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Abstract Rationale The mechanisms that underlie the pathogenesis of chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD) are not clear. Objectives To first evaluate the inflammatory profiles of CRSsNP and CRSwNP tissues and then to investigate whether clinical differences observed between CRSwNP and AERD are in part secondary to differences in inflammatory mediator expression within nasal polyp (NP) tissues. Methods Expression levels of numerous inflammatory mediators were determined by quantitative real-time polymerase chain reaction, ELISA, and multiplex immunoassay. Measurements and Main Results CRSwNP NP had increased levels of type 2 mediators, including IL-5 (P < 0.001), IL-13 (P < 0.001), eotaxin-2 (P  < 0.001), and monocyte chemoattractant protein (MCP)-4 (P < 0.01), compared with sinonasal tissue from subjects with CRSsNP and control subjects. Expression of IFN-γ messenger RNA or protein was low and not different among the chronic rhinosinusitis subtypes examined. Compared with CRSwNP, AERD NP had elevated protein levels of eosinophil cationic protein (ECP) (P < 0.001), granulocyte–macrophage colony–stimulating factor (GM-CSF) (P < 0.01), and MCP-1 (P = 0.01), as well as decreased gene expression of tissue plasminogen activator (tPA) (P = 0.02). Despite the higher eosinophilia in AERD, there was no associated increase in type 2 mediator protein levels observed. Conclusions CRSwNP was characterized by a predominant type 2 inflammatory environment, whereas CRSsNP did not reflect a classic type 1 milieu, as has been suggested previously. AERD can be distinguished from CRSwNP by elevated ECP levels, but this enhanced eosinophilia is not associated with elevations in traditional type 2 inflammatory mediators associated with eosinophil proliferation and recruitment. However, other factors, including GM-CSF, MCP-1, and tPA, may be important contributors to AERD pathogenesis.

Nasal polyps (NPs) are characterized by intense edema or formation of pseudocysts filled with plasma proteins, mainly albumin. However, the mechanisms underlying NP retention of plasma proteins in their submucosa remain unclear. We hypothesized that formation of a fibrin mesh retains plasma proteins in NPs. We assessed the fibrin deposition and expression of the components of the fibrinolytic system in patients with chronic rhinosinusitis (CRS). We assessed fibrin deposition in nasal tissue from patients with CRS and control subjects by means of immunofluorescence. Fibrinolytic components, d-dimer, and plasminogen activators were measured using ELISA, real-time PCR, and immunohistochemistry. We also performed gene expression and protein quantification analysis in cultured airway epithelial cells. Immunofluorescence data showed profound fibrin deposition in NP compared with uncinate tissue (UT) from patients with CRS and control subjects. Levels of the cross-linked fibrin cleavage product protein, d-dimer, were significantly decreased in NP compared with UT from patients with CRS and control subjects, suggesting reduced fibrinolysis (P < 0.05). Expression levels of tissue plasminogen activator (t-PA) mRNA and protein were significantly decreased in NP compared with UT from patients with CRS and control subjects (P < 0.01). Immunohistochemistry demonstrated clear reduction of t-PA in NP, primarily in the epithelium and glands. Th2 cytokine-stimulated cultured airway epithelial cells showed down-regulation of t-PA, suggesting a potential Th2 mechanism in NP. A Th2-mediated reduction of t-PA might lead to excessive fibrin deposition in the submucosa of NP, which might contribute to the tissue remodeling and pathogenesis of CRS with nasal polyps.

There is a clinical association between asthma and chronic rhinosinusitis (CRS). This study was designed to determine whether severity of coexistent asthma affects the clinical presentation of CRS. Cross-sectional analysis was performed of prospectively collected data in 187 patients with CRS who were evaluated in a large, tertiary academic nasal and sinus center. Patients were stratified into three groups based on asthma status using National Institutes of Health criteria: (1) nonasthmatic, (2) intermittent/mild asthma, (3) or moderate/severe asthma. Mean Lund-Mackay scores were 9.7, 11.6, and 15.6, respectively. ANOVA testing with post-hoc Tukey analysis revealed that Lund-MacKay scores were significantly greater in group 3 than either group 1 (p < 0.05) or group 2 (p < 0.01). The prevalence of allergic sensitization was 72.4, 82.8, and 100% in groups 1, 2, and 3, respectively (p = 0.03). The prevalence of nasal polyposis was 31.4% in group 1, 48.3% in group 2, and 94.4% in group 3 (p < 0.0001). No differences were observed regarding demographic factors or the incidence of the triad of aspirin sensitivity, asthma, and nasal polyposis among those with different severities of asthma. Increasing severity of asthma is associated with advancing radiological severity of CRS and a greater prevalence of allergic sensitization and nasal polyposis. This large adult series shows that asthma severity may have a significant correlation with the presentation of CRS. This study adds to the growing support for the unified airway theory.

The effect of comorbid conditions such as asthma and atopy on the severity of chronic rhinosinusitis (CRS) and the presence of nasal polyps (NPs) remains an area of investigation. We sought to elucidate the relationship among these entities. The study population included 106 consecutive patients who were referred to a multidisciplinary, university-based allergy and sinus clinic that underwent computed tomography (CT) scan, skin-prick testing, and had CRS. Data were analyzed to determine Lund-MacKay score (LMS), presence of NPs, asthma status, and sensitivity to seven classes of aeroallergens. Skin tests were positive in 52 cases and negative in 54 cases. Although, there was no statistical relationship between LMS and atopic status in the entire group, among the asthmatic subgroup, mean LMS was greater in nonatopic asthmatic patients than in atopic asthmatic patients. Asthmatic patients had a higher LMS than nonasthmatic patients (p < 0.0001). Asthmatic patients were more likely than nonasthmatic patients to have NPs (57.6% versus 25%; p = 0.0015), regardless of atopic status. Mean LMS was higher in NP patients compared with nonpolyp patients (p < 0.0001), independent of atopic status. Mean LMS was not affected by sensitivity to any particular allergen, with the exception of cockroach-allergic patients who were more likely to have an LMS of >10 (p = 0.0236) and had more severe maxillary sinus involvement (p = 0.0391). These data indicate a strong relationship between CRS severity, as measured by LMS, and chronic airway inflammatory diseases, asthma, and NPs. The association between LMS and atopic status appears weak. The present study suggests that CRS is an inflammatory disease that occurs independently of systemic IgE-mediated pathways.

The olfactory system is vulnerable to sensory deprivation owing to the prevalence of rhinosinusitis, but how the brain encodes and maintains odor information under such circumstances remains poorly understood. Using fMRI, the authors find evidence for transient changes in olfactory brain regions that sustain odor perception following disrupted sensory input. Ongoing sensory input is critical for shaping internal representations of the external world. Conversely, a lack of sensory input can profoundly perturb the formation of these representations. The olfactory system is particularly vulnerable to sensory deprivation, owing to the widespread prevalence of allergic, viral and chronic rhinosinusitis, but how the brain encodes and maintains odor information under such circumstances remains poorly understood. Here we combined functional magnetic resonance imaging (fMRI) with multivariate (pattern-based) analyses and psychophysical approaches to show that a 7-d period of olfactory deprivation induces reversible changes in odor-evoked fMRI activity in piriform cortex and orbitofrontal cortex (OFC). Notably, multivoxel ensemble codes of odor quality in OFC became decorrelated after deprivation, and the magnitude of these changes predicted subsequent olfactory perceptual plasticity. Our findings suggest that transient changes in these key olfactory brain regions are instrumental in sustaining odor perception integrity in the wake of disrupted sensory input.

Background Cryoablation of the posterior nasal nerve at the middle meatus has been shown to successfully treat nasal obstruction and symptoms of chronic rhinitis. Cryoablation of both the middle and inferior meatus has not yet been studied. Objectives To evaluate the safety and feasibility of cryoablation of the posterior nasal nerve at both the middle and inferior meatus locations to treat chronic rhinitis. Methods Participants underwent bilateral cryoablation of the posterior nasal nerve at both the middle meatus and inferior meatus and were assessed through 3 months post treatment. The primary endpoint is the change from baseline to 3-month follow-up in the reflective Total Nasal Symptom Score (rTNSS). Other assessments include additional patient-reported outcomes, physician assessment, and independent review and scoring of imaging. Results Thirty participants were enrolled at 3 US centers. There was a significant improvement from baseline in the median rTNSS (–4.0, P < .001) at 3 months. Statistically significant improvements from baseline (P < .001) were also observed with the Nasal Obstruction Symptom Score (NOSE), nasal symptom visual analog scale (VAS), Sino-Nasal Outcomes Score (SNOT-22), and mini Rhinoconjunctivitis Quality of Life Questionnaire (mini RQLQ). Clinical Global Impression – Improvement (CGI-I) indicated that 89.7% (26/29) of participants experienced improvement at 3 months. No serious adverse events were reported. Conclusion Cryoablation at both the middle meatus and inferior meatus appears to be a safe and feasible option for treatment of chronic rhinitis. In this feasibility study, there is significant improvement in symptoms post treatment. Adverse events are minor and transient.

ObjectivesTo develop and evaluate a simulation-based mastery learning (SBML) curriculum for cricothyrotomy using wet towels to suppress aerosolisation during a pandemic.DesignQuasi-experimental, pre–post study.SettingTertiary care, academic medical centre in Chicago.ParticipantsEar, nose and throat and general surgery residents, fellows and attendings.InterventionCricothyroidotomy simulation-based mastery learning curriculum.Outcomes measurePretest to posttest simulated cricothyrotomy skills checklist performance.Results37 of 41 eligible surgeons participated in the curriculum. Median pretest score was 72.5 (IQR 55.0–80.0) and 100.0 (IQR 98.8–100.0) for the posttest p<0.001. All participants scored at or above a minimum passing standard (93% checklist items correct) at posttest.ConclusionsUsing SBML is effective to quickly train clinicians to competently perform simulated cricothyrotomy during a pandemic.

Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease of the nose and paranasal sinuses that presents without or with nasal polyps (CRSwNP). Notable features of CRSwNP are the frequent presence of type 2 allergic inflammation and high prevalence of Staphylococcus aureus (SA) colonization. As inflammation persists, sinus tissue undergoes epithelial damage and repair along with polyp growth, despite active medical management. Because one feature of damaged tissue is enhancement of growth factor signaling, we evaluated the presence of epidermal growth factor receptor (EGFR) ligands and matrix metalloproteinases (MMPs) in CRS. The objectives of this study were to analyze the expression of EGFR ligands and MMPs in patients with CRS and to investigate the possible role of SA on epithelial activation. Sinonasal tissues were collected during surgery from control subjects and patients with CRS. Tissues were processed as described previously for analysis of mRNA (RT-PCR) and proteins (ELISA) for the majority of EGFR ligands within the tissue extracts. CRS tissue was used for evaluation of the distribution of epiregulin (EREG), an EGFR ligand, and MMP-1 by immunohistochemistry. In parallel studies, expression of these genes and proteins was analyzed in cultured primary airway epithelial cells. Elevated expression of EREG and MMP-1 mRNA and protein was observed in uncinate and polyp tissue from patients with CRSwNP. Immunohistochemistry study of clinical samples revealed that airway epithelial cells expressed both of these proteins. Cultured primary human airway epithelial cells expressed MMP-1, and MMP-1 was further induced by stimulation with EREG or heat-killed SA (HKSA). The induction of MMP-1 by HKSA was blocked by an antibody against EREG, suggesting that endogenous EREG induces MMP-1 after stimulation with HKSA. EREG and MMP-1 were found to be elevated in nasal polyp and uncinate tissues in patients with CRSwNP. Elevated expression of EREG and MMP-1 may be related to polyp formation in CRS, and colonization of SA might further enhance this process.

Olfaction is impaired in chronic rhinosinusitis (CRS). The study has two aims: (1) to determine whether changes in cation concentration occur in the olfactory mucus of mice with CRS, which may affect chemo-electrical transduction, (2) and to examine whether these alterations are physiologically significant in humans. Animal study in mice and translational study in humans. Inflammation was induced by sensitization and chronic exposure of 16 C57BL/6 mice to Aspergillus fumigatus. The control group included 16 untreated mice. Ion-selective microelectrodes were used to measure free cation concentrations in the olfactory mucus of 8 mice from each treatment group, while the remaining mice were sacrificed for histology. To validate the findings in the animal model, olfactory threshold was measured in 11 healthy human participants using Sniffin' Sticks before and after nasal irrigation with solutions that were composed of either of the cation concentrations. In 8 mice, olfactory mucus of chronically inflamed mice had lower [Na(+)] (84.8±4.45 mM versus 93.73±3.06 mM, p = 0.02), and higher [K(+)] (7.2±0.65 mM versus 5.7±0.20 mM, p = 0.04) than controls. No difference existed in [Ca(2+)] (0.50±0.12 mM versus 0.54±0.06 mM, p = 0.39). In humans, rinsing with solutions replicating ion concentrations of the mouse mucosa with chronic inflammation caused a significant elevation in the median olfactory threshold (9.0 to 4.8, p = 0.003) but not with the control solution (8.3 to 7.8, p = 0.75). Chronic inflammation elevates potassium and lowers sodium ion concentration in mice olfactory mucus. Nasal irrigation with a corresponding solution induced olfactory threshold shift in humans.

Elevated numbers of antibody-secreting cells (ASCs) and anti–double-stranded DNA (anti-dsDNA) antibodies are found in nasal polyp (NP) tissue. The presence of anti-dsDNA IgG in tissue prospectively predicts recurrent NP but the characteristics of the source ASCs are unknown. Here, we investigated whether NP B cells expressing the extrafollicular marker EBI2 have increased propensity for autoantibody production and evaluated the molecular characteristics of NP ASCs. NPs showed increased frequencies of anti-dsDNA IgG and total IgG ASCs compared with tonsils, with more pronounced differences among EBI2 + cells. In NPs, EBI2 + cells were frequently double negative (IgD – CD27 – ) and ASCs. Single-cell RNA-Seq analysis of tonsils and NPs revealed substantial differences in B lineage composition, including differences in percentages of ASCs, germinal centers, proliferative cells, and non-ASCs. NPs exhibited higher expression of specific isotypes ( IGHE , IGHA1 , IGHA2 , and IGHG4 ) and mature plasma genes, including SDC1 and XBP1 , than tonsils. Gene Ontology biological processes indicated upregulated NF-κB and downregulated apoptosis pathways in NP ASCs. Together, these data indicate that NP EBI2 + ASCs secret increased total and anti-dsDNA IgG compared with those from tonsils and had molecular features of mature plasma cell differentiation.