Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 152
Filter
1.
Article in English | MEDLINE | ID: mdl-38797240

ABSTRACT

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation in the United States, but the actual roles that eosinophils play in CRSwNP remain largely unclear. OBJECTIVE: To reveal the roles and heterogeneity of eosinophils in nasal polyp (NP) tissue, we performed 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 before processing for scRNA-Seq. The gene expression profiles in eosinophils were determined by microwell-based scRNA-Seq technology (BD Rhapsody platform). We predicted the overall function of NP eosinophils by Gene Ontology (geneontology.org) 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 downregulated and 354 genes upregulated in NP eosinophils compared to all PB eosinophils (>1.5-fold, Padj < .05). Upregulated genes in NP eosinophils were associated with activation, cytokine-mediated signaling, growth factor activity, NF-κB signaling, and antiapoptotic 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 by controlling inflammation and hyperproliferation of other cells.

2.
Curr Opin Allergy Clin Immunol ; 24(1): 1-8, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-37966157

ABSTRACT

PURPOSE OF REVIEW: This review aims to provide updates in realms of endotypic heterogeneity, pathogenesis at the molecular level, potential of biomarkers, and cutting-edge scope of biologics in CRS. RECENT FINDINGS: High-dimensional analyses, such as transcriptomes, and machine learning, have significantly enhanced CRS endotyping, uncovering diverse pathogenetic mechanisms contributing to its heterogeneity. The dynamic process of epithelial remodeling in CRS pathogenesis has gained more clarity and support as exemplified by IL-13 and oncostatin M (OSM) that are shown intricately linked to epithelial barrier dysfunction. Moreover, anti-dsDNA autoantibody, BAFF, periostin, and cystatin SN show promise as potentials biomarkers, offering diagnostic and prognostic value for CRS. SUMMARY: The identification of inflammatory molecules involved in endotype specific signaling pathways provides insights into the underlying mechanisms and verifiable biomarkers for diagnosis and prediction of disease severity. More comprehensive clinical studies should be conducted to facilitate biologics from bench to bedside in treating CRS.


Subject(s)
Biological Products , Nasal Polyps , Rhinitis , Rhinosinusitis , Sinusitis , Humans , Sinusitis/drug therapy , Biomarkers/analysis , Chronic Disease , Biological Products/therapeutic use , Nasal Polyps/diagnosis
3.
J Allergy Clin Immunol ; 153(5): 1292-1305, 2024 May.
Article in English | MEDLINE | ID: mdl-38157944

ABSTRACT

BACKGROUND: Type 2 (T2) inflammation plays a pathogenic role in chronic rhinosinusitis (CRS). The effects of endoscopic sinus surgery (ESS) on T2 inflammation are unknown. OBJECTIVE: The aim of this study was to compare T2 inflammatory biomarkers from middle meatal (MM) mucus for distinguishing patients with CRS from CRS-free patients, identifying major phenotypes (CRS without nasal polyps [CRSsNP] and CRS with nasal polyps [CRSwNP]), assessing endotypic change, and establishing cross-sectional and longitudinal outcomes in patients undergoing ESS. METHODS: MM mucus samples were collected from patients with CRSsNP and patients with CRSwNP before and 6 to 12 months after ESS and compared with samples from CRS-free control patients. T2 biomarkers were evaluated both continuously and using threshold-based definitions of T2 endotype to identify relationships with patient-reported (based on the 22-Item Sinonasal Outcomes Test and Chronic Rhinosinusitis Patient-Reported Outcomes Measure) and clinician-reported (radiographic and endoscopic) severity. Linear mixed models were developed to analyze clinical variables associated with T2 biomarker levels. RESULTS: A total of 154 patients with CRS (89 with CRSsNP and 65 with CRSwNP) were enrolled, with a mean interval of 9 months between ESS and follow-up. An analysis of pre-ESS MM mucus samples revealed elevated levels of T2 mediators in patients with CRSwNP versus in patients with CRSsNP and CRS-free controls. Temporally stable correlations between levels of IL-13 and IL-5, levels of periostin and complement 5a, and levels of eosinophil cationic protein (ECP) and eotaxin-3 were observed. On this basis and on the basis of pathologic significance, levels of IL-13, periostin and ECP were further analyzed. After ESS, levels of IL-13 and periostin decreased significantly, whereas ECP levels remained unchanged. Across pre- and post-ESS evaluation, the T2 endotype was associated with radiographic severity but did not predict outcomes. CRSwNP status and African American race were associated with higher levels of IL-13 and periostin, whereas ECP level was higher in patients undergoing extensive surgery. CONCLUSION: ESS decreased levels of IL-13 and periostin in the middle meatus. T2 inflammation after ESS was correlated with patient- and clinician-reported severity across phenotypes. Pre-ESS T2 inflammation did not predict post-ESS outcomes.


Subject(s)
Biomarkers , Cell Adhesion Molecules , Endoscopy , Interleukin-13 , Nasal Polyps , Rhinitis , Sinusitis , Humans , Sinusitis/surgery , Rhinitis/surgery , Rhinitis/immunology , Chronic Disease , Female , Male , Middle Aged , Adult , Nasal Polyps/surgery , Nasal Polyps/immunology , Paranasal Sinuses/surgery , Aged , Cross-Sectional Studies , Mucus/metabolism , Rhinosinusitis , Periostin
4.
Allergy ; 78(10): 2698-2711, 2023 10.
Article in English | MEDLINE | ID: mdl-37571876

ABSTRACT

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.


Subject(s)
Nasal Polyps , Rhinitis , Sinusitis , Humans , Rhinovirus , Sinusitis/metabolism , Chronic Disease , Epithelial Cells/metabolism , Epigenesis, Genetic
5.
Allergy ; 78(10): 2659-2668, 2023 10.
Article in English | MEDLINE | ID: mdl-37195236

ABSTRACT

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.


Subject(s)
Asthma , Paranasal Sinuses , Rhinitis , Sinusitis , Adult , Humans , Female , Middle Aged , Rhinitis/diagnosis , Rhinitis/epidemiology , Rhinitis/complications , Sinusitis/diagnosis , Sinusitis/epidemiology , Sinusitis/complications , Asthma/diagnosis , Asthma/epidemiology , Asthma/complications , Chronic Disease , Inflammation/complications
6.
Am J Rhinol Allergy ; 37(2): 182-192, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36848269

ABSTRACT

BACKGROUND: Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) are two prevalent nasal diseases where both type 2 inflammation and immunoglobulin E (IgE) may play important roles. Although they can exist independently or comorbidly, subtle but important differences exist in immunopathogenesis. OBJECTIVE: To summarize current knowledge of pathophysiological roles of B lineage cells and IgE in AR and CRS with nasal polyps (CRSwNP). METHODS: Searched PubMed database, reviewed AR and CRSwNP-related literature, and discussed disease diagnosis, comorbidity, epidemiology, pathophysiology, and treatment. Similarities and differences in B-cell biology and IgE are compared in the 2 conditions. RESULTS: Both AR and CRSwNP have evidence for pathological type 2 inflammation, B-cell activation and differentiation, and IgE production. However, distinctions exist in the clinical and serological profiles at diagnosis, as well as treatments utilized. B-cell activation in AR may more frequently be regulated in the germinal center of lymphoid follicles, whereas CRSwNP may occur via extrafollicular pathways although controversies remain in these initial activating events. Oligoclonal and antigen-specific IgE maybe predominate in AR, but polyclonal and antigen-nonspecific IgE may predominate in CRSwNP. Omalizumab has been shown efficacious in treating both AR and CRSwNP in multiple clinical trials but is the only Food and Drug Administration-approved anti-IgE biologic to treat CRSwNP or allergic asthma. Staphylococcus aureus frequently colonizes the nasal airway and has the ability to activate type two responses including B-cell responses although the extent to which it modulates AR and CRSwNP disease severity is being investigated. CONCLUSION: This review highlights current knowledge of the roles of B cells and IgE in the pathogenesis of AR and CRSwNP and a small comparison between the 2 diseases. More systemic studies should be done to elevate the understanding of these diseases and their treatment.


Subject(s)
Immunoglobulin E , Rhinitis, Allergic , United States , Humans , Omalizumab/therapeutic use , Rhinitis, Allergic/drug therapy , Rhinitis, Allergic/epidemiology , B-Lymphocytes , Inflammation
7.
Int Forum Allergy Rhinol ; 13(9): 1715-1725, 2023 09.
Article in English | MEDLINE | ID: mdl-36756720

ABSTRACT

BACKGROUND: Chronic rhinosinusitis (CRS) is accompanied by burdensome comorbid conditions. Understanding the relative timing of the onset of these conditions could inform disease prevention, detection, and management. OBJECTIVE: To evaluate the association between CRS and new-onset and prevalent asthma, noncystic fibrosis bronchiectasis (NCFBE), chronic obstructive pulmonary disease (COPD), gastroesophageal reflux disease (GERD), and obstructive sleep apnea (OSA). METHODS: We conducted a prospective cohort study among primary care patients using a detailed medical and symptom questionnaire in 2014 and again in 2020. We used questionnaire and electronic health record (EHR) data to determine CRS status: CRSSE (moderate to severe symptoms with EHR evidence), CRSE (limited symptoms with EHR evidence), CRSS (moderate to severe symptoms without EHR evidence), CRSneg (limited symptoms and no EHR evidence; reference). We evaluated the association between CRS status and new-onset and prevalent disease using logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: There were 7847 and 4445 respondents to the 2014 and 2020 questionnaires, respectively. CRSSE (vs CRSneg ) was associated with increased odds of new-onset asthma (OR, 1.74 [CI, 1.09-2.77), NCFBE (OR, 1.87 [CI, 1.12-3.13]), COPD (OR, 1.73 [CI, 1.14-2.68]), GERD (OR, 1.95 [CI, 1.61-2.35]), and OSA (OR, 1.91 [CI, 1.39-2.62]). Similarly, increased odds were observed for associations with the prevalence of these conditions. CONCLUSION: The findings from the study support further exploration of CRS as a target for the prevention and detection of asthma, NCFBE, COPD, GERD, and OSA.


Subject(s)
Asthma , Bronchiectasis , Gastroesophageal Reflux , Pulmonary Disease, Chronic Obstructive , Sinusitis , Sleep Apnea, Obstructive , Humans , Prospective Studies , Chronic Disease , Gastroesophageal Reflux/epidemiology , Pulmonary Disease, Chronic Obstructive/complications , Asthma/epidemiology , Sleep Apnea, Obstructive/epidemiology , Sinusitis/epidemiology , Sinusitis/complications
8.
J Allergy Clin Immunol ; 151(5): 1379-1390.e11, 2023 05.
Article in English | MEDLINE | ID: mdl-36623776

ABSTRACT

BACKGROUND: Oncostatin M (OSM) may promote type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) by inducing thymic stromal lymphopoietin (TSLP). OBJECTIVE: We sought to study the impact of OSM on TSLP synthesis and release from nasal epithelial cells (NECs). METHODS: OSM receptors, IL-4 receptors (IL-4R), and TSLP were evaluated in mucosal tissue and primary NECs from patients with CRSwNP by quantitative PCR and immunofluorescence. Air-liquid interface-cultured NECs were stimulated with cytokines, including OSM, and quantitative PCR, ELISA, Western blot, and flow cytometry were used to assess the expression of OSM receptors, IL-4R, and TSLP. RESULTS: Increased levels of OSM receptor ß chain (OSMRß), IL-4Rα, and TSLP were observed in nasal polyp tissues and primary epithelial cells from nasal polyps of patients with CRSwNP compared with control tissues or cells from control subjects. The level of expression of OSMRß in tissue was correlated with levels of both IL-4Rα and TSLP. OSM stimulation of NECs increased the expression of OSMRß and IL-4Rα. Stimulation with IL-4 plus OSM augmented the production of TSLP; the response was suppressed by a signal transducer and activator of transcription 6 inhibitor. Stimulation of NECs with IL-4 plus OSM increased the expression of proprotein convertase subtilisin/kexin 3, an enzyme that truncates and activates TSLP. CONCLUSIONS: OSM increases the expression of IL-4Rα and synergizes with IL-4 to induce the synthesis and release of TSLP in NECs. Because the combination of IL-4 and OSM also augmented the expression of proprotein convertase subtilisin/kexin 3, these results suggest that OSM can induce both synthesis and posttranslational processing/activation of TSLP, promoting type 2 inflammation.


Subject(s)
Interleukin-4 , Nasal Polyps , Oncostatin M , Rhinitis , Sinusitis , Humans , Chronic Disease , Cytokines/metabolism , Inflammation/metabolism , Interleukin-4/metabolism , Nasal Mucosa/metabolism , Nasal Polyps/metabolism , Oncostatin M/metabolism , Proprotein Convertases/metabolism , Rhinitis/metabolism , Sinusitis/metabolism , Subtilisins/metabolism , Thymic Stromal Lymphopoietin
9.
Int Forum Allergy Rhinol ; 13(1): 15-24, 2023 01.
Article in English | MEDLINE | ID: mdl-35670482

ABSTRACT

BACKGROUND: Patients with chronic rhinosinusitis (CRS) may have persistence of polyps, discharge, or edema after endoscopic sinus surgery (ESS). Inflammation in CRS can be classified into three endotypes, with the presence of polyps associated with the type 2 endotype. Here, we evaluate the endotypic underpinnings of discharge or edema without polyps after ESS. METHODS: At a visit 6-12 months post ESS, patients underwent endoscopy and completed the CRS-PRO and SNOT-22. Luminex analysis of middle meatal mucus obtained at that visit was performed for IFN-γ, ECP, and IL-17a. Type 1, 2, and 3 endotypes were defined as greater than the 90th percentile expression of each marker, respectively, in controls. Wilcoxon rank-sum and chi-squared tests were used to compare cytokine levels and endotype prevalence between those with and without endoscopic findings. RESULTS: A total of 122 CRS patients completed a clinical exam (median: 8.2 months post ESS). Of the 122 patients, 107 did not have polyps on endoscopy. Of these 107 patients, 48 had discharge, 44 had edema, and 46 had neither discharge nor edema. Compared with those patients without any findings, patients with discharge or edema reported significantly worse severity as measured by CRS-PRO (10.5 vs. 7.0, p = 0.009; 12.0 vs. 7.0, p < 0.001; respectively), and had higher post-ESS IFN-γ, ECP, and IL-17a. Patients with discharge had higher prevalence of only T1 and T3 endotypes, while patients with edema had higher prevalence of only the T3 endotype. CONCLUSIONS: Post-ESS discharge or edema in the absence of polyps was associated with higher patient-reported outcome severity and was more strongly associated with type 1 or 3 inflammation.


Subject(s)
Nasal Polyps , Rhinitis , Sinusitis , Humans , Interleukin-17 , Patient Discharge , Rhinitis/epidemiology , Nasal Polyps/epidemiology , Sinusitis/epidemiology , Inflammation , Chronic Disease , Endoscopy , Edema
10.
Int Forum Allergy Rhinol ; 13(9): 1758-1782, 2023 09.
Article in English | MEDLINE | ID: mdl-36579899

ABSTRACT

BACKGROUND: Despite the significant morbidity associated with chronic rhinosinusitis (CRS) in individuals with asthma (CRSwA), there is a paucity of codified, evidence-based management strategies for CRS in this population. METHODS: Using PubMed, Embase, and Cochrane Review Databases, a systematic review was performed covering management strategies for CRSwA. A total of 5903 articles were screened, and 70 were included for full-text analysis. After application of exclusion criteria, 53 articles comprised the qualitative synthesis. The level of evidence was graded and benefit-harm assessments, as well as value judgment and recommendations, were provided RESULTS: Strong evidence confirms the benefit of oral and topical medications on sinonasal-specific outcomes in individuals with CRSwA; there is low-grade evidence demonstrating that these agents improve lung function and/or asthma control. Moderate to strong evidence suggests that endoscopic sinus surgery (ESS) improves both sinonasal- and asthma-specific quality of life. Although there is insufficient to low evidence to indicate that ESS improves pulmonary function in this population, data indicate a positive impact of this intervention on asthma control. Biologic medications strongly improve both subjective and objective sinonasal- and asthma-specific outcomes. CONCLUSION: Evidence supports managing CRS in individuals with CRSwA in a stepwise fashion, starting with traditional nonbiologic oral and topical medication, and escalating to second-line treatments, such as ESS and biologics. Optimal treatment of individuals who have CRSwA often requires concurrent, directed management of asthma, as not all CRS interventions impact asthma status.


Subject(s)
Asthma , Rhinitis , Sinusitis , Humans , Quality of Life , Rhinitis/therapy , Rhinitis/complications , Sinusitis/therapy , Sinusitis/complications , Asthma/therapy , Chronic Disease , Endoscopy
11.
Laryngoscope Investig Otolaryngol ; 7(6): 1704-1711, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36544956

ABSTRACT

Background: COVID-19 measures such as masking, social distancing, and staying indoors may mitigate chronic rhinosinusitis (CRS) symptoms. We evaluate whether these measures correlated with improved symptoms in patients with CRS. Methods: This retrospective study compared SNOT-22 survey data from the Northwestern CRS Registry at the time of enrollment and at years 1-5 of follow-up. The final sample consisted of 1826 SNOT-22 surveys for 598 patients. April 10, 2020 to December 31, 2021 was considered "during the pandemic" and prior to March 11, 2020 was considered "pre-pandemic." Wilcoxon test was used to compare SNOT22 at enrollment pre-pandemic versus during pandemic. Separate linear mixed models were performed to estimate SNOT22 at 1 to 5 years after enrollment pre-pandemic versus during pandemic. Results: Subjects enrolled during the pandemic had worse SNOT22 scores than those enrolled pre-pandemic (53 vs. 42, p = .0024). Total SNOT-22 scores were improved during the pandemic than before the pandemic at 1 year follow-up (18.17 vs. 12.22, p = .001). This effect persists when evaluating the nasal (7.33 vs. 5.13, p = .003), sleep (2.63 vs. 1.39, p = .008), function (1.40 vs. 0.72, p = .015), and emotion (0.77 vs. 0.17, p < .001) domains individually. There was no statistically significant difference in total SNOT-22 score at Years 2-5 of follow-up. Conclusions: Patients with CRS experience a greater reduction in symptom severity in their first year of treatment during the pandemic than before the pandemic, plausibly from measures such as masking and staying indoors. Level of Evidence: 4.

12.
Front Pharmacol ; 13: 888610, 2022.
Article in English | MEDLINE | ID: mdl-35847037

ABSTRACT

Background: Proton-pump inhibitors (PPIs) block acid secretion from gastric parietal cells; however, recent studies have reported that PPIs have antioxidant and anti-inflammatory properties in various cells. Newer PPIs are stronger inhibitors of acid secretion; however, the anti-inflammatory effects of these drugs have not been assessed. We evaluated anti-inflammatory effect of PPIs on the development of asthma/asthma exacerbation (AE) in a national health screening cohort. Methods: This case-control study comprised 64,809 participants with asthma who were 1:1 matched with controls from the Korean National Health Insurance Service-Health Screening Cohort. Conditional logistic regression analysis was used to evaluate the effect of previous PPI use on an asthma diagnosis in all participants. Unconditional logistic regression was used to assess the effect of PPI use on AE in participants with asthma. These relationships were estimated in a subgroup analysis according to PPI generation. Results: Overall, PPI use increased the risk of asthma diagnosis [adjusted odds ratio (aOR) = 1.29, 95% confidence interval (CI) = 1.23-1.35, p < 0.001]. Use of the first-generation PPIs was associated with asthma (aOR = 1.34, 95% CI = 1.18-1.52, p < 0.001), while use of second-generation PPIs was not (aOR = 0.97, 95% CI = 0.82-1.15, p = 0.748). In contrast, overall PPI use decreased the risk of AE in participants with asthma (aOR = 0.79, 95% CI = 0.75-0.84, p < 0.001), although this effect was observed only for second-generation PPIs (aOR = 0.76, 95% CI = 0.65-0.89, p = 0.001). Conclusion: PPI use increased the risk for subsequent asthma diagnosis. However, this effect was confined to first-generation PPIs. Second-generation PPIs decreased the risk of AE.

14.
J Allergy Clin Immunol ; 150(5): 1114-1124.e3, 2022 11.
Article in English | MEDLINE | ID: mdl-35728655

ABSTRACT

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.


Subject(s)
Asthma, Aspirin-Induced , Nasal Polyps , Rhinitis , Sinusitis , Humans , Nasal Polyps/metabolism , Rhinitis/metabolism , Tissue Plasminogen Activator , Interleukin-13 , Fibrinolysis , Tretinoin/pharmacology , Endothelial Cells/metabolism , Sinusitis/metabolism , Asthma, Aspirin-Induced/complications , Chronic Disease , Fibrin
15.
Clin Exp Allergy ; 52(7): 859-867, 2022 07.
Article in English | MEDLINE | ID: mdl-35524339

ABSTRACT

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.


Subject(s)
Nasal Polyps , Rhinitis , Sinusitis , Acetates , Adrenal Cortex Hormones/therapeutic use , Adult , Chronic Disease , Humans , Immunity, Innate , Indoles , Lymphocytes , Nasal Polyps/complications , Nasal Polyps/drug therapy , Quality of Life , Rhinitis/complications , Rhinitis/drug therapy , Sinusitis/drug therapy
16.
Int Forum Allergy Rhinol ; 12(4): 327-680, 2022 04.
Article in English | MEDLINE | ID: mdl-35373533

ABSTRACT

BACKGROUND: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O). METHODS: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus. RESULTS: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies. CONCLUSION: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further.


Subject(s)
Hypersensitivity , Smell , Consensus , Cost of Illness , Humans
17.
Int Forum Allergy Rhinol ; 12(11): 1330-1339, 2022 11.
Article in English | MEDLINE | ID: mdl-35362251

ABSTRACT

BACKGROUND: Mometasone-eluting stents (MES) have demonstrated improvement in short-term endoscopic outcomes and reduce short- to medium-term rescue interventions. Their effect on the local inflammatory environment, longer-term patient-reported outcomes, and radiographic severity have not been studied. METHODS: Middle meatal mucus and validated measures of disease severity were collected before and 6 to 12 months after endoscopic surgery in 52 patients with chronic rhinosinusitis with nasal polyps (CRSwNPs). Operative findings, type 2 mediator concentrations, intraoperative variables, and disease severity measures were compared between those who did and those who did not receive intraoperative frontal MES. RESULTS: A total of 52 patients with CRSwNPs were studied; 33 received frontal MES and were compared with 19 who did not. Pre-endoscopic sinus surgery (ESS) middle meatus (MM) interleukin (IL) 13 and eosinophil cationic protein (ECP) were higher in the stented group (p < 0.05), but pre-ESS clinical measures of disease severity were similar as were surgical extent and post-ESS medical management. Intraoperative eosinophilic mucin was more frequent in the stented group (58% vs 11%, p = 0.001). IL-5 (p < 0.05) and IL-13 (p < 0.001) decreased post-ESS in the stented group, but this was not observed in the nonstented group. Post-ESS IL-4 and IL-13 were higher in the nonstented vs stented group (p < 0.05 for both). CONCLUSION: Although patients who received intraoperative frontal MES had significantly higher pre-ESS MM IL-13 and ECP, patients who received frontal MES had lower concentrations of IL-4 and IL-13 than those who did not at a median of 8 months post-ESS. However, these changes did not correspond to significantly different measures of symptomatic or radiographic disease severity.


Subject(s)
Drug-Eluting Stents , Frontal Sinus , Nasal Polyps , Rhinitis , Sinusitis , Humans , Nasal Polyps/surgery , Interleukin-5 , Interleukin-13 , Mometasone Furoate/therapeutic use , Rhinitis/surgery , Interleukin-4 , Sinusitis/surgery , Endoscopy , Chronic Disease
18.
Int Forum Allergy Rhinol ; 12(11): 1377-1386, 2022 11.
Article in English | MEDLINE | ID: mdl-35363947

ABSTRACT

The 22-item Sino-Nasal Outcome Test (SNOT-22) and 12-item Patient Reported Outcomes in Chronic Rhinosinusitis (CRS-PRO) instrument are validated patient-reported outcomes measures in CRS. In this study we assess the correlation of these with type 2 (T2) biomarkers before and after endoscopic sinus surgery (ESS). METHODS: Middle meatal mucus data were collected and the SNOT-22 and CRS-PRO were administered to 123 patients (71 CRS without nasal polyps [CRSsNP], 52 CRS with nasal polyps [CRSwNP]) with CRS before and 6 to 12 months after undergoing ESS. Interleukin (IL)-4, IL-5, IL-13, and eosinophilic cationic protein (ECP) were measured using a multiplexed bead assay and enzyme-linked immunoassay. Pre- and post-ESS SNOT-22 and CRS-PRO were compared with T2 biomarkers. RESULTS: Before ESS neither PROM correlated with any biomarker. After ESS, CRS-PRO showed a correlation with 2 mediators (IL-5 and IL-13: p = 0.012 and 0.003, respectively) compared with none for the SNOT-22. For CRSwNP patients, pre-ESS CRS-PRO and SNOT-22 correlated with IL-4 (p = 0.04 for both). However, after ESS, CRS-PRO correlated with 3 biomarkers (IL-5, IL-13, and ECP: p = 0.02, 0.024, and 0.04, respectively) and SNOT-22 with 2 biomarkers (IL-5 and IL-13: p = 0.038 and 0.02, respectively). There were no significant relationships between any of the T2 biomarkers pre- or post-ESS among patients with CRSsNP. Exploratory analyses of the subdomains showed the SNOT-22 rhinologic and CRS-PRO rhinopsychologic subdomains correlated better with the T2 biomarkers. On individual item analysis, IL-13 correlated significantly post-ESS with 8 of 12 items on the CRS-PRO vs 6 of 22 items on the SNOT-22. CONCLUSION: The CRS-PRO total score showed a significant correlation with T2 biomarkers especially when assessed post-ESS and among CRSwNP patients.


Subject(s)
Nasal Polyps , Rhinitis , Sinusitis , Humans , Nasal Polyps/surgery , Sino-Nasal Outcome Test , Rhinitis/surgery , Interleukin-13 , Inflammation Mediators , Interleukin-5 , Sinusitis/surgery , Endoscopy , Chronic Disease , Biomarkers
19.
J Allergy Clin Immunol ; 150(3): 701-708.e4, 2022 09.
Article in English | MEDLINE | ID: mdl-35314187

ABSTRACT

BACKGROUND: Chronic rhinosinusitis (CRS) and bronchiectasis commonly co-occur, but most prior studies were not designed to evaluate temporality and causality. OBJECTIVES: In a sample representing the general population in 37 counties in Pennsylvania, and thus the full spectrum of sinonasal and relevant lung diseases, we aimed to evaluate the temporality and strength of associations of CRS with non-cystic fibrosis bronchiectasis. METHODS: We completed case-control analyses for each of 3 primary bronchiectasis case finding methods. We used electronic health records to identify CRS and bronchiectasis with diagnoses, procedure orders, and/or specific text in sinus or chest computerized tomography scan radiology reports. The controls never had any indication of bronchiectasis and were frequency-matched to the 3 bronchiectasis groups on the basis of age, sex, and encounter year. There were 5,329 unique persons with bronchiectasis and 33,363 without bronchiectasis in the 3 analyses. Important co-occurring conditions were identified with diagnoses, medication orders, and encounter types. Logistic regression was used to evaluate associations (odds ratios [ORs] and 95% CIs) of CRS with bronchiectasis while adjusting for confounding variables. RESULTS: In adjusted analyses, CRS was consistently and strongly associated with all 3 bronchiectasis definitions. The strongest associations for CRS (ORs and 95% CIs) were those that were based on the text of sinus computerized tomography scan reports; the associations were generally stronger for CRS without nasal polyps (eg, OR = 4.46 [95% CI = 2.09-9.51] for diagnosis-based bronchiectasis). On average, CRS was identified more than 6 years before bronchiectasis. CONCLUSION: Precedent CRS was strongly and consistently associated with increased risk of bronchiectasis.


Subject(s)
Bronchiectasis , Nasal Polyps , Rhinitis , Sinusitis , Bronchiectasis/diagnosis , Bronchiectasis/epidemiology , Chronic Disease , Fibrosis , Humans , Nasal Polyps/complications , Rhinitis/diagnosis , Sinusitis/diagnosis
20.
J Allergy Clin Immunol ; 150(2): 352-361.e7, 2022 08.
Article in English | MEDLINE | ID: mdl-35305978

ABSTRACT

BACKGROUND: Chronic rhinosinusitis with nasal polyps is frequently managed with endoscopic sinus surgery (ESS). Prior studies describe individual clinical variables and eosinophil density measures as prognostic for polyp recurrence (PR). However, the relative prognostic significance of these have not been extensively investigated. OBJECTIVES: We sought to evaluate the impact of PR on measures of disease severity post-ESS and quantify the prognostic value of various clinical variables and biomarkers. METHODS: Ninety-four patients with chronic rhinosinusitis with nasal polyps and prospectively biobanked polyp homogenates at the time of ESS were recruited 2 to 5 years post-ESS. Patients were evaluated with patient-reported outcome measures and endoscopic and radiographic scoring pre- and post-ESS. Biomarkers in polyp homogenates were measured with ELISA and Luminex. Relaxed least absolute shrinkage and selection operator regression optimized predictive clinical, biomarker, and combined models. Model performance was assessed using receiver-operating characteristic curve and random forest analysis. RESULTS: PR was found in 39.4% of patients, despite significant improvements in modified Lund-Mackay (MLM) radiographic and 22-item Sinonasal Outcomes Test scores (both P < .0001). PR was significantly associated with worse post-ESS MLM, modified Lund-Kennedy, and 22-item Sinonasal Outcomes Test scores. Relaxed least absolute shrinkage and selection operator identified 2 clinical predictors (area under the curve = 0.79) and 3 biomarkers (area under the curve = 0.78) that were prognostic for PR. When combined, the model incorporating these pre-ESS factors: MLM, asthma, eosinophil cationic protein, anti-double-stranded DNA IgG, and IL-5 improved PR predictive accuracy to area under the curve of 0.89. Random forest analysis identified and validated each of the 5 variables as the strongest predictors of PR. CONCLUSIONS: PR had strong associations with patient-reported outcome measures, endoscopic and radiographic severity. A combined model comprised of eosinophil cationic protein, IL-5, pre-ESS MLM, asthma, and anti-double-stranded DNA IgG could accurately predict PR.


Subject(s)
Asthma , Nasal Polyps , Rhinitis , Sinusitis , Biomarkers , Chronic Disease , DNA , Endoscopy , Eosinophil Cationic Protein , Humans , Immunoglobulin G , Interleukin-5 , Nasal Polyps/surgery , Prognosis , Rhinitis/surgery , Sinusitis/surgery
SELECTION OF CITATIONS
SEARCH DETAIL
...