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Chronic rhinosinusitis (CRS) is a broad clinical syndrome that is characterized by prolonged mucosal inflammation of the nose and paranasal sinuses, and is typically divided into two subtypes based on the presence or absence of nasal polyps. The etiology and pathogenesis of both forms remain areas of active research. Over the last 15 years, a number of hypotheses have been proposed to explain all or part of the clinical CRS spectrum. These hypotheses reflect the concept that CRS results from a dysfunctional interplay between individual host characteristics and factors exogenous to the host. Six broad theories on CRS etiology and pathogenesis are discussed as follows: (1) the “fungal hypothesis,” (2) the “superantigen hypothesis,” (3) the “biofilm hypothesis,” and (4) the “microbiome hypothesis,” all of which emphasize key environmental factors, and (5) the “eicosanoid hypothesis” and (6) the “immune barrier hypothesis,” which describe specific host factors. These theories are reviewed, and the evidence supporting them is critically appraised.

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.

Background An understanding of future healthcare needs of patients with chronic rhinosinusitis (CRS) is essential for patients and providers to make informed treatment decisions. Data on the predictors of long-term CRS-related healthcare utilization are limited. While there is evidence of sex differences in CRS, it is unknown whether the factors associated with long-term healthcare needs differ by sex. Objective The objectives of this study were to evaluate associations between CRS symptoms and CRS-related healthcare utilization and how these associations differ by sex. Methods We conducted a prospective study of 7,847 subjects, utilizing questionnaire and electronic health record data to assess CRS-related healthcare utilization. Individuals who met CRS symptom criteria were categorized into one of four symptom profiles in 2014: obstruction and discharge; pain or pressure without smell loss; smell loss without pain or pressure; and pain or pressure and smell loss. Healthcare utilization (2014–2019) was classified into one of six categories based on CRS-related clinical encounters and diagnostic imaging: minimal overall utilization, no CRS-related utilization; one-year of CRS-related utilization; repeated CRS-related utilization; episodic CRS-related utilization; and discontinued utilization. We evaluated associations between symptom profiles and utilization categories using multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), assessing effect modification by sex using cross-product terms. Results Of the 7,847 subjects, 62.7% were women and 37.3% were men. Among women, there was no association between CRS symptoms in 2014 and repeated CRS-related healthcare utilization (versus discontinued CRS-related utilization), whereas men with CRS symptoms had nearly twice the odds (OR 1.81 CI: 1.02, 3.20) of repeated utilization. Women who had CRS with pain and pressure, had higher odds of discontinued CRS-related utilization. This was not observed for other symptom profiles. Conclusion Healthcare utilization patterns for CRS varied by symptoms and sex. Women with facial pain/pressure were uniquely at risk for discontinuation of CRS-related care, providing further evidence of sex differences among individuals reporting sinonasal symptoms.

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.

Chronic rhinosinusitis (CRS) is a prevalent condition. Clinical diagnosis requires subjective evidence (i.e. symptoms) and objective evidence of inflammation (e.g. sinus computed tomography [CT]). Few studies have assessed differences in common CT scoring approaches for CRS, the Lund-Mackay (LM) system and its modified version (mLM); none in a general population sample. The aims of this study were to answer the following: (1) Is mLM superior to LM? (2) Should nasal cavity opacification be included in scoring? (3) How should location-specific scores be utilized? (4) If location-specific scores are summed, what should be the cutoff? (5) Are associations of opacification with symptoms observed when using different measurement approaches? We scored sinus CTs using LM and mLM from 526 subjects selected from a larger CRS study. Exploratory factor analysis (EFA) assessed similarity of mLM and LM. Latent class analysis (LCA) identified subgroups of sinus opacification patterns. Factors associated with group membership and relations with nasal and sinus symptoms (NSS) guided clinical relevance. EFA suggested no differences between LM and mLM, or after addition of nasal cavity opacification. LCA identified three opacification groups: no/mild, localized, and diffuse. Males were 2.7x more likely to have diffuse opacification than females, as were those with asthma or hay fever. A LM cutoff of 3 had similar performance to the currently used 4. Diffuse opacification was associated with nasal blockage and smell loss. Differing patterns of opacification may be clinically relevant, improving measurement of objective evidence in studies of CRS and sinus diseases.

Background Genome-wide association studies (GWASs) have identified thousands of variants associated with asthma and other complex diseases. However, the functional effects of most of these variants are unknown. Moreover, GWASs do not provide context-specific information on cell types or environmental factors that affect specific disease risks and outcomes. To address these limitations, we used an upper airway epithelial cell (AEC) culture model to assess transcriptional and epigenetic responses to rhinovirus (RV), an asthma-promoting pathogen, and provide context-specific functional annotations to variants discovered in GWASs of asthma. Methods Genome-wide genetic, gene expression, and DNA methylation data in vehicle- and RV-treated upper AECs were collected from 104 individuals who had a diagnosis of airway disease ( n =66) or were healthy participants ( n =38). We mapped cis expression and methylation quantitative trait loci ( cis -eQTLs and cis -meQTLs, respectively) in each treatment condition (RV and vehicle) in AECs from these individuals. A Bayesian test for colocalization between AEC molecular QTLs and adult onset asthma and childhood onset asthma GWAS SNPs, and a multi-ethnic GWAS of asthma, was used to assign the function to variants associated with asthma. We used Mendelian randomization to demonstrate DNA methylation effects on gene expression at asthma colocalized loci. Results Asthma and allergic disease-associated GWAS SNPs were specifically enriched among molecular QTLs in AECs, but not in GWASs from non-immune diseases, and in AEC eQTLs, but not among eQTLs from other tissues. Colocalization analyses of AEC QTLs with asthma GWAS variants revealed potential molecular mechanisms of asthma, including QTLs at the TSLP locus that were common to both the RV and vehicle treatments and to both childhood onset and adult onset asthma, as well as QTLs at the 17q12-21 asthma locus that were specific to RV exposure and childhood onset asthma, consistent with clinical and epidemiological studies of these loci. Conclusions This study provides evidence of functional effects for asthma risk variants in AECs and insight into RV-mediated transcriptional and epigenetic response mechanisms that modulate genetic effects in the airway and risk for asthma.

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.

Primary diffuse type 2‐dominant chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease of the nasal cavity and paranasal sinuses associated with significant morbidity. Impaired sense of smell is a cardinal symptom of CRSwNP and one of the most burdensome for patients, impacting quality of life, mental health, and even safety. Mechanisms of smell loss in CRSwNP may be related to conductive losses due to significant burden of nasal polyps, as well as the impact of type 2 inflammatory mediators on olfactory sensory neurons. Initial medical management frequently involves intranasal or oral corticosteroids. Patients whose symptoms remain uncontrolled by medical treatment may be offered sinonasal surgery; however, patients may experience recurrence of smell loss following surgery. Guidelines recommend biologics for certain patients with CRSwNP after undergoing complete endoscopic sinus surgery, and data from clinical trials and real‐world evidence support their effectiveness in improving sense of smell. Given the impact of smell loss, shared decision‐making is important in identifying treatment options best suited to achieving patient goals. This review provides an overview of the importance of smell loss in CRSwNP and its known mechanisms, and reviews the evidence for the efficacy of current treatment options in restoring sense of smell. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a long‐term inflammatory disease of the nose and sinuses. In CRSwNP, small growths called polyps form inside the nasal passages. Symptoms include blocked and runny nose, loss of sense of smell, and facial pain or pressure. Loss of sense of smell is one of the worst symptoms for patients, and it affects their safety, mental health, and quality of life. The way that sense of smell is affected by CRSwNP is not fully understood, but there appears to be both a conductive component as well as a “type 2” immune component. Patients with loss of smell and CRSwNP are usually treated with steroids that can be applied locally in the nose or taken as a tablet. If steroids can’t control the symptoms, patients can have surgery to remove the polyps. Surgery can help, but many patients lose their sense of smell again. For some patients with CRSwNP, medical guidelines recommend biologic drugs (“biologics”) after complete sinus surgery, which can improve sense of smell. It’s important that healthcare providers work together with patients to understand what they want to achieve with their treatment, and to help find the right treatment for them.