammatory markers associated with COVID-19-related persistent olfactory dysfunction.

INTRODUCTION: While localized inflammation has been implicated in the pathophysiology of acute coronavirus disease of 2019 (COVID-19) olfactory dysfunction (OD), persistent COVID-19 OD remains poorly understood with limited therapeutics. Our prospective study evaluated olfactory cleft (OC) biomarkers as predictors of persistent OD in mucus sampling. METHODS: COVID-19 subjects with persistent OD >3 months confirmed by psychophysical olfaction tests were compared to COVID-19 subjects with no OD and those with no prior infection. OC mucus samples were evaluated for 13 anti-viral and inflammatory biomarkers. Cohorts were compared using analysis of variance (ANOVA) and Mann-Whitney tests with multi-comparison adjustment. Viral RNA was assessed through RT-PCR using the COVID-19 N2 primer. RESULTS: Thirty-five samples were collected (20 COVID persistent OD, 8 COVID no OD, and 7 non-COVID no OD). Significant differences in IFN-λ1 (p = 0.007) and IFN-γ (p = 0.006) expression in OC mucus were found across all three groups, with the highest cytokine concentrations corresponding to COVID OD. IFN-α2 levels were elevated in COVID OD versus no OD (p = 0.026). Mean IFN-γ levels were the highest in COVID OD, but there were higher levels found in COVID no OD compared to non-COVID no OD (p = 0.008). No difference was seen in IL6. No N2 gene expression was detected in all cohorts. CONCLUSION: IFN pathway cytokines were found elevated in the olfactory microenvironment of COVID-19 persistent OD compared to those with no OD and no prior history of COVID-19 infection.

Bilateral Inferior Turbinate Flaps for Salvage Reconstruction after Proton Beam Radiotherapy for Clival Chordoma.

Clival chordoma is a rare, aggressive, notochord-derived tumor primarily managed with surgery via an endoscopic endonasal approach (EEA) and adjuvant proton beam radiotherapy. Reconstruction is commonly performed with a nasoseptal flap (NSF) at the time of initial surgery. While failures of the NSF are rare, they can occur following the initial surgery or in the setting of osteoradionecrosis. Salvage repair typically requires transfer of alternative vascularized tissues outside of the previously radiated field including regional scalp flaps such as pericranial or temporoparietal fascial flaps, or free vascularized tissue transfer. Here we describe the case of a 29-year-old woman with a history of clival chordoma with widespread skull base osteomyelitis secondary to NSF necrosis after proton beam radiotherapy. We describe successful skull base reconstruction with intranasal bilateral inferior turbinate flaps based on the sphenopalatine artery with lateral nasal wall extension, despite prior proton beam therapy and a failed prior vascularized intranasal reconstruction.

Lower serum 15-HETE level predicts nasal ILC2 accumulation during COX-1 inhibition in AERD.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D2, and low levels of prostaglandin E2. Further, 15-hydroxyeicosatetraenoic acid (15-HETE) levels may have predictive value in therapeutic outcomes of aspirin desensitization. Accumulation of nasal group 2 innate lymphoid cells (ILC2s) has been demonstrated during COX-1 inhibition in AERD, although the relationships between tissue ILC2 accumulation, reaction symptom severity, and novel lipid biomarkers are unknown. OBJECTIVE: We sought to determine whether novel lipid mediators are predictive of nasal ILC2 accumulation and symptom scores during COX-1 inhibitor challenge in patients with AERD. METHODS: Blood and nasal scraping samples from patients with AERD were collected at baseline and COX-1 inhibitor reaction and then processed for flow cytometry for nasal ILC2s and serum for lipidomic analysis. RESULTS: Eight patients with AERD who were undergoing aspirin desensitization were recruited. Of the 161 eicosanoids tested, 42 serum mediators were detected. Baseline levels of 15-HETE were negatively correlated with the change in numbers of airway ILC2s (r = -0.6667; P = .0428). Docosahexaenoic acid epoxygenase metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) was positively correlated with both changes in airway ILC2s (r = 0.7143; P = .0305) and clinical symptom scores (r = 0.5000; P = .0081). CONCLUSION: Low levels of baseline 15-HETE predicted a greater accumulation of airway ILC2s in patients with AERD who were receiving COX-1 inhibition. Further, increases in the cytochrome P pathway metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) were associated with increased symptoms and nasal ILC2 accumulation. Future studies to assess how these mediators might control ILC2s may improve the understanding of AERD pathogenesis.

Impact of COVID-19 versus chronic rhinosinusitis/rhinitis associated olfactory dysfunction on health utility and quality of life.

Background: Olfactory dysfunction (OD) is associated with both post-viral and inflammatory etiologies such as COVID-19 and chronic rhinosinusitis/rhinitis (CRS/R) respectively, to result in reduced quality of life (QoL). However, the former typically induces a sudden-onset OD while the latter has a gradual presentation. This study aims to establish and compare health utility values (HUVs) and olfactory-specific QoL measurements between patients with COVID-19 and CRS/R related OD. Methods: This prospective study surveyed COVID-19 and CRS/R patients with self-reported OD using HUV assessments (EuroQol-visual analog scale [EQ-VAS], EuroQol-5 dimension [EQ-5D], time trade-off [TTO]) and olfactory and sinonasal QoL measures (questionnaire of olfactory disorders -negative and positive statements [QOD-NS + PS] and sino-nasal outcome test [SNOT-22]). A subgroup of subjects completed objective olfactory testing. Intergroup mean scores were compared using Mann-Whitney U tests. Results: One hundred eleven subjects were enrolled: mean age ± SD (43.0 ± 15.4 years), 55.9% female. CRS/R was associated with lower HUVs as measured by EQ-VAS (CRS/R: 0.67 ± 0.18 vs. COVID-19: 0.74 ± 0.19, p = .03) and worse SNOT-22 scores in both overall (CRS/R: 49.03 ± 21.04 vs. COVID-19: 27.58 ± 18.45, p < .001) and subgroup analysis of objectively confirmed OD subjects (CRS/R: 52.40 ± 22.78 vs. COVID-19: 29.84 ± 21.10, p = .01). On the other hand, COVID-19 has greater burden on olfactory-specific QoL (QOD-NS + PS, COVID-19: 23.19 ± 13.73 vs. CRS/R: 17.25 ± 11.38, p = .04). Both groups demonstrated a similar decrease in health using the EQ-5D assessment. Conclusion: CRS/R associated OD has a more severe impact on general health and sinonasal specific QoL outcomes, while COVID-19 associated OD has a greater burden on olfactory-specific QoL. Level of evidence: Level 2c.

Impact of Race, Ethnicity, and Socioeconomic Status on Nasopharyngeal Carcinoma Disease-Specific and Conditional Survival.

Introduction Race, ethnicity, and socioeconomic status (SES) are complex, interconnected social determinants of health outcomes. This study uses multivariable analysis on a combination of large national datasets to examine the effects of these factors on 5-year disease-specific survival (DSS) and conditional DSS (CDSS) for nasopharyngeal carcinoma (NPC). Methods A retrospective study of adults with NPC between 2000 and 2017 from the Surveillance, Epidemiology, End Results (SEER) registry was performed, using the National Cancer Institute Yost Index, a census tract-level composite score of SES to categorize patients. Kaplan-Meier analysis and Cox's regression for DSS and CDSS were stratified by SES. Logistic regression was conducted to identify risk factors for advanced cancer stage at time of diagnosis and receiving multimodal therapy. Results Our analysis included 5,632 patients. DSS was significantly associated with race and SES ( p < 0.01). Asian/Pacific Islander patients exhibited increased survival when controlling for other variables (hazard ratio [HR] = 0.73, p < 0.01). Although Black patients were more likely to be diagnosed with advanced disease (Black odds ratio [OR] = 1.47, p < 0.01), Black patients were also less likely to receive multimodal therapy; however, this relationship lost statistical significance once SES was incorporated into the multivariable analysis. DSS was decreased among the lowest (first) and middle (second) tertiles of SES (first HR = 1.34, p < 0.01; second HR = 1.20, p < 0.01) compared with the highest (third). Conclusion Our results indicate that race, ethnicity, and SES significantly affect survival, stage at diagnosis, and treatment of NPC. An interplay of tumor biology and inequalities in access to care likely drives these disparities.

Modified Endoscopic Denker's Approach for Management of Anterior Maxillary Sinus Tumors: Multicenter Series of 58 Cases.

OBJECTIVES: Tumors involving the anterior portion of the maxillary sinus remain technically challenging to access via an endoscopic approach. The modified endoscopic Denker's (MED) procedure was recently introduced to address such lesions. We present a multicenter series of 58 patients with tumors involving the anterior maxillary sinus successfully resected using a MED procedure and present the clinical outcomes and complications. METHODS: A multi-institution retrospective chart review was performed on patients who underwent the MED approach for the management of tumors involving the anterior maxillary sinus from 2009 to 2020. Demographic data, pathology, surgical outcomes, and complications were reviewed. RESULTS: Fifty-eight patients were identified, including 34 (58.6%) male and 24 (41.4%) female patients. The most common pathologies included: inverted papilloma (n = 27; 46.6%), adenoid cystic carcinoma (n = 9; 15.5%), and squamous cell carcinoma (n = 8; 13.8%). Thirty-eight patients (65.5%) underwent MED alone, while 20 (34.5%) had combined expanded endonasal approaches for lesions extending beyond the maxillary sinus. All maxillary sinus lesions were successfully accessed with the MED procedure without the need for an additional approach. After a mean follow-up of 30 months (range, 1-127), 8 of 58 (13.8%) patients developed complications related to the MED, including epiphora requiring an additional procedure (n = 4; 6.9%), prolonged facial/palatal numbness (n = 3; 5.2%), severe epistaxis (n = 1; 1.7%), and vestibular stenosis (n = 1; 1.7%), the latter of which occurred following postoperative radiation. CONCLUSION: The MED procedure is a safe and highly effective approach for benign and malignant tumors involving the anterior maxillary sinus. However, patients should be counseled preoperatively on potential complications including the risk of facial numbness and epiphora.

Steroid-eluting Stent Placement for Refractory Stenosis of Parotid Megaduct After Sialodochoplasty.

Salivary megaduct with stricture is characterized by recurrent pain, swelling, and infection, leading to reduced quality of life. Surgical management includes sialodochoplasty, however, recurrence is common and repeated surgery can lead to further scarring. In the sinuses, drug-eluting stents (DES) are used to reduce scarring after surgery, yet no such technology exists for salivary megaduct with stricture.We trialed DES for this condition with promising results which may pave the way for future development.

Open and endoscopic surgery improve survival for squamous and nonsquamous cell nasopharyngeal carcinomas: An NCDB cohort study.

BACKGROUND: Nasopharyngeal tumors (NPTs) are primarily treated with nonsurgical therapy. Recent studies have demonstrated endoscopic salvage surgery for NPT recurrences may improve survival relative to reirradiation. However, there are very limited data on open compared with endoscopic approaches for NPTs. We investigated whether endoscopic and open surgical approaches to the nasopharynx improve overall survival for all histologic subtypes of NPTs. METHODS: We performed a retrospective cohort study using the National Cancer Database (NCDB). All adult patients with NPTs from 2004 to 2016 without distant metastasis who underwent treatment with curative intent were included. We extracted clinical and treatment variables to assess our primary outcome of overall survival. RESULTS: On univariate analysis, patients undergoing endoscopic surgery, but not open surgery, had significantly improved overall survival relative to those undergoing nonsurgical treatment. Post hoc analysis demonstrated significantly improved overall survival for surgery in patients with minor salivary gland histology, but not squamous cell carcinoma (SCC) histology or by T or N classification. A Cox proportional hazards model was used for multivariate regression. After adjusting for covariates, both endoscopic and open approaches were associated with improved overall survival relative to nonsurgical treatment for all tumor types. A multivariate regression of SCC found that open surgery, but not endoscopic surgery, was significantly associated with improved overall survival. CONCLUSION: Both endoscopic and open surgical approaches are associated with improved overall survival of patients with NPT. These findings highlight important oncologic validity as endoscopic and robotic platforms to the nasopharynx become more widely adopted.

Clinical factors associated with lower health scores in COVID-19-related persistent olfactory dysfunction.

BACKGROUND: Patients with persistent COVID-19 olfactory dysfunction (OD) commonly report parosmia. Understanding the impact of COVID-19 OD and parosmia is critical to prioritizing research and interventions. In this study we investigate the impact of parosmia and other clinical and disease characteristics on health state utility values (HUVs) for those with persistent COVID-19 OD. METHODS: Patients with a history of COVID-19 diagnosis and persistent OD were recruited from a tertiary medical center and a social media support forum for chemosensory dysfunction. Clinical characteristics and disease-specific symptoms were obtained along with self-reported history of smell function and presence of parosmia. HUVs were calculated using indirect (EuroQol 5-Dimension [EQ-5D]) and direct (VAS) measures. RESULTS: Our study included 286 subjects (75.52% women) with persistent COVID-19-related OD. Results (mean ± standard deviation) of HUVs based on EQ-5D and VAS were 0.81 ± 0.14 and 0.73 ± 0.21, respectively. Mean self-reported smell function (on a 0-10 scale) was 9.67 ± 1.25 pre-COVID-19, 0.93 ± 2.34 at diagnosis, and 3.39 ± 2.32 at most current assessment. A total of 89.16% of the subjects reported parosmia and 24.13% sought medical care for anosmia. Seeing an MD for OD (p < 0.001), female gender (EQ-5D only, p = 0.002), a history of chronic pain (p < 0.05) and depression/anxiety (EQ-5D only, p < 0.001) predicted worse health. Parosmia and persistent symptoms, such as shortness of breath, were associated with lower EQ-5D and VAS scores, but did not independently predict poorer health scores on multivariable analysis. CONCLUSION: Persistent COVID-19 OD results in health states comparable to other chronic diseases.

Immunohistochemical and qPCR Detection of SARS-CoV-2 in the Human Middle Ear Versus the Nasal Cavity: Case Series.

Viral infections have already been implicated with otitis media and sudden sensorineural hearing loss. However, the pathophysiology of COVID-19 as it relates to otologic disorders is not well-defined. With the spread of SARS-CoV-2, it is important to evaluate its colonization of middle ear mucosa. Middle ear and nasal tissue samples for quantitative RT-PCR and histologic evaluations were obtained from post-mortem COVID-19 patients and non-diseased control patients. Here we present evidence that SARS-CoV-2 colonizes the middle ear epithelium and co-localizes with the primary viral receptor, angiotensin-converting enzyme 2 (ACE2). Both middle ear and nasal epithelial cells show relatively high expression of ACE2, required for SARS-CoV-2 entry. The epithelial cell adhesion molecule (EpCAM) was use as a biomarker of epithelia. Furthermore, we found that the viral load in the middle ear is lower than that present in the nasal cavity.

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.

Assessment of patient recognition of coronavirus disease 2019 (COVID-19)-associated olfactory loss and recovery: a longitudinal study.

BACKGROUND: The clinical course of coronavirus disease 2019 (COVID-19) olfactory dysfunction remains poorly characterized, often limited by self-reported measures. Given the logistical challenges of psychophysical testing, understanding the longitudinal relationship between self-reported and quantitative measures can help accurately identify patients with persistent olfactory dysfunction. This study aimed to longitudinally correlate measured and subjective olfactory function in COVID-19 subjects. METHODS: A prospective, longitudinal study evaluating subjective and measured olfaction was conducted on ambulatory COVID-19 subjects. Olfaction scores were obtained using a visual analogue scale (VAS) (0 = anosmia, 10 = normosmia) and the validated 12-item Brief Smell Identification Test (BSIT). Weekly testing was performed until recovery (BSIT ≥ 9/12 and/or VAS = 10/10) or study completion. RESULTS: Eighty-six polymerase chain reaction (PCR)-positive COVID-19 subjects were recruited ≤3 days from diagnosis and 52 completed longitudinal testing. Among those with self-reported smell loss at recruitment, similar levels (75.8%) of objective (BSIT ≥ 9/12) and subjective recovery were obtained using a VAS cutoff ≥8, yet only 30.3% reported complete subjective recovery (VAS = 10). Median times to objective and complete subjective olfactory recovery were 12 ± 2.3 and 24 ± 3.5 days, respectively. Although both measures showed chemosensory improvement, the distributions of objective and full subjective olfactory recovery differed significantly (log rank test χ2 = 6.46, degrees of freedom [df] = 1, p = 0.011). Overall correlation between BSIT and VAS scores was moderate to strong across longitudinal follow-up (rs = 0.41-0.65). CONCLUSION: Self-reported and psychophysically measured COVID-19 olfactory dysfunction improve at similar levels and are moderately correlated longitudinally, yet there is a significant delay in complete subjective recovery. Psychophysical testing in conjunction with qualitative assessments may be considered for counseling and follow-up of patients with COVID-19 smell loss.

Pediatric Nasal Chondromesenchymal Tumors: Case Report and Review of the Literature.

INTRODUCTION: Nasal chondromesenchymal tumors (NCMT) are rare benign neoplasms that usually present in children <1 year of age. They can display rapid growth and significant local bony remodeling that can mimic a malignant process. Of the ∼50 published cases to date, few have documented the need for neurosurgical intervention. We herein report a NCMT in an infant treated with a staged cranial and transnasal approach, as well as summarize the available literature on this pathology. CASE REPORT: A newborn male with a compromised airway was noted to have a large sinonasal lesion. After stabilization, MRI demonstrated a 4-cm enhancing mass with diffuse sinus involvement and significant extension into the anterior cranial fossa, with displacement of the optic apparatus and hypothalamic pituitary axis. After an initial biopsy, the patient underwent a bifrontal craniofacial approach at 2 months of age, followed by a second-stage transnasal endoscopic approach at 15 months which resulted in a complete resection. There were no neurosurgical complications. Pathology was consistent with a NCMT. DISCUSSION: Although rare, neurosurgical involvement is critical for the treatment of NCMTs with intracranial extension. Staged cranial and endonasal endoscopic approaches may be needed for complete resection of such lesions.

A case of mistaken identity: Saksenaea vasiformis of the orbit.

The authors describe a rare presentation of invasive fungal rhino-orbital cellulitis caused by Saksenaea vasiformis in an immunocompetent child. The patient was initially diagnosed and treated as Mucoraceae, which has a high mortality rate and is primarily seen in immunocompromised patients. Though of the same order, Mucorales, the families Mucoraceae and Saksenaeacae, may be difficult to differentiate on histologic examination and must be distinguished by fungal culture and speciation. Our patient responded well to sino-orbital debridement and systemic treatment with amphotericin and posaconazole.

Rate and Factors Associated With Change in Surgeon for Revision Endoscopic Sinus Surgery.

OBJECTIVES/HYPOTHESIS: A subset of patients will undergo revision endoscopic sinus surgery (ESS) with a different otolaryngologist than the one who performed their primary surgery. The purpose of this study is to report the incidence of and clinicodemographic factors associated with a change in surgeon for revision ESS. STUDY DESIGN: Retrospective cohort study. METHODS: Adult patients who underwent at least two outpatient ESS procedures between 2009 and 2014 using the State Ambulatory Surgery Database for Florida were included in the study. Change in surgeon was defined by a change in a unique provider identifier for the revision procedure. Multivariable regression analysis was used to determine characteristics associated with a change in surgeon. RESULTS: A total of 2,963 patients were included. For the revision procedure, 47.7% of patients changed their surgeon. On multivariable logistic regression, a medium- (odds ratio [OR]: 0.64; 95% confidence interval [CI]: 0.53-0.77) or high-volume (OR: 0.50; 95% CI: 0.42-0.61) surgeon performing the index surgery and advanced age (≥65 years) (OR: 0.79; 95% CI: 0.63-0.99) were associated with decreased odds of surgeon change for revision ESS. Longer time elapsed between index and revision surgery (OR: 1.15; 95% CI: 1.13-1.17) was associated with increased odds of surgeon change. CONCLUSIONS: Nearly half of patients who undergo revision ESS select a surgeon other than the one who performed their primary procedure. Surgeon volume, age, and time between surgeries affect the likelihood of a change in surgeon for revision ESS. These findings may provide introductory insights into patient preferences and decision making in the surgical management of recalcitrant chronic rhinosinusitis. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1049-E1053, 2021.