Single-cell RNA sequencing of human eosinophils from nasal polyps reveals eosinophil heterogeneity in chronic rhinosinusitis tissue.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation in the US, yet the actual roles of eosinophils in CRSwNP are largely unclear. OBJECTIVE: To reveal the roles and heterogeneity of eosinophils in nasal polyp (NP) tissue by single cell RNA-Sequencing (scRNA-Seq) analysis of NP tissue. METHODS: Sinonasal tissues (NP and control sinus tissue) and patient matched peripheral blood (PB) samples were obtained from 5 control patients and 5 patients with CRSwNP. Eosinophils were enriched prior to processing for scRNA-Seq. The gene expression profiles in eosinophils were determined by the microwell-based scRNA-Seq technology (BD Rhapsody platform). We predicted the overall function of NP eosinophils by gene ontology (GO) enrichment and pathway analyses and confirmed expression of selected genes by flow cytometry. RESULTS: After filtering out contaminating cells, we detected 5,542 eosinophils from control PB, 3,883 eosinophils from CRSwNP PB, 101 eosinophils from control sinus tissues (not included in further analyses) and 9,727 eosinophils from NPs by scRNA-Seq. We found that 204 genes were down-regulated, and 354 genes were up-regulated in NP eosinophils, compared to all PB eosinophils (>1.5-fold, Padj<0.05). Up-regulated genes in NP eosinophils were associated with activation, cytokine-mediated signaling, growth factor activity, NF-κB signaling and anti-apoptotic molecules. NP eosinophils displayed 4 clusters revealing potential heterogeneity of eosinophils in NP tissue. CONCLUSIONS: Elevated eosinophils in NP tissue appear to exist in several subtypes that may play important pathogenic roles in CRSwNP, in part via controlling inflammation and hyperproliferation of other cells.

Assessing social vulnerabilities of salivary gland cancer care, prognosis, and treatment in the United States.

BACKGROUND: Salivary gland cancers (SGC)-social determinants of health (SDoH) investigations are limited by narrow scopes of SGC-types and SDoH. This Social Vulnerability Index (SVI)-study hypothesized that socioeconomic status (SES) most contributed to SDoH-associated SGC-disparities. METHODS: Retrospective cohort of 24 775 SGCs assessed SES, minority-language status (ML), household composition (HH), housing-transportation (HT), and composite-SDoH measured by the SVI via regressions with surveillance and survival length, late-staging presentation, and treatment (surgery, radio-, chemotherapy) receipt. RESULTS: Increasing social vulnerability showed decreases in surveillance/survival; increased odds of advanced-presenting-stage (OR: 1.12, 95% CI: 1.07, 1.17), chemotherapy receipt (OR: 1.13, 95% CI: 1.03, 1.23); decreased odds of primary surgery (0.89, 0.84, 0.94), radiotherapy (0.91, 0.85, 0.97, p = 0.003) for SGCs. Trends were differentially correlated with SES, ML, HH, and HT-vulnerabilities. CONCLUSIONS: Through quantifying SDoH-derived SGC-disparities, the SVI can guide targeted initiatives against SDoH that elicit the most detrimental associations for specific sociodemographics.

Influence of Social Vulnerability in Treatment and Prognosis of Squamous Cell Carcinoma of the Tongue.

OBJECTIVE: To investigate the association of social determinants of health (SDoH) in squamous cell carcinoma of the tongue in the United States and to evaluate the real-world contribution of specific disparities. STUDY DESIGN: Retrospective cohort study. SETTING: United States. METHODS: The Centers for Disease Control and Prevention-Social Vulnerability Index (SVI) and National Cancer Institute-Surveillance, Epidemiology, and End Results Program database were used to study 62,103 adult tongue squamous cell carcinoma patients from 1975 to 2017. Regression analysis assessed trends in months of follow-up and survival across social vulnerability and 4 subcategories of social vulnerability. RESULTS: As overall SVI score increases (increased social vulnerability), there is a significant decrease in the average length of follow-up (22.95% decrease from 63.99 to 49.31 months; P < .001) across patients from the lowest and highest social vulnerability groups. As overall SVI score increases, there is a significant decrease in the average months of survival (28.00% decrease from 49.20 to 35.43 months; P < .001). There is also a significantly greater odds ratio (OR = 1.05; P < .001) of advanced cancer staging upon presentation at higher SVI scores. Patients with higher SVI scores have a lower OR (0.93; P < .001) of receiving surgery as their primary treatment when compared to patients with lower SVI scores. Patients with higher SVI scores also have a significantly greater OR (OR = 1.05; P < .001) of receiving chemotherapy as their primary treatment when compared to patients with lower SVI scores. CONCLUSION: Increased social vulnerability is shown to have a detrimental impact on the treatment and prognosis of patients with squamous cell carcinoma of the tongue.

Assessment of social vulnerability impact in care and prognosis of sinonasal cancers in the United States.

KEY POINTS: Social determinants of health interactively influence sinonasal cancer care and prognosis. Housing-transportation and socioeconomic status showed the largest associations with disparities. The social vulnerability index can reveal the social determinants of sinonasal cancers.

Social Vulnerability Association with Thyroid Cancer Disparities in the United States.

Background: As thyroid cancer incidence rises, it is increasingly valuable to recognize disparities in treatment and diagnosis. Prior investigations into social determinants of health (SDoH) are limited to pediatric populations or studies looking at single factors such as race or environmental influences. Utilizing the CDC-social vulnerability index and SEER-patient database to assess the amalgamated, real-world influence of varied SDoH and their quantifiable impact on thyroid cancer disparities across the United States. Methods: In a retrospective cohort study, 199,340 adult thyroid cancer patients from 1975 to 2017 were assessed for significant regression trends in months of follow-up/surveillance, survival, late staging, and treatment receipt across thyroid cancer-subtypes with increasing overall social vulnerability, as well as in 15 SDoH variables regarding socioeconomic status, minority-language status, household composition, and housing-transportation across all the U.S. counties while accounting for sociodemographic regional differences. Results: With increasing overall social vulnerability, decreases in months of follow-up were observed with patients with papillary, follicular, medullary, oncocytic, and anaplastic thyroid cancer (p = 0.001). Comparing lowest with highest vulnerability cohorts, relative decreases in months of surveillance ranged from 55.6% (14.5-6.5 months) with anaplastic to 17% (108.6-90.2) with oncocytic. Socioeconomic status vulnerabilities, followed by vulnerabilities in household composition and housing-transportation type, contributed to these overall trends. Similar survival decreases occurred across all thyroid cancer patients, ranging from 55.9% (9.6-4.2) with anaplastic to 28.3% (97-69.5) with oncocytic. Minority-language status vulnerabilities and housing-transportation types largely contributed to these trends. Increasing overall vulnerability was associated with increased odds of advanced staging for papillary (odds ratio [OR] = 1.07 [confidence interval, CI 1.03-1.12]) and decreased odds of indicated treatment via surgery (lowest, medullary: 0.91 [CI 0.84-0.99]), radiation therapy (lowest, anaplastic: 0.88 [CI 0.82-0.93]), and chemotherapy (lowest, oncocytic: 0.81 [CI 0.67-0.98]) were observed. Vulnerabilities in minority-language status and housing-transportation, followed by socioeconomic status vulnerabilities, were differential contributors to these overall vulnerability trends. Conclusions: Our results show significant detriments in thyroid cancer care and prognosis in the United States with increasing overall social vulnerability while identifying which SDoH quantifiably contribute more to disparities in inter-relational, real-world-like contexts.

Assessment of Social Vulnerability in Pediatric Head and Neck Cancer Care and Prognosis in the United States.

Importance: Prior investigations in social determinants of health (SDoH) in pediatric head and neck cancer (HNC) have only considered a narrow scope of HNCs, SDoH, and geography while lacking inquiry into the interrelational association of SDoH with disparities in clinical pediatric HNC. Objectives: To evaluate the association of SDoH with disparities in HNC among children and adolescents and to assess which specific aspects of SDoH are most associated with disparities in dynamic and regional sociodemographic contexts. Design, Setting, and Participants: This retrospective cohort study included data about patients (aged ≤19 years) with pediatric HNC who were diagnosed from 1975 to 2017 from the Surveillance, Epidemiology, and End Results Program (SEER) database. Data were analyzed from October 2021 to October 2022. Exposures: Overall social vulnerability and its subcomponent contributions from 15 SDoH variables, grouped into socioeconomic status (SES; poverty, unemployment, income level, and high school diploma status), minority and language status (ML; minoritized racial and ethnic group and proficiency with English), household composition (HH; household members aged ≥65 and ≤17 years, disability status, single-parent status), and housing and transportation (HT; multiunit structure, mobile homes, crowding, no vehicle, group quarters). These were ranked and scored across all US counties. Main Outcomes and Measures: Regression trends were performed in continuous measures of surveillance and survival period and in discrete measures of advanced staging and surgery receipt. Results: A total of 37 043 patients (20 729 [55.9%] aged 10-19 years; 18 603 [50.2%] male patients; 22 430 [60.6%] White patients) with 30 different HNCs in SEER had significant relative decreases in the surveillance period, ranging from 23.9% for malignant melanomas (mean [SD] duration, lowest vs highest vulnerability: 170 [128] months to 129 [88] months) to 41.9% for non-Hodgkin lymphomas (mean [SD] duration, lowest vs highest vulnerability: 216 [142] months vs 127 [94] months). SES followed by ML and HT vulnerabilities were associated with these overall trends per relative-difference magnitudes (eg, SES for ependymomas and choroid plexus tumors: mean [SD] duration, lowest vs highest vulnerability: 114 [113] months vs 86 [84] months; P < .001). Differences in mean survival time were observed with increasing social vulnerability, ranging from 11.3% for ependymomas and choroid plexus tumors (mean [SD] survival, lowest vs highest vulnerability: 46 [46] months to 41 [48] months; P = .43) to 61.4% for gliomas not otherwise specified (NOS) (mean [SD] survival, lowest vs highest vulnerability: 44 [84] months to 17 [28] months; P < .001), with ML vulnerability followed by SES, HH, and HT being significantly associated with decreased survival (eg, ML for gliomas NOS: mean [SD] survival, lowest vs highest vulnerability: 42 [84] months vs 19 [35] months; P < .001). Increased odds of advanced staging with non-Hodgkin lymphoma (OR, 1.21; 95% CI, 1.02-1.45) and retinoblastomas (OR, 1.31; 95% CI, 1.14-1.50) and decreased odds of surgery receipt for melanomas (OR, 0.79; 95% CI, 0.69-0.91) and rhabdomyosarcomas (OR, 0.90; 95% CI, 0.83-0.98) were associated with increasing overall social vulnerability. Conclusions and Relevance: In this cohort study of patients with pediatric HNC, significant decreases in receipt of care and survival time were observed with increasing SDoH vulnerability.

Retinoic acid promotes fibrinolysis and may regulate polyp formation.

BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) regularly exhibit severe nasal polyposis. Studies suggest that chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by excessive fibrin deposition associated with a profound decrease in epithelial tissue plasminogen activator (tPA). Retinoids, including vitamin A and its active metabolite retinoic acid (RA), are necessary for maintaining epithelial function and well-known inducers of tPA in endothelial cells. OBJECTIVES: This study sought to determine whether endogenous retinoids are involved in NP pathophysiology and disease severity in patients with CRSwNP and AERD. METHODS: NP tissue was collected from patients with AERD or CRSwNP, and concentrations of retinoids and fibrinolysis markers were measured using ELISA. Normal human bronchial epithelial cells were stimulated alone or in combination with RA and IL-13 for 24 hours. RESULTS: This study observed lower retinoid levels in nasal polyps of patients with AERD than those with CRSwNP or healthy controls (P < .01). Levels of the fibrin-breakdown product d-dimer were the lowest in AERD polyps (P < .01), which is consistent with lower tPA expression (P < .01). In vitro, all-trans RA upregulated tPA levels in normal human bronchial epithelial cells by 15-fold and reversed the IL-13-induced attenuation of tPA expression in cultured cells (P < .01). CONCLUSIONS: RA, a potent inducer of epithelial tPA in vitro, is reduced in tissue from patients with AERD, a finding that may potentially contribute to decreased levels of tPA and fibrinolysis in AERD. RA can induce tPA in epithelial cells and can reverse IL-13-induced tPA suppression in vitro, suggesting the potential utility of RA in treating patients with CRSwNP and/or AERD.

Efficacy of an oral CRTH2 antagonist (AZD1981) in the treatment of chronic rhinosinusitis with nasal polyps in adults: A randomized controlled clinical trial.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease of the upper airways. AZD1981 is a selective antagonist of chemoattractant receptor-homologous molecule expressed on T helper type 2 and other type 2 cells, including innate lymphoid cells type 2, eosinophils, and basophils. OBJECTIVE: To evaluate the efficacy of AZD1981 in reducing nasal polyp size when added to intranasal corticosteroids in adult patients with CRSwNP. METHODS: Eighty-one subjects (18-70 years of age) with CRSwNP were recruited and screened for trial eligibility from allergy and otolaryngology clinics from a single tertiary care site between June 2016 and August 2019. Eligible patients were randomized in a double-blind fashion to receive either AZD1981 (n = 22) or placebo (n = 21) orally three times a day for 12 weeks, added to intranasal corticosteroids. The primary endpoint was a change in nasal polyp score (NPS) at 12 weeks. Secondary endpoints included improvement in sinus computed tomography using Lund Mackay scoring, symptoms using visual analog scale, quality of life using Sino Nasal Outcome Test-22, and the Brief Smell Identification Test. RESULTS: Forty-three patients met the inclusion criteria and were enrolled. At 12 weeks, there was no difference in NPS change in the AZD1981 arm (mean 0, standard error 0.34, n = 15) compared with placebo (mean 0.20, standard error 0.36, n = 17); mean difference -0.20 (95% confidence interval: -1.21, 0.81; p = .69). No significant differences were observed for Lund Mackay score, symptoms, quality of life, or smell test. AZD1981 was well tolerated except for one case of hypersensitivity reaction. CONCLUSION: In patients with CRSwNP, the addition of AZD1981 to intranasal corticosteroids did not change nasal polyp size, radiographic scores, symptoms, or disease-specific quality of life.

Elevation of activated neutrophils in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is well characterized by type 2 (T2) inflammation characterized by eosinophilia in Western countries. However, the presence and roles of neutrophils in T2 CRSwNP are poorly understood. OBJECTIVE: We sought to clarify accumulation and inflammatory roles of neutrophils in CRSwNP in a Western population. METHODS: Sinonasal tissues and nasal lavage fluids were obtained from control patients and patients with CRS, and neutrophil markers were determined by ELISA. The presence of neutrophils in tissue was determined by flow cytometry. The gene expression profiles in neutrophils were determined by RNA sequencing. RESULTS: A neutrophil marker elastase was selectively elevated in nasal polyp (NP) tissue, whereas eosinophilic cationic protein (an eosinophil marker) was elevated in both uncinate and NP tissues of CRSwNP patients. Nasal lavage fluid myeloperoxidase (another neutrophil marker) was also significantly elevated in CRSwNP compared to control patients. Neutrophil markers were more greatly elevated in CRSwNP patients with recurrent disease. Flow cytometric analysis confirmed that neutrophil numbers were significantly elevated in NPs compared to control tissues. RNA sequencing analysis found that 344 genes were >3-fold and significantly elevated in NP neutrophils compared to peripheral blood neutrophils. Gene Ontology analysis suggested that the elevated genes in NP neutrophils were significantly associated with activation. Results suggest that neutrophils are accumulated in T2 NP tissues and that accumulated neutrophils are highly activated and contribute to inflammation in NPs. CONCLUSIONS: Neutrophils may play a heretofore unrecognized meaningful role in the pathogenesis of CRSwNP in Western countries and may be a potentially important therapeutic target in T2 CRSwNP.

Health-Related Quality of Life: Longitudinal Analysis From the Time of Breast Biopsy Into the Post-treatment Period.

Background: The physical, psychological, social, and spiritual quality of life (QoL) may be affected by breast cancer diagnosis and treatment, with mixed findings for psychological quality of life and cognitive ability performance. The present study aimed to evaluate QoL in women over 1 year from biopsy for a breast abnormality. Methods: Self-reported measures of physical, psychological, social, and spiritual QoL were obtained after biopsy results but prior to treatment initiation (baseline), 4 and 12 months later. CogState computerized neuropsychological screening battery also provided an evaluation of psychological QoL. Three groups of women including those with benign biopsy results, those with malignancy treated with chemotherapy, and those with malignancy not treated with chemotherapy were compared at 4 and 12 months after adjusting for baseline to isolate the effects of treatment. Additional covariates included are age, level of education, and income. Results: Benign biopsy results group included 72 women, whereas malignancy was found in 87 women of whom 33 were treated with chemotherapy and 54 without chemotherapy. At the time of diagnosis, women with cancer had worse psychological and social QoL but better spiritual QoL than those with benign biopsy results. Only CogState monitoring accuracy was worse for women with cancer compared with the controls at the time of biopsy results. After adjusting for QoL at baseline, women treated for cancer had worse physical and social QoL at 4 and 12 months later. Psychological well-being was worse for women with cancer at 4th month but improved at 1 year. No differences in cognition were found at 4 and 12 months when adjusted for baseline cognition and covariates. Discussion: Breast cancer is a traumatic life event for women, affecting psychological and social QoL domains, yet increasing spiritual QoL. Later, cancer treatment worsens physical, psychological, and social QoL compared with those without cancer. Conclusions: These findings suggest that interventions to improve psychological QoL may be especially important at the time of cancer diagnosis, while interventions to improve physical well-being are the most needed during and following cancer treatment. Support to improve social QoL is needed from the time of diagnosis into post-treatment survivorship.

Impact of type 2 targeting biologics on acute exacerbations of chronic rhinosinusitis.

Background: Acute exacerbations of chronic rhinosinusitis (AECRS) are associated with significant morbidity and decreased quality of life. There are sparse data assessing the real-world impact of biologics on AECRS. Objectives: We sought to determine the impact of type 2-targeting biologics on the frequency of medication use for AECRS episodes. Methods: Antibiotic and/or systemic corticosteroid courses for AECRS were identified in a retrospective study from November 2015 to February 2020, at a single academic health system. The estimated yearly rates for antibiotic and corticosteroid courses were evaluated before and after initiation of type 2 biologics. Results: One-hundred and sixty-five patients with chronic rhinosinusitis (CRS) had received either omalizumab (n = 12), mepolizumab (n = 42), benralizumab (n = 44), dupilumab (n = 61), or reslizumab (n = 6). Seventy percent had CRS with nasal polyps, and 30% had CRS without nasal polyps. All the patients had asthma. When all the biologics were combined, the estimated yearly rate for antibiotics for AECRS decreased from 1.34 (95% confidence interval [CI], 1.12-1.59) to 0.68 (95% CI, 0.52-0.88) with biologic use (49% reduction, p < 0.001). Those with frequent AECRS (three or more courses of antibiotics in the 1 year before biologic use) had a larger degree of reduction, with an estimated yearly rate of 4.15 (95% CI, 3.79-4.55) to 1.58 (95% CI, 1.06-2.35) with biologic use (n = 27; 62% reduction; p < 0.001). Within the total cohort, the estimated yearly rate for systemic corticosteroids for AECRS decreased from 1.69 (95% CI, 1.42-2.02) to 0.68 (95% CI, 0.53-0.88) with biologic use (60% reduction; p < 0.001). Conclusion: Type 2-targeting biologics reduced medication use for AECRS. This suggested that biologics may be a therapeutic option for patients with frequent AECRS.

Prevalence of Bronchiectasis in Patients with Chronic Rhinosinusitis in a Tertiary Care Center.

BACKGROUND: Whereas chronic rhinosinusitis (CRS) is associated with asthma, and vice versa, the association between CRS and other lower respiratory conditions is not well-established. Bronchiectasis is characterized by permanent damage of the airways, and as many as 45% of bronchiectasis patients have CRS, but the prevalence of bronchiectasis among CRS patients is not known. OBJECTIVE: To determine the prevalence of bronchiectasis among CRS patients and to characterize demographic and clinical features of patients with bronchiectasis and CRS. METHODS: Electronic medical records of patients with rhinosinusitis were searched by computer algorithm supplemented with manual chart review to identify patients with CRS, asthma, and/or bronchiectasis. Demographic and clinical features and antibiotic courses for sinopulmonary infections 2 years before and after sinus surgery were obtained by manual chart review. RESULTS: The prevalence of bronchiectasis as determined by International Classification of Diseases, Ninth Revision code was significantly higher in CRS patients than in asthmatic patients (2.3% vs 1.7%; P < .003). Similarly, based on a text word search of "bronchiectasis" in the chest computed tomography (CT) scan reports, patients with CRS who had chest CT scans had a higher prevalence of bronchiectasis than did asthmatic patients with chest CT scans (24.3% vs 19.5%; P = .005). Patients with CRS and concurrent bronchiectasis did not have a reduction in the frequency of sinopulmonary infections after sinus surgery compared with patients with CRS without bronchiectasis (P < .05). CONCLUSIONS: Bronchiectasis is an important comorbidity in patients with CRS and may identify a severe phenotype of chronic sinonasal disease.

Mechanisms and biomarkers of inflammatory endotypes in chronic rhinosinusitis without nasal polyps.

BACKGROUND: Chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP) is a common disease that is characterized by multiple inflammatory endotypes. However, the molecular mechanisms in CRSsNP are poorly understood compared with those of polypoid CRS. OBJECTIVE: Our aim was to identify mechanisms and biomarkers associated with inflammatory endotypes underpinning CRSsNP. METHODS: Ethmoid tissues and nasal lavage fluids (NLFs) were obtained from control patients and patients with CRS. The gene expression profiles were determined by microarray analysis and quantitative RT-PCR, and expression of proteins was measured by ELISA and Luminex analysis. RESULTS: Microarray found that compared with their levels of expression in control tissue, the levels of expression of 126, 241, and 545 genes were more than 3-fold and significantly elevated in CRSsNP with type 1 (T1) endotype, type 2 (T2) endotype, and type 3 (T3) endotype, respectively. Selected identified genes were confirmed by RT-PCR. Gene set enrichment analysis suggested that T1 CRSsNP was associated with IFN-γ signaling and antiviral immunity controlled by T cells (TH1 and CD8+), natural killer cells, and antigen-presenting cells; T2 CRSsNP was associated with STAT6 signaling and IgE-mediated activation controlled by eosinophils, mast cells, TH2 cells, group 2 innate lymphoid cells, and antigen-presenting cells; and T3 CRSsNP was associated with IL-17 signaling, acute inflammatory response, complement-mediated inflammation, and infection controlled by neutrophils, TH17 cells, B cells, and antigen-presenting cells. The results suggest that T1 (CXCL9 and CXCL10), T2 (eosinophilic proteins and CCL26), and T3 (CSF3) endotypic biomarkers in NLF may be able to distinguish tissue endotypes in CRSsNP. CONCLUSIONS: Inflammatory endotypes in CRSsNP were controlled by different molecular mechanisms. NLF biomarker assays may allow for more precise and personalized medical treatments in CRS.

Clinical factors associated with acute exacerbations of chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is complicated by frequent acute exacerbations leading to significant health care burden and impaired quality of life. OBJECTIVE: The objective of this study was to identify clinical factors associated with frequent acute exacerbation of CRS (AECRS). METHODS: This is a retrospective cohort study of patients with CRS from January 1, 2014, to May 31, 2016. Frequent AECRS was defined as at least 4 episodes over a 12-month period in which an antibiotic was prescribed for worsening sinus symptoms, and infrequent AECRS was defined as 0 to 3 episodes. Clinical factors, including asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, and autoimmune disease, were evaluated for associations between the 2 groups. RESULTS: Of the 3109 patients with CRS who were identified, 600 (19.3%) were classified as having frequent exacerbation. Asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, and autoimmune disease were associated with frequent AECRS with statistically significant adjusted odds ratios (aORs) after controlling for age, race, and sex in multivariate analysis (asthma aOR = 2.61 [95% CI = 2.14-3.18]; allergic rhinitis aOR = 1.96 [95% CI = 1.58-2.42]; eosinophil count of at least 150 cells per microliter aOR = 1.54 [95% CI = 1.21-1.97]; and autoimmune disease aOR = 1.68 [95% CI = 1.36-2.07]). Antibody deficiency, antibiotic allergy, lower FEV1, radiographic sinus disease severity, nasal polyposis, and systemic corticosteroid use were also associated with frequent AECRS. CONCLUSION: Patients with frequent episodes of AECRS were characterized by a higher prevalence of asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, autoimmune disease, and other allergic and immunologic diseases. These findings identify a high-risk phenotype of patients with CRS for preventive interventions to reduce exacerbation frequency.

Sample collection for laboratory-based study of the nasal airway and sinuses: a research compendium.

BACKGROUND: Collection of biologic samples from the nasal cavity and paranasal sinuses is of critical importance to the study of infectious or inflammatory conditions that affect both upper and lower airways. Numerous techniques for the study of ex-vivo samples exist, with specific applications, strengths, and weaknesses associated with each of them. In this compendium we summarize the available methods for collection of primary human samples and incorporate expert discussion of the pros, cons, and applications associated with each technique. METHODS: An expert panel containing members of the American Rhinologic Society's Research and Grants Committee compiled this educational reference. Rationale for use and the potential advantages and disadvantages are discussed. Research protocols and key references are enumerated. RESULTS: Sampling of the nasal cavity and paranasal sinuses can be achieved through a number of methods. Nonspecific sinonasal secretions may be collected via forced exhalation, nasal lavage, and nasal spray aspiration. Targeted collection of sinonasal secretions may be achieved via endoscopic placement of absorbent matrices. Nasal cytology or collection of superficial epithelium may be completed via brushing or scraping of endonasal structures. Collection of mucosal biopsies may be completed via sinonasal explant or full-thickness biopsy. CONCLUSION: Multiple sampling techniques are available to collect biologic samples from the sinonasal cavity. These techniques differ in their ease of application, reproducibility, sample yield, and utility for different sinonasal pathologies or research goals. An appreciation of the benefits and drawbacks of each approach will allow investigators to select the techniques most appropriate for achieving research objectives.

Role of RANK-L as a potential inducer of ILC2-mediated type 2 inflammation in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation with accumulation of activated group 2 innate lymphoid cells (ILC2s) and elevation of thymic stromal lymphopoietin (TSLP). A member of the TNF superfamily (TNFSF), TNFSF15, is known to induce the production of type 2 cytokines in ILC2s. Although ILC2s have been implicated in CRSwNP, the presence and role of TNFSFs in ILC2-mediated type 2 inflammation in CRSwNP has not been elucidated. Here, we investigate the involvement of TNFSFs in ILC2-mediated type 2 inflammation in CRSwNP. We found that receptor activator of NF-κB (RANK) ligand (RANK-L (TNFSF11)) was significantly elevated in nasal polyps (NPs), and that the receptor of RANK-L, RANK, was expressed on ILC2s in human peripheral blood and NPs. An agonistic antibody against RANK induced production of type 2 cytokines in human ILC2s, and TSLP significantly enhanced this reaction. The membrane-bound RANK-L was detected mainly on CD45 + immune cells, including TH2 cells in NPs. The co-culture of NP-derived ILC2s and TH2 cells significantly enhanced production of type 2 cytokines, and anti-RANK-L monoclonal antibody suppressed this enhancement. In conclusion, RANK-L, together with TSLP, may play an inductive role in the ILC2-mediated type 2 inflammation in CRSwNP.

Prevalence and characterization of chronic rhinosinusitis in patients with non-cystic fibrosis bronchiectasis at a tertiary care center in the United States.

BACKGROUND: Chronic rhinosinusitis (CRS) is associated with bronchiectasis; however, this relationship has not been well studied in the United States (US) population. In this work we aimed to determine the prevalence of CRS among patients with bronchiectasis affiliated with a US tertiary medical center and identify which comorbid diseases are associated with the presence of CRS in patients with bronchiectasis. METHODS: This was a retrospective cohort study in which data were obtained from a large database warehouse at a tertiary care center. Patients with bronchiectasis were identified from 2007 to 2017 using diagnosis codes from the the ninth and tenth revisions of the International Classification of Diseases (ICD-9/10) and confirmed by radiographic evidence of bronchiectasis on chest computed tomography (CT) scans. Patients were divided into cohorts based on presence or absence of concomitant CRS. Characteristics analyzed included demographics, comorbidities, peripheral eosinophil counts, and pulmonary function testing. RESULTS: CRS was present in 45% (408 of 900) of patients with bronchiectasis. Females represented a majority of bronchiectasis patients, both with and without CRS (69% and 64%, respectively, p = 0.09). After controlling for demographic factors, asthma (p < 0.01), allergic rhinitis (p < 0.01), gastroesophageal reflux disease (p < 0.01), and antibody deficiency (p < 0.01) were associated with the presence of CRS in patients with bronchiectasis. CONCLUSION: CRS had a high prevalence and was associated with numerous comorbid conditions in patients with bronchiectasis. These findings have clinical implications for the treatment of patients with bronchiectasis and future research.

Associations Between Inflammatory Endotypes and Clinical Presentations in Chronic Rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by mucosal inflammation in the nose and paranasal sinuses. Inflammation in CRS is also heterogeneous and is mainly characterized by type 2 (T2) inflammation, but subsets of patients show type 1 (T1) and type 3 (T3) inflammation. Whether inflammatory endotypes are associated with clinical phenotypes has yet to be explored in detail. OBJECTIVE: To identify associations between inflammatory endotypes and clinical presentations in CRS. METHODS: We compared 121 patients with nonpolypoid CRS (CRSsNP) and 134 patients with polypoid CRS (CRSwNP) and identified inflammatory endotypes using markers including IFN-γ (T1), eosinophil cationic protein (T2), Charcot-Leyden crystal galectin (T2), and IL-17A (T3). We collected clinical parameters from medical and surgical records and examined whether there were any associations between endotype and clinical features. RESULTS: The presence of nasal polyps, asthma comorbidity, smell loss, and allergic mucin was significantly associated with the presence of T2 endotype in all patients with CRS. The T1 endotype was significantly more common in females, and the presence of pus was significantly associated with T3 endotype in all patients with CRS. We further analyzed these associations in CRSsNP and CRSwNP separately and found that smell loss was still associated with T2 endotype and pus with the T3 endotype in both CRSsNP and CRSwNP. Importantly, patients with CRS with T2 and T3 mixed endotype tended to have clinical presentations shared by both T2 and T3 endotypes. CONCLUSIONS: Clinical presentations are directly associated with inflammatory endotypes in CRS. Identification of inflammatory endotypes may allow for more precise and personalized medical treatments in CRS.