The Serpentine Sign: A Reliable Endoscopic and Radiographic Finding in Empty Nose Syndrome.

OBJECTIVE: Empty nose syndrome (ENS) is a relatively uncommon disease that greatly impacts the quality of life and presents diagnostic challenges. We sought to identify objective clinical findings unique to patients with ENS, and in doing so identified compensatory mucosal hypertrophy in an alternating, undulating swelling on endoscopy and coronal computerized tomography (CT) that we have termed the "Serpentine Sign." Here, we investigated whether this radiographic finding is a reliable manifestation in ENS patients. METHODS: Retrospective review was undertaken to identify ENS patients with past turbinoplasty, an ENS6Q score of at least 11/30, and symptomatic improvement with the cotton placement test. Control patients without complaints of ENS symptoms (ENS6Q < 11) were identified for comparison. ENS and control patients had coronal CT imaging available to evaluate for the Serpentine Sign, as well as ENS6Q scores, and histologic analysis of nasal tissue. RESULTS: 34 ENS and 74 control patients were evaluated for the presence of the Serpentine Sign. Of the 34 patients with ENS, 18 exhibited this radiographic finding on CT imaging (52.9%) compared to 0 of the 74 control patients (p < 0.0001). Further analysis demonstrated that ENS patients with the Serpentine Sign had lower median scores on ENS6Q than ENS patients without (17.5 vs. 22, p = 0.033). Histology revealed disorganized subepithelium rich in seromucinous glands similar to the nasal septum swell body. CONCLUSION: The "Serpentine Sign" is a unique presentation of hypertrophic change to the nasal septum soft tissue that is specific to ENS patients and may serve as a reliable radiographic and endoscopic finding in diagnosis. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1089-1095, 2024.

Impact of SARS-CoV-2 vaccination in healthcare workers in a network of clinics in Latin America.

Objectives: Healthcare workers (HCWs) have been severely affected in terms of both morbidity and mortality since the beginning of the COVID-19 pandemic. During the first few months of 2021, Colombia experienced a surge in positive cases. This study aimed to evaluate the effect of vaccination on the incidence of new positive cases in HCWs. Design: This was a retrospective cohort study of frontline employees in a network of clinics in Colombia, who were prioritized for COVID-19 vaccination from February to March 2021. Results: Our findings were consistent with recent reports. During early 2020, the incidence of HCWs positively diagnosed with COVID-19 in Colombia was higher than that for the general population. With the start of the national vaccination program, the incidence among HCWs decreased from April 2021, while that for the general population remained relatively unchanged. Our study identified lower infection rates among HCWs during April (odds ratio [OR], 0.72 [95% CI 0.58-0.90]; p < 0.01) and May (odds ratio [OR], 0.25 [95% CI 0.18-0.36]; p < 0.01). Conclusions: COVID-19 vaccination rollout in Colombia during early 2021 led to a decrease in the incidence of new positive cases among HCWs, in contrast to a continuing surge in the general population. Our findings suggested that COVID-19 vaccination provided adequate immunity, which guaranteed protection to HCWs.

The Effect of Povidone-Iodine Nasal Spray on Nasopharyngeal SARS-CoV-2 Viral Load: A Randomized Control Trial.

OBJECTIVES/HYPOTHESIS: To determine the effect of povidone-iodine (PVP-I) nasal sprays on nasopharyngeal (NP) viral load as assessed by cycle threshold (Ct) on quantitative polymerase chain reaction (qPCR) of SARS-CoV-2 in outpatients. STUDY DESIGN: Three arm, triple blinded, randomized, placebo-controlled clinical trial. METHODS: Participants were randomized within 5 days of testing positive for COVID-19 to receive nasal sprays containing placebo (0.9% saline), 0.5% PVP-I, or 2.0% PVP-I. NP swabs for qPCR analysis were taken at baseline, 1-hour post-PVP-I spray (two sprays/nostril), and 3 days post-PVP-I spray (20 sprays/nostril). Symptom and adverse event questionnaires were completed at baseline, day 3, and day 5. University of Pennsylvania Smell Identification Tests (UPSIT) were completed at baseline and day 30. RESULTS: Mean Ct values increased over time in all groups, indicating declining viral loads, with no statistically significant difference noted in the rate of change between placebo and PVP-I groups. The 2.0% PVP-I group showed statistically significant improvement in all symptom categories; however, it also reported a high rate of nasal burning. Olfaction via UPSIT showed improvement by at least one category in all groups. There were no hospitalizations or mortalities within 30 days of study enrollment. CONCLUSIONS: Saline and low concentration PVP-I nasal sprays are well tolerated. Similar reductions in SARS-CoV-2 NP viral load were seen over time in all groups. All treatment groups showed improvement in olfaction over 30 days. These data suggest that dilute versions of PVP-I nasal spray are safe for topical use in the nasal cavity, but that PVP-I does not demonstrate virucidal activity in COVID-19 positive outpatients. LEVEL OF EVIDENCE: 2 Laryngoscope, 132:2089-2095, 2022.

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.

Shortwave infrared otoscopy for diagnosis of middle ear effusions: a machine-learning-based approach.

Otitis media, a common disease marked by the presence of fluid within the middle ear space, imparts a significant global health and economic burden. Identifying an effusion through the tympanic membrane is critical to diagnostic success but remains challenging due to the inherent limitations of visible light otoscopy and user interpretation. Here we describe a powerful diagnostic approach to otitis media utilizing advancements in otoscopy and machine learning. We developed an otoscope that visualizes middle ear structures and fluid in the shortwave infrared region, holding several advantages over traditional approaches. Images were captured in vivo and then processed by a novel machine learning based algorithm. The model predicts the presence of effusions with greater accuracy than current techniques, offering specificity and sensitivity over 90%. This platform has the potential to reduce costs and resources associated with otitis media, especially as improvements are made in shortwave imaging and machine learning.

Short-Wave Infrared Fluorescence Chemical Sensor for Detection of Otitis Media.

Otitis media (OM) or middle ear infection is one of the most common diseases in young children around the world. The diagnosis of OM is currently performed using an otoscope to detect middle ear fluid and inflammatory changes manifested in the tympanic membrane. However, conventional otoscopy cannot visualize across the tympanic membrane or sample middle ear fluid. This can lead to low diagnostic certainty and overdiagnoses of OM. To improve the diagnosis of OM, we have developed a short-wave infrared (SWIR) otoscope in combination with a protease-cleavable biosensor, 6QC-ICG, which can facilitate the detection of inflammatory proteases in the middle ear with an increase in contrast. 6QC-ICG is a fluorescently quenched probe, which is activated in the presence of cysteine cathepsin proteases that are up-regulated in inflammatory immune cells. Using a preclinical model and custom-built SWIR otomicroscope in this proof-of-concept study, we successfully demonstrated the feasibility of robustly distinguishing inflamed ears from controls (p = 0.0006). The inflamed ears showed an overall signal-to-background ratio of 2.0 with a mean fluorescence of 81 ± 17 AU, while the control ear exhibited a mean fluorescence of 41 ± 11 AU. We envision that these fluorescently quenched probes in conjunction with SWIR imaging tools have the potential to be used as an alternate/adjunct tool for objective diagnosis of OM.

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.

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.

Identification of early inflammatory changes in the tympanic membrane with Raman spectroscopy.

The tympanic membrane (TM) is a dynamic structure that separates the middle ear from the external auditory canal. It is also integral for the transmission of sound waves. In this study, we demonstrate the feasibility of using Raman spectroscopy to identify early chemical changes resulting from inflammation in the TM that can serve as an indicator of acute otitis media. Bacterial lipopolysaccharide (LPS) was injected trans-tympanicaly in a murine model. Presence of inflammatory response was assessed with binocular microscopy, confirmed with histopathology and immunofluorescence staining. Successful discrimination suggesting spectral differences among the control and LPS treated groups was achieved using principal component analysis. Raman imaging revealed major differences in collagen distribution and nucleic acid content. Image segmentation analysis on the trichrome stained tissue sections was performed to corroborate the Raman spectra. The spectral co-localization study suggests changes in the expression of collagen IV specific signals in LPS treated samples. The overall findings of the study support prospective application of RS in the diagnosis and therapeutic monitoring of otitis media.

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.

Barosinusitis: Comprehensive review and proposed new classification system.

BACKGROUND: Barosinusitis, or sinus barotrauma, may arise from changes in ambient pressure that are not compensated by force equalization mechanisms within the paranasal sinuses. Barosinusitis is most commonly seen with barometric changes during flight or diving. Understanding and better classifying the pathophysiology, clinical presentation, and management of barosinusitis are essential to improve patient care. OBJECTIVES: To perform a comprehensive review of the available literature regarding sinus barotrauma. METHODS: A comprehensive literature search that used the terms "barosinusitis," "sinus barotrauma," and "aerosinusitis" was conducted, and all identified titles were reviewed for relevance to the upper airway and paranasal sinuses. All case reports, series, and review articles that were identified from this search were included. Selected cases of sinus barotrauma from our institution were included to illustrate classic signs and symptoms. RESULTS: Fifty-one articles were identified as specifically relevant to, or referencing, barosinusitis and were incorporated into this review. The majority of articles focused on barosinusitis in the context of a single specific etiology rather than independent of etiology. From analysis of all the publications combined with clinical experience, we proposed that barosinusitis seemed to fall within three distinct subtypes: (1) acute, isolated barosinusitis; (2) recurrent acute barosinusitis; and (3) chronic barosinusitis. We introduced this terminology and suggested independent treatment recommendations for each subtype. CONCLUSION: Barosinusitis is a common but potentially overlooked condition that is primed by shifts in the ambient pressure within the paranasal sinuses. The pathophysiology of barosinusitis has disparate causes, which likely contribute to its misdiagnosis and underdiagnosis. Available literature compelled our proposed modifications to existing classification schemes, which may allow for improved awareness and management strategies for barosinusitis.

Selective expansion of human regulatory T cells in nasal polyps, and not adjacent tissue microenvironments, in individual patients exposed to steroids.

Severe forms of chronic rhinosinusitis (CRS), a common upper airway inflammatory disorder, are associated with nasal polyps (NPs). NP disease is ameliorated by glucocorticoid (GC) treatment, whose cellular effects are poorly understood. We therefore assessed the influence of GC therapy on NPs in CRS patients, focusing on regulatory T (Treg) cells. Treg cell populations were analyzed by flow cytometry in NPs and control tissues from GC-treated CRS patients and controls. After GC exposure, selective expansion of Treg cells was seen within NPs, and not blood or adjacent ethmoid tissues. To confirm direct GC effects, NPs from the same patients were biopsied prior to, and following, 1week of oral GC exposure. Direct expansion of Tregs into the same NP bed was detected in 4/4 CRS patients following GC exposure. Treg cell spikes into NPs were secondary to cellular recruitment given limited Ki67 expression within these regulatory cells. Chemokine gene expression profiling identified several chemokines, notably CCL4, induced within NPs upon GC treatment. Neutralization of chemokine receptor/ligand interactions using CCR4 small molecule antagonists reduced Treg migration towards GC-treated NPs in an ex vivo migration assay. Our findings suggest that the common use of GCs in the treatment of NP disease leads to recruitment of Treg cells from peripheral sites into NP tissues, which may be critical to the anti-inflammatory effect of GCs. Mechanistically Treg expansion appears to be conferred, in part, by chemokine receptor/ligand interactions induced following corticosteroid therapy.

Defining surgical criteria for empty nose syndrome: Validation of the office-based cotton test and clinical interpretability of the validated Empty Nose Syndrome 6-Item Questionnaire.

OBJECTIVES/HYPOTHESIS: The validated Empty Nose Syndrome 6-Item Questionnaire (ENS6Q) identifies empty nose syndrome (ENS) patients. The unvalidated cotton test assesses improvement in ENS-related symptoms. By first validating the cotton test using the ENS6Q, we define the minimal clinically important difference (MCID) score for the ENS6Q. STUDY DESIGN: Individual case-control study. METHODS: Fifteen patients diagnosed with ENS and 18 controls with non-ENS sinonasal conditions underwent office cotton placement. Both groups completed ENS6Q testing in three conditions-precotton, cotton in situ, and postcotton-to measure the reproducibility of ENS6Q scoring. Participants also completed a five-item transition scale ranging from "much better" to "much worse" to rate subjective changes in nasal breathing with and without cotton placement. Mean changes for each transition point, and the ENS6Q MCID, were then calculated. RESULTS: In the precotton condition, significant differences (P < .001) in all ENS6Q questions between ENS and controls were noted. With cotton in situ, nearly all prior ENS6Q differences normalized between ENS and control patients. For ENS patients, the changes in the mean differences between the precotton and cotton in situ conditions compared to postcotton versus cotton in situ conditions were insignificant among individuals. Including all 33 participants, the mean change in the ENS6Q between the parameters "a little better" and "about the same" was 4.25 (standard deviation [SD] = 5.79) and -2.00 (SD = 3.70), giving an MCID of 6.25. CONCLUSIONS: Cotton testing is a validated office test to assess for ENS patients. Cotton testing also helped to determine the MCID of the ENS6Q, which is a 7-point change from the baseline ENS6Q score. LEVEL OF EVIDENCE: 3b. Laryngoscope, 127:1746-1752, 2017.