Evidence that oncostatin M synergizes with IL-4 signaling to induce TSLP expression in chronic rhinosinusitis with nasal polyps.

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.

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.

Anti-phospholipid antibodies are elevated and functionally active in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Polyps from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) contain increased levels of autoreactive antibodies, B cells and fibrin deposition. Anti-phospholipid antibodies (APA) are autoantibodies known to cause thrombosis but have not been implicated in chronic rhinosinusitis (CRS). OBJECTIVE: To compare APA levels (anti-cardiolipin, anti-phosphatidylethanolamine (anti-PE), and anti-ß2 -glycoprotein (anti-B2GP)) in nasal polyp (NP) tissue with tissue from control and CRS without nasal polyp (CRSsNP) patients, we tested whether NP antibodies affect coagulation, and correlate APAs with anti-dsDNA IgG and markers of coagulation. METHODS: Patient specimens were assayed for APA IgG, anti-dsDNA IgG and thrombin-anti-thrombin (TaT) complex by ELISA. Antibodies from a subset of specimens were tested for modified activated partial thromboplastin time (aPTT) measured on an optical-mechanical coagulometer. RESULTS: Anti-cardiolipin IgG in NP was 5-fold higher than control tissue (p < .0001). NP antibodies prolonged aPTT compared to control tissue antibodies at 400 µg/mL (36.7 s vs. 33.8 s, p = .024) and 600 µg/mL (40.9 s vs. 34.7 s, p = .0037). Anti-PE IgG antibodies were increased in NP (p = .027), but anti-B2GP IgG was not significantly higher (p = .084). All APAs correlated with anti-dsDNA IgG levels, which were also elevated (R = .77, .71 and .54, respectively, for anti-cardiolipin, anti-PE, and anti-B2GP; all p < .001), but only anti-cardiolipin (R = .50, p = .0185) and anti-PE (R = 0.45, p = .037) correlated with TaT complex levels. CONCLUSIONS: APA IgG antibodies are increased in NP and correlate with autoreactive tissue antibodies. NP antibodies have in vitro anti-coagulant activity similar to those observed in anti-phospholipid syndrome, suggesting that they may have pro-coagulant effects in polyp tissue.

Studies on activation and regulation of the coagulation cascade in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Increased activation of the coagulation cascade and diminished fibrinolysis combine to promote fibrin deposition and polyp formation in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). More information is needed concerning mechanisms of coagulation in CRSwNP. OBJECTIVE: We investigated the mechanisms as well as the initiation and regulation of coagulation cascade activation in CRS. METHODS: Samples were collected from 135 subjects with CRSwNP, 80 subjects with chronic CRS without nasal polyps (NP), and 65 control subjects. The levels of activated factor X (FXa), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex, tissue factor (TF), and TF pathway inhibitor (TFPI) were monitored in CRS by real-time PCR, ELISA, immunohistochemistry, or immunofluorescence. Heteromeric complexes of TF with activated factor VII (FVII) and TF with activated FVII and FXa were assessed by coimmunoprecipitation and Western blotting. RESULTS: Increased levels of FXa, F1+2, and thrombin-antithrombin complex were detected in NP tissue compared to uncinate tissue from CRS and control subjects. Although free TF protein levels were not increased in NP, immunoprecipitation of TF in NP tissue revealed increased complexes of TF with FVII. Local expression of FVII was detected in sinonasal mucosa, and the ratio of TFPI to FXa was lower in NP tissue. CONCLUSION: The coagulation cascade is associated with NP compared to control and uncinate tissue from CRS patients, and TF and FVII are produced locally in sinonasal mucosa in patients. TF and FVII can activate the extrinsic coagulation pathway, suggesting that this pathway may activate fibrin deposition in CRSwNP. Reduced formation of the complex of FXa and TFPI in NP may reduce natural suppression of the extrinsic coagulation pathway in CRSwNP.

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.

COVID-19 vaccine-related presumed allergic reactions and second dose administration by using a two-step graded protocol.

Background: Acute allergic reactions to messenger RNA (mRNA) vaccines are rare but may limit public health immunization efforts. Objectives: To characterize suspected allergic reactions to the first dose of coronavirus disease 2019 (COVID-19) mRNA vaccine and to assess the safety and utility of a two-step graded-dose protocol for the second dose of the Pfizer-BioNTech vaccine in patients with a history of low suspicion of anaphylaxis to their first dose. Methods: This was a retrospective evaluation of referrals to the allergy and immunology clinic for a presumed allergic reaction to the first dose of the COVID-19 mRNA vaccine (Pfizer-BioNTech or Moderna) between December 17, 2020, and February 28, 2021. Recommendations for the second dose and outcomes were evaluated by trained board-certified allergists. Results: Seventy-seven patients presented with a Pfizer-BioNTech reaction (56 [72.7%]) or with a Moderna reaction (21 [27.3%]). Most patients (69.7%) had symptom onset within 4 hours. Most commonly reported symptoms were cutaneous (51.9%), cardiovascular (48.1%), and respiratory (33.8%) symptoms. Recommendations included to proceed with the single dose (70.1%), two-step graded dose (19.5%), or deferral (10.4%). Twelve of 15 patients completed the second dose with a graded-dose protocol. Of these patients, five reported at least one or more similar symptoms as experienced with their first dose. Conclusion: Of the patients with presumed allergic reactions to their first dose of COVID-19 mRNA vaccine, most were able to safely receive the second dose. For those with a low suspicion of anaphylaxis, the two-step graded protocol with the Pfizer-BioNTech vaccine was well tolerated. A graded-dose protocol could be an effective strategy for second-dose vaccination in those who may otherwise defer the second dose.

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.

Studies of the role of basophils in aspirin-exacerbated respiratory disease pathogenesis.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and intolerance to cyclooxygenase-1 enzyme inhibitors. The underlying mechanisms contributing to AERD pathogenesis are not fully understood, but AERD is characterized by an enhanced type 2 inflammatory phenotype. Basophils are potent type 2 effector cells, but their involvement in AERD pathophysiology remains unclear. OBJECTIVE: We sought to characterize the systemic and local basophil responses in patients with AERD compared with patients with CRSwNP. METHODS: Sinonasal tissues including inferior turbinate and/or nasal polyps (NPs) and peripheral blood were collected from controls, patients with AERD, and patients with CRSwNP. Expression of cell surface (CD45, FcεRI, CD203c), activation (CD63), and intracellular (2D7) markers associated with basophils was characterized using flow cytometry. Clinical data including Lund-Mackay scores and pulmonary function were obtained. RESULTS: The mean number of basophils (CD45+CD203c+FcεRI+CD117-) detected in AERD NPs (147 ± 28 cells/mg tissue) was significantly elevated compared with that detected in CRSwNP NPs (69 ± 20 cells/mg tissue; P = .01). The number of circulating basophils was significantly elevated in patients with AERD (P = .04). Basophils in NPs had significantly higher CD203c and CD63 mean fluorescence intensity compared with blood in both conditions (P < .01). Basophils from AERD NPs had lower expression of the granule content marker 2D7 compared with those from matched blood (P < .01) or NPs of patients with CRSwNP (P = .06), suggesting ongoing degranulation. Basophil 2D7 mean fluorescence intensity significantly correlated with pulmonary function (r = 0.62; P = .02) and inversely correlated with sinonasal inflammation (r = -0.56; P = .004). CONCLUSIONS: Increased basophil numbers and extent of ongoing degranulation in NPs of patients with AERD compared with patients with CRSwNP may contribute to the exaggerated disease pathogenesis and severity unique to AERD.

Activation of the 15-lipoxygenase pathway in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance of medications that inhibit cyclooxygenase-1. Patients with AERD have more severe upper and lower respiratory tract disease than do aspirin-tolerant patients with CRSwNP. A dysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD. OBJECTIVE: Our aim was to utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD. METHODS: Single-cell RNA sequencing (10× Genomics, Pleasanton, Calif) was utilized to compare the transcriptional profile of nasal polyp (NP) cells from patients with AERD and patients with CRSwNP and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional real-time PCR. Lipid mediators in sinonasal tissue were measured by mass spectrometry. Localization of various proteins within NPs was assessed by immunofluorescence. RESULTS: The gene encoding for 15-lipooxygenase (15-LO), ALOX15, was significantly elevated in NPs of patients with AERD compared to NPs of patients with CRSwNP (P < .05) or controls (P < .001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r = 0.56; P < .001) and were associated with asthma. The level of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a downstream product of 15-LO, was significantly elevated in NPs from patients with CRSwNP (27.93 pg/mg of tissue) and NPs from patients with AERD (61.03 pg/mg of tissue) compared to inferior turbinate tissue from controls (7.17 pg/mg of tissue [P < .001]). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-Oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO+ epithelium in NPs from patients with AERD. CONCLUSIONS: Epithelial and mast cell interactions, leading to the synthesis of 15-Oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway and to the enhanced sinonasal disease severity observed in AERD.

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.

Prevalence and characterization of asthma in hospitalized and nonhospitalized patients with COVID-19.

BACKGROUND: The Centers for Disease Control and Prevention advises that patients with moderate to severe asthma belong to a high-risk group that is susceptible to severe coronavirus disease 2019 (COVID-19). However, the association between asthma and COVID-19 has not been well-established. OBJECTIVE: The primary objective was to determine the prevalence of asthma among patients with COVID-19 in a major US health system. We assessed the clinical characteristics and comorbidities in asthmatic and nonasthmatic patients with COVID-19. We also determined the risk of hospitalization associated with asthma and/or inhaled corticosteroid use. METHODS: Medical records of patients with COVID-19 were searched by a computer algorithm (March 1 to April 15, 2020), and chart review was used to validate the diagnosis of asthma and medications prescribed for asthma. All patients had PCR-confirmed COVID-19. Demographic and clinical features were characterized. Regression models were used to assess the associations between asthma and corticosteroid use and the risk of COVID-19-related hospitalization. RESULTS: Of 1526 patients identified with COVID-19, 220 (14%) were classified as having asthma. Asthma was not associated with an increased risk of hospitalization (relative risk, 0.96; 95% CI, 0.77-1.19) after adjusting for age, sex, and comorbidities. The ongoing use of inhaled corticosteroids did not increase the risk of hospitalization in a similar adjusted model (relative risk, 1.39; 95% CI, 0.90-2.15). CONCLUSIONS: Despite a substantial prevalence of asthma in our COVID-19 cohort, asthma was not associated with an increased risk of hospitalization. Similarly, the use of inhaled corticosteroids with or without systemic corticosteroids was not associated with COVID-19-related hospitalization.

Development and Preliminary Validation of a New Patient-Reported Outcome Measure for Chronic Rhinosinusitis (CRS-PRO).

BACKGROUND: Patient-reported outcome (PRO) measures developed and validated on patients with the currently defined phenotypes of chronic rhinosinusitis (CRS) are needed to support clinical trials in CRS. OBJECTIVE: This study developed and examined the initial reliability and validity of the CRS-PRO, a new PRO measure of CRS. METHODS: Instrument development was performed through structured interviews and focus groups with clinical experts and 45 patients with CRS meeting current definitions of disease, 21 patients with CRS without nasal polyps (CRSsNP), and 24 patients with CRS with nasal polyps (CRSwNP) to identify items important to patients. Then another 50 patients (32 with CRSsNP and 18 with CRSwNP) with stable CRS symptoms were enrolled to evaluate the reliability of the instrument. Each patient completed the CRS-PRO, Sinonasal Outcome Test-22 (SNOT-22), and 4 Patient-Reported Outcome Measurement Information System short forms at the baseline visit and then at least 7 days later. RESULTS: After the development process, 21 items were identified from the conceptual domains of physical symptoms, sensory impairment, psychosocial effects, and life impact. Using the responses of the 50 patients with CRS, 21 draft items were further refined to 12 items by eliminating conceptually similar or highly correlated items or those with low mean symptom severity. The 12-item questionnaire was shown to have excellent internal consistency (Cronbach α, 0.86) and test-retest reliability with a high intraclass correlation coefficient (0.89) and Pearson's correlation (r = 0.82, P < .0001). The 12-item CRS-PRO correlated highly with the longer SNOT-22 (r = 0.83, P < .0001) demonstrating its concurrent validity. We also demonstrated validity and reliability in a separate analysis for patients with CRSsNP and CRSwNP. CONCLUSION: The CRS-PRO is a concise, valid, and reliable measure that was developed with extensive input from patients with CRS with current disease definitions.

Responsiveness and Convergent Validity of a New Patient-Reported Outcome Measure for Chronic Rhinosinusitis (CRS-PRO).

BACKGROUND: The CRS-PRO is a new patient-reported outcome measure (PROM) for chronic rhinosinusitis (CRS) that was developed using extensive patient input per Food and Drug Administration guidance on PROMs acceptable for use as end points in clinical trials. OBJECTIVE: To assess the responsiveness and convergent validity of the CRS-PRO following standard-of-care medical therapy. METHODS: This was a prospective study of 51 patients (21 with nasal polyps and 30 without) with newly diagnosed CRS or having an acute CRS exacerbation who were initiated on appropriate medical therapy. At the baseline visit each patient completed the CRS-PRO questionnaire, the 22-item Sino-Nasal Outcome Test, the EuroQol 5-dimensional questionnaire, and 4 Patient-Reported Outcome Measure Information System short forms along with objective testing including endoscopic and radiographic scores, smell discrimination, and nasal inspiratory flow testing. This same battery of questionnaires and testing was administered at a follow-up visit 4 to 8 weeks later. RESULTS: We verified that shortening the 21-item CRS-PRO to 12 items as previously described maintains its psychometric properties. The 12-item CRS-PRO was responsive with a large effect size (Cohen's d, 0.94) comparable to the longer 22-item Sino-Nasal Outcome Test (Cohen's d, 0.93). The instrument was slightly more responsive to medically treated patients with CRS without nasal polyps compared with patients with CRS with nasal polyps (Cohen's d, 1.1 vs 0.89, respectively). The change in 12-item CRS-PRO total score has moderate correlation with change in Lund-Mackay computed tomography scores. CONCLUSIONS: The CRS-PRO is a 12-item rigorously developed, responsive, and valid PROM that was developed using extensive input from patients with current definitions of CRS, including its 2 major phenotypes.

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.

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.