Tezepelumab improved chronic rhinosinusitis with nasal polyps in a Patient with aspirin exacerbated respiratory disease.

Introduction: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) have more severe sinus disease than those without AERD. CRSwNP associated with type 2 inflammation and AERD can be difficult to control with standard medical therapy and sinus surgery. Case study: 74-year-old Japanese woman with chronic sinusitis since age 50 and asthma since age 60. At age 64, she began to experience asthma exacerbations and was started on short-term corticosteroid therapy with prednisolone. At age 70, she experienced urticaria, nasal congestion, and wheezing after taking an NSAID; based on an NSAID provocation test, we diagnosed the patient with AERD and CRSwNP. A diagnosis of severe eosinophilic chronic rhinosinusitis was also made based on the scoring system and algorithm used in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis. Results: Treatment with benralizumab (30 mg), formoterol-fluticasone combination via pressurized metered inhaler (1000 µg), and leukotriene receptor antagonist improved the asthma symptoms and exacerbations so the short-term prednisolone was stopped; however, nasal congestion and olfactory dysfunction (hyposmia) persisted, and peripheral blood eosinophil count (peak, 1500 cells/µL) and fractional exhaled nitric oxide (peak, 42 ppb) became elevated. Swapping the benralizumab for monthly tezepelumab (210 mg) improved not only the asthma symptoms but also the nasal congestion, olfactory dysfunction, eosinophil count (<300 cells/µL), and fractional exhaled nitric oxide level [8ppb]. Conclusion: Changing from benralizumab to tezepelumab improved asthma symptoms, nasal obstruction, and olfactory dysfunction in elderly, female, Japanese patient with AERD and CRSwNP.

Mast cells control lung type 2 inflammation via prostaglandin E2-driven soluble ST2.

Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E2 (PGE2) drives production of sST2 to limit features of lung T2I. PGE2-deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE2 metabolites correlate with serum sST2. In mice, PGE2 enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs, or E prostanoid (EP)2 receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE2 or ST2 expression by MCs back to control levels. PGE2 deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE2 thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE2 states.

IL-4Rα signaling promotes barrier-altering oncostatin M and IL-6 production in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a severe disease involving dysregulated type 2 inflammation. However, the role other inflammatory pathways play in AERD is poorly understood. OBJECTIVE: We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation. METHODS: Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro. RESULTS: Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family-related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts. CONCLUSION: In addition to type 2 inflammation, innate and IL-6-related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab's therapeutic efficacy in AERD.

Biologic Therapies across Nasal Polyp Subtypes.

Chronic rhinosinusitis with nasal polyposis is a common inflammatory condition, with subtypes like aspirin-exacerbated respiratory disease, allergic fungal rhinosinusitis, and central compartment atopic disease sharing a common type 2 inflammatory pathway. Respiratory biologic therapies have been developed that target type 2 inflammation. In this article, we discuss the use of respiratory biologic therapies for nasal polyposis in general, as well as within the various subtypes of nasal polyps. Further, we discuss future roles of novel biologic therapies targeting type 2 inflammation in nasal polyposis.

Aspirin Challenge-Induced Genome-Wide DNA Methylation Profile of Peripheral Blood Lymphocytes in Aspirin-Exacerbated Respiratory Disease.

Genetic variation and epigenetic factors are thought to contribute to the development of hypersensitivity to aspirin. DNA methylation fluctuates dynamically throughout the day. To discover new CpG methylation in lymphocytes associated with aspirin-exacerbated respiratory disease (AERD), we evaluated changes in global CpG methylation profiles from before to after an oral aspirin challenge in patients with AERD and aspirin-tolerant asthma (ATA). Whole-genome CpG methylation levels of peripheral blood mononuclear cells were quantified with an Illumina 860K Infinium Methylation EPIC BeadChip array and then adjusted for inferred lymphocyte fraction (ILF) with GLINT and Tensor Composition Analysis. Among the 866,091 CpGs in the array, differentially methylated CpGs (DMCs) were found in 6 CpGs in samples from all 12 patients with asthma included in the study (AERD, n = 6; ATA, n = 6). DMCs were found in 3 CpGs in the 6 ATA samples and in 615 CpGs in the 6 AERD samples. A total of 663 DMCs in 415 genes and 214 intergenic regions differed significantly in the AERD compared with the ATA. In promoters, 126 CpG loci were predicted to bind to 38 transcription factors (TFs), many of which were factors already known to be involved in the pathogenesis of asthma and immune responses. In conclusion, we identified 615 new CpGs methylated in peripheral blood lymphocytes by oral aspirin challenge in AERD but not in ATA. These findings indicate that oral aspirin challenge induces epigenetic changes in ILFs, specifically in AERD patients, possibly via changes in TF binding, which may have epigenetic effects on the development of AERD.

Aspirin-exacerbated respiratory disease is associated with variants in filaggrin, epithelial integrity, and cellular interactions.

Background: Previous studies have determined that up to 6% of patients with aspirin-exacerbated respiratory disease (AERD) have family history of AERD, indicating a possible link with genetic polymorphisms. However, whole exome sequencing (WES) studies of such associations are currently lacking. Objectives: We sought to examine whether WES can identify pathogenic variants associated with AERD. Methods: Diagnoses of AERD were confirmed in patients with nasal polyps and asthma. WES was performed using an Illumina sequencing platform. Human Phenotype Ontology terms were used to define the patients' phenotypes. Exomiser was used to annotate, filter, and prioritize possible disease-causing genetic variants. Results: Of 39 patients with AERD, 41% reported a family history of asthma and 5% reported a family history of AERD. Pathogenic exome variants in the filaggrin gene (FLG) were found in 2 patients (5%). Other variants not known to be pathogenic were detected in an additional 16 patients (41%) in genes related to epithelial integrity and cellular interactions, including genes encoding desmoglein 3 (DSG3), dynein axonemal heavy chain 9 (DNAH9), collagen type VII alpha 1 chain (COL7A1), collagen type XVII alpha 1 chain (COL17A1), chromodomain helicase DNA binding protein-7 (CHD7), TSC complex subunit 2/tuberous sclerosis-2 protein (TSC2), P-selectin (SELP), and platelet-derived growth factor receptor-alpha (PDGFRA). Conclusion: WES identified a monogenic susceptibility to AERD in 5% of patients with FLG pathogenic variants. Other variants not previously identified as pathogenic were found in genes relevant to epithelial integrity and cellular interactions and may further reveal genetic factors that contribute to this condition.

Nasal polyp antibody-secreting cells display proliferation signature in aspirin-exacerbated respiratory disease.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) causes nasal obstruction and olfactory dysfunction. Aspirin-exacerbated respiratory disease (AERD) is the triad of CRSwNP, asthma, and respiratory reactions to COX-1 inhibitors. Patients with AERD have elevated nasal IL-5 levels and high numbers of antibody-secreting cells (ASCs), including plasma cells and plasmablasts, in their polyp tissue; in addition, their nasal polyp (NP) IgE levels are correlated with disease severity and recurrence of nasal polyposis. OBJECTIVE: We sought to explore differences in the transcriptomic profile, activation markers, and IL-5Rα expression and function of NP ASCs from patients with AERD and CRSwNP. METHODS: NP tissue was collected from patients with AERD and CRSwNP and digested into single-cell suspensions. NP cells were analyzed for protein expression by mass cytometry. For IL-5Rα functional studies, plasma cells were purified and cultured in vitro with or without IL-5 and analyzed by bulk RNA sequencing. RESULTS: Compared with polyp tissue from patients with CRSwNP, polyp tissue from patients with AERD contained significantly more ASCs and had increased ASC expression of IL-5Rα. ASCs from patients with AERD expressed higher protein levels of B-cell activation and regulatory markers (CD40, CD19, CD32, and CD38) and the proliferation marker Ki-67. ASCs from patients with AERD also expressed more IL5RA, IGHE, and cell cycle- and proliferation-related transcripts (CCND2, MKI67, CDC25A, and CDC25B) than did ASCs from patients with CRSwNP. Stimulation of plasma cells from patients with AERD with IL-5 induced key cell cycle genes (CCND2 and PTP4A3), whereas IL-5 stimulation of ASCs from patients with CRSwNP induced few transcriptomic changes. CONCLUSION: NP tissue ASCs from patients with AERD express higher levels of functional IL-5Rα and markers associated with cell cycling and proliferation than do ASCs from patients with aspirin-tolerant CRSwNP.

Should Biologics Be Used Before Aspirin Desensitization in Aspirin-Exacerbated Respiratory Disease?

There has been a paradigm shift in the management of aspirin-exacerbated respiratory disease (AERD). It started in 2015 when the first biologic was Food and Drug Administration (FDA) approved for severe eosinophilic asthma. Thus, there emerged a new era in the treatment of patients with type 2-mediated airway diseases. This has led to an increasing number of options for patients, undoubtably a great thing, but has left clinicians without a clear answer for how to balance the therapies that exist for AERD, what to recommend for treatment, and how to best assess the benefits and risks of each therapy. This paper aims to explore these benefits and risks, and to provide a roadmap for future studies.

Allergy and Asthma Prevalence and Management Across Nasal Polyp Subtypes.

Allergy and asthma prevalence vary across different subsets of chronic rhinosinusitis with nasal polyposis. In this article, the authors investigate the management of allergy and asthma within populations of patients with aspirin-exacerbated respiratory disease, allergic fungal rhinosinusitis, and central compartment atopic disease. Topical steroids, nasal rinses, and endoscopic sinus surgery are frequently employed in the management of nasal polyposis. Further, other causes of upper and lower airway inflammation like allergy and asthma should be considered in the overall treatment plan in order to optimize outcomes.

Management of Aspirin-Exacerbated Respiratory Disease: What Does the Future Hold?

Aspirin-exacerbated respiratory disease (AERD) is a subtype of chronic rhinosinusitis with polyps (CRSwNP) and asthma with higher recurrence of nasal polyps after surgery and severe asthma. Patients with CRSwNP and asthma should be screened for AERD by detailed history of aspirin/nonsteroidal anti-inflammatory drug reactions and review of medications that may mask aspirin reaction or directly by aspirin challenge. Treatment of AERD may require more intensive therapy, including endoscopic sinus surgery, daily aspirin therapy, leukotriene modifiers, or biologics.

Quantifying surgical completeness in patients with aspirin exacerbated respiratory disease.

BACKGROUND: Aspirin exacerbated respiratory disease (AERD) in patients who have had sinus surgery remains a management challenge. Aspirin desensitization and biologics are additional treatment options. It remains unclear if patients require a more comprehensive surgery prior to implementing such additional therapies. The purpose of this study was to quantify prior surgery completeness in AERD patients at a tertiary rhinology practice. METHODS: Paranasal sinus CT scans were reviewed by four academic rhinologists to assess surgery completeness. Using a published CT grading system, each sinus was graded on the completeness of surgery and middle turbinate reduction. A score out of 14 was calculated for each patient (7 per side). RESULTS: Sixty-one patients with AERD out of 141 available were included. Mean inter-rater agreement across all sinuses was moderate (k = 0.42). The mean completeness score was 6.7/14. The following procedures were rated as complete (means): uncinectomy (L: 84%, R: 82%, k = 0.44), maxillary (L: 83%, R: 77%, k = 0.32), middle turbinate reduction (L: 45%, R: 46%, k = 0.31), anterior ethmoid (L: 35%, R: 39%, k = 0.51), sphenoid (L: 36%, R: 35%, k = 0.4), posterior ethmoid (L: 30%, R: 30%, k = 0.48), frontal (L: 22%, R: 21%, k = 0.46). CONCLUSION: Prior surgery in AERD patients were mostly deemed incomplete. Uncinectomy and maxillary antrostomy are the most common procedures previously performed. It remains toe seen whether this would be considered 'adequate' surgery or more 'complete' surgery is required to achieve greater disease control.

Hypersensitivity to intravenous succinate corticosteroids in patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease.

Although there are many case reports of asthma exacerbations with intravenous corticosteroids, especially hydrocortisone succinate, in nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD), the frequency and mechanism remain unclear. We hypothesized that N-ERD patients are potentially hypersensitive to succinates, especially succinate corticosteroids, based on the results of previous provocation studies and considered specific mechanisms. The objective of this study was to determine the frequency and mechanism of succinate corticosteroids hypersensitivity in patients with N-ERD. Eleven patients with stable, moderate to severe N-ERD were tested with hydrocortisone sodium succinate (HCs), hydrocortisone sodium phosphate (HCp), methylprednisolone sodium succinate (MPSLs), prednisolone sodium succinate (PSLs), and chloramphenicol sodium succinate (CPs, without a steroidal chemical structure) at doses below the normal dose through intravenous administration using a single-blind test. As a comparison, seven patients with aspirin-tolerant asthma (ATA) also underwent an intravenous provocation test of HCs. The positive intravenous provocation test rates of HCs 100-500 mg, HCp 500 mg, MPSLs 80 mg, PSLs 20 mg, and CPs 500 mg in N-ERD patients were 82% (9/11), 9% (1/11), 50% (5/10), 33% (1/3), and 86% (6/7), respectively. Most positive reactions began with a severe cough within 5 min of intravenous injection. The course of these hypersensitivity symptoms differed from those seen with the usual aspirin challenge test. The HCs 100-500 mg intravenous test was negative in all seven patients with ATA. In conclusion, patients with N-ERD have high rates of potential hypersensitivity to the succinate ester structure, which is not linked to the corticosteroid structure, but to the succinate ester structure. We hypothesized that the mechanism of hypersensitivity observed during rapid intravenous administration of succinate corticosteroids is mast cell activation via succinate receptor stimulation, rather than due to the corticosteroid itself.

One- versus 2-day aspirin desensitization in aspirin exacerbated respiratory disease: A quality improvement project.

Background: Current aspirin desensitization protocols for aspirin-exacerbated respiratory disease (AERD) require from 1 to 3 days to complete. Objective: Our aim was to assess the implementation of a 1-day versus 2-day aspirin desensitization protocol in patients with aspirin-exacerbated respiratory disease. Methods: We used a preintervention-postintervention quality improvement design to compare the completion rates, reaction rates, and estimated costs of a 2-day versus 1-day aspirin desensitization. The cost for each desensitization was estimated on the basis of 2017-2020 US Medicare standards. We included the predesensitization variables for FEV1 value, urinary leukotriene E4 level, absolute eosinophil count (AEC), and total IgE level for each group. Results: A total of 15 patients underwent a 2-day aspirin desensitization in the 4-year (2017-2020) preintervention period and were compared with 8 patients who underwent a 1-day aspirin desensitization in the 1-year (2021) postintervention period. The desensitization completion rate (93% vs 100% [P = 1]) and the mean number of reactions requiring intervention during the desensitization protocols (0.26 vs 0.8 [P = .14]) were similar between groups. The average time frame between last polypectomy and desensitization was longer in the 2-day group (1946 vs 39.2 days [P = .03]). The mean values for FEV1 level, urinary leukotriene E4 level, absolute eosinophil count, and total IgE level were 76% vs 83% (P = .6), 1084 vs 385 pg/mg (P = .2), 686 vs 306 cells/µL (P = .74), and 735 vs 278 kU/L (P = .5), respectively. The estimated direct cost reduction was $762 per aspirin desensitization for using 1-day vs 2-day aspirin desensitization. Conclusion: Compared with a 2-day protocol, the implementation of a 1-day aspirin desensitization was characterized by similar completion and reaction rates as well as lower costs.

A Complicated Case of Aspirin-Exacerbated Respiratory Disease With Kounis Syndrome.

Kounis syndrome is angina or acute coronary syndrome caused by mast cell degranulation and inflammatory cell activation. We present a case of a patient with underlying aspirin-exacerbated respiratory disease (AERD) and previous anaphylaxis to aspirin. The patient underwent aspirin desensitization and was then treated with high-dose aspirin. Unfortunately, he developed recurrent angina and myocardial infarction (MI). Numerous left heart catheterizations revealed vasospasms as the etiology of his MIs; however, therapy with increasing doses of vasodilators yielded no improvement in the patient's condition. Ultimately the patient's aspirin was discontinued and he had no recurrence of angina or MI.

Coronary Artery Vasospasm in Patients With Eosinophilia.

Coronary vasospasm is a relatively well-documented cause for ischemia and myocardial infarction in patients with nonobstructive coronary artery disease. Patients with coexisting eosinophilia present with severe manifestations and are often refractory to traditional therapies. There are few reported cases in the literature. We describe 3 cases occurring within 10 months. (Level of Difficulty: Intermediate.).

Mepolizumab Reduces Systemic Corticosteroid Use in Chronic Rhinosinusitis With Nasal Polyps.

BACKGROUND: Systemic corticosteroids (SCSs) are associated with short- and long-term adverse effects. OBJECTIVE: To assess mepolizumab efficacy according to prior SCS use and characterize mepolizumab's SCS-sparing capabilities, in patients with severe chronic rhinosinusitis with nasal polyps. METHODS: In the randomized, double-blind, phase III SYNAPSE trial (NCT03085797), adults with severe chronic rhinosinusitis with nasal polyps eligible for repeat sinus surgery despite standard of care treatment received mepolizumab (100 mg subcutaneously) or placebo every 4 weeks for 52 weeks. The impact of prior SCS courses (0/1/>1) on mepolizumab versus placebo treatment responses (changes from baseline in total endoscopic nasal polyp [week 52], nasal obstruction visual analog scale [weeks 49-52], and 22-item Sino-Nasal Outcome Test total [week 52] scores) was analyzed post hoc. To characterize mepolizumab's SCS-sparing capabilities, time-to-first SCS course for nasal polyps (prespecified) and total prednisolone-equivalent oral corticosteroid dose by patient baseline characteristics (post hoc, in patients with ≥1 SCS course during SYNAPSE) were assessed up to week 52. RESULTS: Mepolizumab versus placebo improved treatment responses, irrespective of prior SCS use. By week 52, the probability of requiring SCSs for nasal polyps (Kaplan-Meier estimate [95% CI]) was lower with mepolizumab (25.4% [20.0-32.1]) versus placebo (37.5% [31.1-44.6]). In patients requiring 1 or more dose of SCSs, total (mean ± SD mg/y) prednisolone-equivalent oral corticosteroid dose was lower with mepolizumab (438.9 ± 350.40) versus placebo (505.2 ± 455.091), overall and irrespective of prior sinus surgeries, blood eosinophil count, or comorbidities. CONCLUSIONS: Mepolizumab is associated with clinical benefits in patients with severe chronic rhinosinusitis with nasal polyps regardless of prior SCS use and has an SCS-sparing effect.

Sex, Ethnicity, Body Mass Index, and Environmental Exposures Associated With NSAID-Exacerbated Respiratory Disease Symptom Sequence.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has a triad of symptoms: nasal polyposis, asthma, and NSAID hypersensitivity. Little is known about symptom timing and disease progression. OBJECTIVE: The aim of this study is to characterize disease progression in N-ERD. METHODS: Patients with N-ERD were prospectively interviewed and classified into 4 groups based on their first symptom at initial N-ERD onset (asthma, nasal polyps, NSAID hypersensitivity, or all concurrently). Associations of patient characteristics with the 4 groups were examined, along with associations within the "asthma first" group. RESULTS: Patients (N = 240) were mostly female (68%) and self-identified as non-White (77%). Half (N = 119) reported asthma as the earliest symptom in the N-ERD triad. Compared with other groups, "asthma first" was associated with younger age of onset (25 years, standard error ±1.3, P < .001) and higher body mass index (BMI) (odds ratio [OR] = 1.3, 95% confidence interval [CI]: 1.06-1.7, P = .02). In this group, age of onset <20 years was associated with female sex, Latino ethnicity, and higher BMI (all P < .05). The "NSAID sensitivity first" group was significantly associated with male sex (OR = 3.3, 95% CI: 1.5-7.4, P = .004) and pollution exposure (OR = 4.4, 95% CI: 1.6-11.9, P = .003). At the initial presentation, 27% of patients were unaware of their N-ERD diagnosis. Black and Latino patients were more likely to be unaware of their N-ERD diagnosis compared with White (P = .003). The median diagnostic delay was 3 years (interquartile range: 0-5 years). CONCLUSIONS: In this cohort, N-ERD is highly variable in onset and progression, with sex, BMI, race and ethnicity, and environmental exposures significantly associated with disease patterns and diagnostic delay.

Association Between Aspirin-Exacerbated Respiratory Disease and Atherosclerotic Cardiovascular Disease: A Retrospective Review of US Claims Data.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) consists of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and hypersensitivity to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). Asthma is associated with increased risk of atherosclerotic cardiovascular diseases (ASCVD). However, there is lack of data on association between AERD and ASCVD. OBJECTIVE: To investigate the relationship between AERD and subsequent risk of ASCVD. METHODS: An algorithm to find patients with AERD was generated and validated through chart review at our home institution. This algorithm was applied to a national insurance claims database to obtain data for a retrospective cohort study. Demographic and comorbidity data were obtained for propensity matching. Several methods of analysis were performed on the data. RESULTS: A total of 571 patients met criteria for AERD; 3909 met criteria for asthma, CRSwNP, and no allergy to aspirin or NSAIDs (group 1); and 75,050 met criteria for asthma, CRS without nasal polyps, and no allergy to aspirin or NSAIDs (group 2). After covariate adjustment, AERD was significantly associated with ASCVD, including severe ASCVD, over groups 1 and 2 regardless of asthma severity. CONCLUSION: Patients with AERD are at higher risk of ASCVD than patients with asthma and CRSwNP or CRS without nasal polyps, underscoring the need for early ASCVD screening and a consideration for aspirin desensitization or use of a nonaspirin antiplatelet agent in the setting of AERD and comorbid ASCVD.

Long-term clinical outcomes of aspirin-exacerbated respiratory disease: Real-world data from an adult asthma cohort.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a phenotype of severe asthma, but its disease course has not been well documented compared with that of aspirin-tolerant asthma (ATA). OBJECTIVES: This study aimed to investigate the long-term clinical outcomes between AERD and ATA. METHODS: AERD patients were identified by the diagnostic code and positive bronchoprovocation test in a real-world database. Longitudinal changes in lung function, blood eosinophil/neutrophil counts, and annual numbers of severe asthma exacerbations (AEx) were compared between the AERD and the ATA groups. Within a year after baseline, two or more severe AEx events indicated severe AERD, whereas less than two AEx events indicated nonsevere AERD. RESULTS: Among asthmatics, 353 had AERD in which 166 and 187 patients had severe and nonsevere AERD, respectively, and 717 had ATA. AERD patients had significantly lower FEV1%, higher blood neutrophil counts, and higher sputum eosinophils (%) (all p < .05) as well as higher levels of urinary LTE4 and serum periostin, and lower levels of serum myeloperoxidase and surfactant protein D (all p < .01) than those with ATA. In a 10-year follow-up, the severe AERD group maintained lower FEV1% with more severe AEs than the nonsevere AERD group. CONCLUSION AND CLINICAL RELEVANCE: We demonstrated that AERD patients presented poorer long-term clinical outcomes than ATA patients in real-world data analyses.