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Background: Chronic rhinosinusitis (CRS) and asthma commonly co-occur. No studies have leveraged large samples needed to formally address whether preexisting CRS is associated with new onset asthma over time., Methods: We evaluated whether prevalent CRS [identified in two ways: validated text algorithm applied to sinus computerized tomography (CT) scan or two diagnoses] was associated with new onset adult asthma in the following year. We used electronic health record data from Geisinger from 2008 to 2019. For each year we removed persons with any evidence of asthma through the end of the year, then identified those with new diagnosis of asthma in the following year. Complementary log-log regression was used to adjust for confounding variables (e.g., sociodemographic, contact with the health system, comorbidities), and hazard ratios (HRs) and 95% confidence intervals (CI) were calculated., Results: A total of 35,441 persons were diagnosed with new onset asthma and were compared to 890,956 persons who did not develop asthma. Persons with new onset asthma tended to be female (69.6%) and younger (mean [SD] age 45.9 [17.0] years). Both CRS definitions were associated (HR, 95% CI) with new onset asthma, with 2.21 (1.93, 2.54) and 1.48 (1.38, 1.59) for CRS based on sinus CT scan and two diagnoses, respectively. New onset asthma was uncommonly observed in persons with a history of sinus surgery., Conclusion: Prevalent CRS identified with two complementary approaches was associated with a diagnosis of new onset asthma in the following year. The findings may have clinical implications for the prevention of asthma., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Viruses may drive immune mechanisms responsible for chronic rhinosinusitis with nasal polyposis (CRSwNP), but little is known about the underlying molecular mechanisms., Objectives: To identify epigenetic and transcriptional responses to a common upper respiratory pathogen, rhinovirus (RV), that are specific to patients with CRSwNP using a primary sinonasal epithelial cell culture model., Methods: Airway epithelial cells were collected at surgery from patients with CRSwNP (cases) and from controls without sinus disease, cultured, and then exposed to RV or vehicle for 48 h. Differential gene expression and DNA methylation (DNAm) between cases and controls in response to RV were determined using linear mixed models. Weighted gene co-expression analysis (WGCNA) was used to identify (a) co-regulated gene expression and DNAm signatures, and (b) genes, pathways, and regulatory mechanisms specific to CRSwNP., Results: We identified 5585 differential transcriptional and 261 DNAm responses (FDR <0.10) to RV between CRSwNP cases and controls. These differential responses formed three co-expression/co-methylation modules that were related to CRSwNP and three that were related to RV (Bonferroni corrected p < .01). Most (95%) of the differentially methylated CpGs (DMCs) were in modules related to CRSwNP, whereas the differentially expressed genes (DEGs) were more equally distributed between the CRSwNP- and RV-related modules. Genes in the CRSwNP-related modules were enriched in known CRS and/or viral response immune pathways., Conclusion: RV activates specific epigenetic programs and correlated transcriptional networks in the sinonasal epithelium of individuals with CRSwNP. These novel observations suggest epigenetic signatures specific to patients with CRSwNP modulate response to viral pathogens at the mucosal environmental interface. Determining how viral response pathways are involved in epithelial inflammation in CRSwNP could lead to therapeutic targets for this burdensome airway disorder., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) often require repeat sinus surgery. Mepolizumab reduced the need for sinus surgery in the SYNAPSE trial; this analysis sought to provide a more in-depth assessment of surgery endpoints in SYNAPSE., Methods: SYNAPSE was a double-blind Phase III trial (NCT03085797) in adults with recurrent, refractory, severe, CRSwNP eligible for repeat sinus surgery despite standard of care treatments and previous surgery. Patients were randomized (1:1) to mepolizumab 100 mg subcutaneously or placebo, plus standard of care, every 4 weeks for 52 weeks. Time to first inclusion on a waiting list for sinus surgery and time to first actual sinus surgery (both up to week 52) were assessed; the latter endpoint was also analyzed post hoc according to time since last sinus surgery before study screening and baseline blood eosinophil count., Results: Among 407 patients (mepolizumab: 206; placebo: 201), mepolizumab versus placebo reduced the risk of being included on a waiting list for sinus surgery (week 52 Kaplan-Meier probability estimate [95% confidence interval]: 13.9% [9.8%, 19.5%] vs. 28.5% [22.7%, 35.4%]). Mepolizumab versus placebo reduced the risk of sinus surgery irrespective of time (<3 vs ≥3 years) since patients' last sinus surgery prior to study screening (hazard ratios [95% confidence intervals] 0.28 [0.09, 0.84] and 0.50 [0.26, 0.98], respectively) and baseline blood eosinophil count., Conclusions: Mepolizumab reduced the risk of further sinus surgery in patients with recurrent, refractory, severe CRSwNP, irrespective of the patient baseline characteristics assessed., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Chronic rhinosinusitis (CRS) is a common clinical syndrome that produces significant morbidity and costs to our health system. The study of CRS has progressed from an era focused on phenotype to include endotype-based information. Phenotypic classification has identified clinical heterogeneity in CRS based on endoscopically observed features such as presence of nasal polyps, presence of comorbid or systemic diseases, and timing of disease onset. More recently, laboratory-based findings have established CRS endotype based upon specific mechanisms or molecular biomarkers. Understanding the basis of widespread heterogeneity in the manifestations of CRS is advanced by findings that the three main endotypes, Type 1, 2, and 3, orchestrate the expression of three distinct large sets of genes. The development and use of improved methods of endotyping disease in the clinic are ushering in an expansion of the use of biological therapies targeting Type 2 inflammation now and perhaps other inflammatory endotypes in the near future. The purpose of this review is to discuss the phenotypic and endotypic heterogeneity of CRS from the perspective of advancing the understanding of the pathogenesis and improvement of treatment approaches and outcomes., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Chronic rhinosinusitis (CRS) epidemiology has been largely studied using symptom-based case definitions, without assessment of objective sinus findings., Objective: To describe radiologic sinus opacification and the prevalence of CRS, defined by the co-occurrence of symptoms and sinus opacification, in a general population-based sample., Methods: We collected questionnaires and sinus CT scans from 646 participants selected from a source population of 200 769 primary care patients. Symptom status (CRS S ) was based on guideline criteria, and objective radiologic inflammation (CRS O ) was based on the Lund-Mackay (L-M) score using multiple L-M thresholds for positivity. Participants with symptoms and radiologic inflammation were classified as CRS S+O . We performed negative binomial regression to assess factors associated with L-M score and logistic regression to evaluate factors associated with CRS S+O . Using weighted analysis, we calculated estimates for the source population., Results: The proportion of women with L-M scores ≥ 3, 4, or 6 (CRS O ) was 11.1%, 9.9%, and 5.7%, respectively, and 16.1%, 14.6%, and 8.7% among men. The respective proportion with CRS S+O was 1.7%, 1.6%, and 0.45% among women and 8.8%, 7.5%, and 3.6% among men. Men had higher odds of CRS S+O compared to women. A greater proportion of men (vs women) had any opacification in the frontal, anterior ethmoid, and sphenoid sinuses., Conclusion: In a general population-based sample in Pennsylvania, sinus opacification was more common among men than in women and opacification occurred in different locations by sex. Male sex, migraine headache, and prior sinus surgery were associated with higher odds of CRS S+O ., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Sinonasal symptoms are common and can have several underlying causes. When symptoms occur in specified patterns lasting 3 months or more they meet criteria for chronic rhinosinusitis (CRS). Approaches to CRS symptom measurement do not specify how to measure symptoms and treat specified sinonasal symptoms as generally interchangeable, suggesting that such symptoms should cluster on 1 or 2 latent factors., Methods: We used questionnaire responses to 37 questions on the presence, severity, bother, and frequency of cardinal sinonasal and related symptoms lasting 3 months, from 3535 subjects at 3 time points over 16 months. We completed 5 exploratory factor analyses (EFA) to identify symptom clustering, 1 for each time point and 2 for the differences between adjacent questionnaires. The baseline EFA was used to provide factor scores that were described longitudinally and examined by CRS status., Results: Five EFAs identified the same 5 factors (blockage and discharge, pain and pressure, asthma and cold/flu symptoms, smell loss, and ear and eye [mainly allergy] symptoms), with clustering determined by symptom frequency, severity, and degree of bother. Responses to individual questions showed changes over time but when combined into factor scores showed less longitudinal change. All symptom factor scores were progressively higher from never to past to current CRS status., Conclusions: Although the current approaches to symptom characterization in CRS imply a single underlying latent construct, our results suggest that there are at least 3 latent constructs relevant to CRS. Further studies are needed to evaluate whether these clusters have identifiable underlying pathobiologies., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Nasal and sinus symptoms (NSS) are common to many health conditions, including chronic rhinosinusitis (CRS). Few studies have investigated the occurrence and severity of, and risk factors for, acute exacerbations of NSS (AENSS) by CRS status (current, past, or never met European Position Paper on Rhinosinusitis [EPOS] criteria for CRS)., Methods: Four seasonal questionnaires were mailed to a stratified random sample of Geisinger primary care patients. Logistic regression was used to identify individual characteristics associated with AENSS occurrence and severity by CRS status (current long-term, current recent, past, never) using EPOS subjective symptoms-only (EPOS S ) CRS criteria. We operationalized 3 AENSS definitions based on prescribed antibiotics or oral corticosteroids, symptoms, and symptoms with purulence., Results: Baseline and at least 1 follow-up questionnaires were available from 4736 subjects. Self-reported NSS severity with exacerbation was worst in the current long-term CRS group. AENSS was common in all subgroups examined and generally more common among those with current EPOS S CRS. Seasonal prevalence of AENSS differed by AENSS definition and CRS status. Associations of risk factors with AENSS differed by definition, but CRS status, body mass index, asthma, hay fever, sinus surgery history, and winter season consistently predicted AENSS., Conclusions: In this first longitudinal, population-based study of 3 AENSS definitions, NSS and AENSS were both common, sometimes severe, and differed by EPOS S CRS status. Contrasting associations of risk factors for AENSS by the different definitions suggest a need for a standardized approach to definition of AENSS., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: The objective of this study was to describe the first US-based study to use the European Position Paper on Rhinosinusitis (EPOS) criteria to study the prevalence of chronic rhinosinusitis (CRS) in a general-population sample., Methods: A CRS symptom questionnaire was mailed to 23 700 primary care patients from Geisinger Clinic, a health system serving 45 counties in Pennsylvania. CRS cases were categorized into four unique subgroups based on EPOS symptoms: obstruction and discharge with no smell loss or pain/pressure; smell loss without pain/pressure; facial pain and/or pressure without smell loss; and both smell loss and pain/pressure. All cases were required to have nasal obstruction or discharge. Logistic regression was used to evaluate potential factors associated with CRS subgroups., Results: We found that 11.9% of patients met criteria for CRS. Prevalence peaked at 15.9% between ages 50 and 59 years and then dropped to 6.8% after age 69. The odds of CRS was higher among patients who were white, younger, smokers, had a history of Medical Assistance, and had other diseases. When CRS subgroups were modeled separately, these associations were no longer significant for some CRS subgroups. Comorbid diseases were most strongly associated with CRS cases who reported smell loss and facial pain and/or pressure and had the weakest associations with CRS cases who did not report these symptoms., Conclusions: CRS is a highly prevalent and heterogeneous condition. Differences in risk factors and health outcomes across symptom subgroups may be indicative of differences in etiology that have implications for disease management., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Chronic rhinosinusitis (CRS) has a broad range of comorbidities. Due to a lack of longitudinal studies, it is not known whether these comorbidities cause CRS, are promoted by CRS, or share a systemic disease process with CRS., Objective: The objective of this study was to determine the risk of incident disease within 5 years after a new diagnosis of CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP)., Methods: We conducted a case-control study nested within the longitudinal cohort of primary care patients in the Geisinger Clinic using electronic health record data. We evaluated incident disease over 5 years in newly diagnosed CRSwNP and CRSsNP cases compared to controls using multivariable Cox regression models., Results: CRSsNP (n = 3612) cases were at greater risk (HR, 95% confidence interval) than controls for incidence of: upper airway diseases, including adenotonsillitis (3.29, 2.41-4.50); lower aerodigestive tract diseases, including asthma (2.69, 2.14-3.38); epithelial conditions, including atopic dermatitis (2.75, 1.23-6.16); and hypertension (1.38, 1.19-1.61). CRSwNP (n = 241) cases were at greater risk for obesity than controls (1.74, 1.08-2.80), but CRSwNP was not associated with other diseases., Conclusion: The risk of other diseases associated with CRS adds to the burden of an already highly burdensome condition, and suggests either that CRS promotes onset of other diseases or is an indicator of systemic disease processes. Different patterns of association with diseases by CRS phenotype may be due to CRSwNP sample size limitations or reflect a different pattern of disease onset by phenotype. These findings have implications for screening guidelines and care of CRS patients., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Chronic rhinosinusitis (CRS) is a disease characterized by inflammation of the nasal mucosa and paranasal sinuses. This inflammation may result in part from decreased epithelial barrier and innate immune responses, leading to frequent bacterial and fungal colonization. The objectives of this study were to investigate the expression of innate immune proteins of the palate lung and nasal epithelium clone (PLUNC) family in patients with CRS., Methods: Nasal tissue samples were collected from control subjects and CRS patients with and without nasal polyps. Expression of the members of the PLUNC family was analyzed by real-time PCR. Expression of SPLUNC1 and LPLUNC2 proteins was analyzed by ELISA, immunoblot, and immunohistochemical analysis., Results: Levels of mRNA for most of the members of the PLUNC family were profoundly reduced in nasal polyps (NPs) compared to uncinate tissue from control subjects or patients with CRS. LPLUNC2 and SPLUNC1 proteins were decreased in NPs of patients with CRS compared to uncinate tissue from control subjects. Immunohistochemical data revealed that within submucosal glands of sinonasal tissues, SPLUNC1 and LPLUNC2 were differentially expressed, in serous and mucous cells, respectively. The decrease in the expression of these molecules is probably explained by a decrease in the number of glands in NPs as revealed by correlations with levels of the glandular marker lactoferrin., Conclusions: Decreased SPLUNC1 and LPLUNC2 in NPs reflect a profound decrease in the number of submucosal glands. Decreased glands may lead to a localized defect in the production and release of glandular innate defense molecules., (© 2012 John Wiley & Sons A/S.)

Background:   Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by local inflammation of the upper airways and sinuses and is frequently divided into polypoid CRS (CRSwNP) and nonpolypoid CRS (CRSsNP). However, the mechanism of inflammation in CRS has still not been fully elucidated. The aim of the study was to investigate the role of interleukin-32 (IL-32), a recently discovered proinflammatory cytokine, in CRS., Methods:   We collected nasal epithelial cells and nasal tissue from patients with CRS and control subjects. We assayed mRNA for IL-32 by real-time PCR and measured IL-32 protein using ELISA, Western blot, and immunohistochemistry., Results:   The expression of mRNA for IL-32 was elevated in epithelial cells from uncinate tissue from patients with CRSsNP compared with patients with CRSwNP (P < 0.05), control subjects (P=0.06), and epithelial cells from nasal polyp (NP) tissue (P < 0.05). Production of IL-32 was induced by IFN-γ, TNF, and dsRNA in primary airway epithelial cells. In whole-tissue extracts, the expression of IL-32 protein was significantly elevated in patients with CRSwNP compared with patients with CRSsNP and control subjects. Immunohistochemistry data showed that IL-32 was detected in mucosal epithelial cells and inflammatory cells in the lamina propria. Levels of IL-32 were correlated with the levels of CD3 and macrophage mannose receptor in NP tissue. Immunofluorescence data showed IL-32 co-localization with CD3-positive T cells and CD68-positive macrophages in NPs., Conclusion:   Overproduction of IL-32 may be involved in the pathogenesis of CRS, although the role of IL-32 in the inflammation in CRSsNP and CRSwNP may be different., (© 2011 John Wiley & Sons A/S.)