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.

Validation of a questionnaire assessing smell loss in an international aspirin-exacerbated respiratory disease population.

Background: Olfactory dysfunction (OD) and smell loss affects aspects of patients' everyday life and lowers their quality of life. OD questionnaires are considered one of the core-outcome measures in chronic rhinosinusitis, but many existing smell loss questionnaires contained pandemic-prohibitive questions on social gatherings or restaurant visits, were too culture specific or gender specific, or were overly long and cumbersome. Objective: We aimed to develop a new brief questionnaire to assess the impact and consequences of smell loss and its burden on daily life. This study validates this new, short, multicultural, dichotomized questionnaire in an international population that has aspirin-exacerbated disease (AERD). Methods: The Consequences of Smell Loss (COSL) questionnaire was developed and content validity was assessed by experts and patients at Brigham and Women's Hospital. The questionnaire, along with other validated quality-of-life surveys, was answered by 853 patients with AERD. We evaluated the factor structure, reliability, validity, and discriminative ability of the COSL questionnaire. Results: The final version of the COSL questionnaire consisted of 13 items divided into three subdomains (emotional distress, food and safety, and physical health) through factor analysis. The Cronbach α for internal consistency was 0.82. Convergent and discriminant validity with the 22-item Sinonasal Outcome Test (SNOT-22), Healthy Days Core Module-4, Patient Health Questionnaire-4, and a specific question on taste and smell were high (p < 0.0001 for all). The COSL questionnaire score was associated with SNOT-22 categories (p < 0.001) and was categorized as follows: normal, 0-1 points; very few consequences, 2-3 points; few, 4 points; moderate, 5-6 points; and severe, 7-13 points. Conclusion: The COSL questionnaire is a new, brief, valid, reliable tool that can effectively screen for a high burden of OD in patients with AERD and has the potential to be used in other patient populations with OD as well.

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.

Trial of thromboxane receptor inhibition with ifetroban: TP receptors regulate eicosanoid homeostasis in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is the triad of asthma, nasal polyposis, and respiratory reactions to COX-1 inhibitors. Overproduction of cysteinyl leukotrienes and underproduction of prostaglandin E2 (PGE2) are hallmarks of AERD. A mouse model predicted a key role for the thromboxane-prostanoid (TP) receptor in AERD. OBJECTIVE: Our aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD. METHODS: A total of 35 patients with AERD completed a 4-week double-blinded, placebo-controlled trial of ifetroban and underwent an oral aspirin challenge. The primary outcome was change in the provocative dose of aspirin that caused a 2-point increase in Total Nasal Symptom Score. Changes in lung function, eicosanoid levels, and platelet and mast cell activation were assessed. Cultured human nasal fibroblasts were stimulated with or without the TP agonist U46619 and assayed for prostanoid production. RESULTS: Ifetroban was well tolerated in AERD and did not change the mean 2-point increase in Total Nasal Symptom Score (P = .763). Participants taking ifetroban had greater aspirin-induced nasal symptoms and a greater decline in FEV1 value than did participants receiving placebo (-18.8% ± 3.6% with ifetroban vs -8.4% ± 2.1% with placebo [P = .017]). Four weeks of ifetroban significantly increased urinary leukotriene E4 levels and decreased nasal PGE2 levels compared with placebo. Peak aspirin-induced urinary thromboxane levels correlated with peak urinary leukotriene E4 and prostaglandin D2 metabolite levels in participants taking ifetroban. U46119 significantly potentiated the production of PGE2 by cultured nasal fibroblasts from subjects with AERD but not by cultured nasal fibroblasts from controls without polypoid sinusitis. CONCLUSION: Contrary to our hypothesis, TP receptor blockade worsened aspirin-induced reactions in AERD, possibly by exacerbating dysregulation of the eicosanoid system. TP signaling on stromal cells may be critical to maintaining PGE2 production when COX-2 function is low.

Mechanistic and clinical updates in AERD: 2021-2022.

Aspirin-exacerbated respiratory disease (AERD) is a unique and often clinically severe disease affecting a subgroup of adults with asthma and chronic rhinosinusitis with nasal polyposis. Works published in 2021-2022 confirmed the critical role of lipid mediator dysregulation and mast cell activation and expanded our understanding of basophils, macrophages, fibrin dysregulation, and the 15-lipoxygenase pathway in disease pathogenesis. Translational studies established inflammatory heterogeneity in the upper and lower airway at baseline and during aspirin-induced respiratory reactions. Clinical cohorts provided insights into the mechanistic actions of frequently utilized biologic therapies in AERD. These advances are already changing clinical care delivery and affecting patient outcomes. Despite this, further work is needed to improve clinical tools to reliably diagnose AERD and identify factors that could prevent development of the disease altogether. Additionally, the impact of inflammatory heterogeneity on clinical trajectories and the utility and safety of combination biologic and daily aspirin therapies remains unanswered.

Algorithmic Identification of Patients With Aspirin-Exacerbated Respiratory Disease Using an Electronic Health Record.

OBJECTIVE: To determine whether an electronic health record (EHR) system can be used to identify cases of aspirin-exacerbated respiratory disease (AERD) in an area outside of a regional referral center with low rates of aspirin desensitization therapy. STUDY DESIGN: Retrospective chart review single academic tertiary care hospital. SETTING: Single-site academic tertiary care hospital. METHODS: Using Epic's SlicerDicer function, an algorithm was created and applied to all patient charts from 2013 to 2021. The algorithm was as follows: "Allergy/Contraindication to NSAIDs OR aspirin" AND "Diagnosis of Nasal polyp AND "Diagnosis of Asthma." Clinical data including demographics, NSAID reaction, and specialist involvement was collected. RESULTS: A total of 54 potential cases of AERD were identified. Thirty-two were determined to have AERD after chart review, yet 12 of these patients (37.5%) had no mention of AERD within the chart. The 54 patients were stratified into 2 cohorts based on reaction to NSAIDs: respiratory (n = 29) or unspecified (n = 25). Of the patients in the respiratory reaction group, 26 were found to have clinical AERD, demonstrating a positive predictive values (PPV) of 89.7%. The overall PPV was 59.3%. Those with a respiratory reaction to NSAIDS listed in the EHR were more likely to have clinical AERD (odds ratio 27.44; confidence interval 6.08-123.85; p < 0.0001). Only 2 patients (6.3%) underwent aspirin desensitization. CONCLUSION: AERD remains under-diagnosed in the study population. The informatics algorithm presented here has a high positive predictive value for identifying clinical AERD patients in a geographical area with low rates of aspirin desensitization and may aid in identifying candidates for expanded treatment options.

SNOT-22 scores after 6 months of aspirin therapy are predictive of long-term quality of life in AERD.

Background: Aspirin exacerbated respiratory disease (AERD) is an inflammatory condition that consists of eosinophilic asthma, chronic rhinosinusitis with nasal polyps, and respiratory reactions to cyclooxygenase-1 inhibitors. Aspirin therapy after aspirin desensitization (ATAD) is the most extensively studied treatment paradigm for AERD. Objective: The objective was to identify which time point of ATAD was most predictive of long-term outcomes as measured by the 22-item Sino-Nasal Outcome Test (SNOT-22). Methods: A retrospective chart review was conducted of patients at a single institution who underwent endoscopic sinus surgery, followed by ATAD, and had remained on ATAD for 2 consecutive years. SNOT-22 scores were recorded at predesensitization as well as at the 3-, 6-, 12-, and 24-month postdesensitization time points. The patients were separated into two cohorts at each of the data collection time points based on whether their SNOT-22 scores were < 20 (responders) or ≥ 20 (nonresponders). Responder status was compared between each time point and at 24-month postdesensitization. The odds ratios (OR) were then calculated between the two groups at each of the following time points: postsurgery/predesensitization, and 3-, 6-, and 12-month postdesensitization. Results: There were 70 patients who met the inclusion criteria of having 24-month postdesensitization SNOT-22 scores available. Responder status at 6 months after surgery had the most predictive OR 16.5 (95% confidence interval, 3.71-73.44) for long-term outcomes at 24 months. Conclusion: The SNOT-22 scores after 6 months of ATAD showed the greatest predictive value for long-term quality-of-life outcomes and, therefore, poor 6-month SNOT-22 scores could serve as a basis for consideration of alternative therapies.

Aspirin-Exacerbated Respiratory Disease and the Unified Airway: A Contemporary Review.

Aspirin-exacerbated respiratory disease (AERD) is characterized by abnormal arachidonic acid metabolism leading to chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, and upper and/or lower respiratory symptoms after ingestion of cyclooxygenase-1 inhibiting nonsteroidal antiinflammatory drugs. Diagnosis is clinical and may involve an aspirin challenge. Inflammatory biomarkers may be useful for diagnosis and treatment monitoring. Conventional medical management for asthma and CRSwNP is often inadequate. Endoscopic sinus surgery followed by continued medical management with or without aspirin desensitization frequently improves symptoms and objective disease measures. Biological agents targeting eosinophilic inflammation are promising alternatives to conventional management.

The Utility of Nasal Challenges to Phenotype Asthma Patients.

Asthma is a heterogeneous disease in terms of both phenotype and response to therapy. Therefore, there is a great need for clinically applicable tools allowing for improved patient classification, and selection for specific management approaches. Some interventions are highly helpful in selected patients (e.g., allergen immunotherapy or aspirin desensitization), but they are costly and/or difficult to implement. Currently available biomarkers measurable in peripheral blood or exhaled air display many limitations for asthma phenotyping and cannot identify properly the specific triggers of the disease (e.g., aeroallergens or NSAID). The united airway concept illustrates the relevant epidemiological and pathophysiological links between the upper and lower airways. This concept has been largely applied to patient management and treatment, but its diagnostic implications have been less often explored. Of note, a recent document by the European Academy of Allergy and Clinical Immunology proposes the use of nasal allergen challenge to confirm the diagnosis of allergic asthma. Similarly, the nasal challenge with lysine acetylsalicylate (L-ASA) can be used to identify aspirin-sensitive asthma patients. In this review, we will summarize the main features of allergic asthma and aspirin-exacerbated respiratory disease and will discuss the methodology of nasal allergen and L-ASA challenges with a focus on their capacity to phenotype the inflammatory disease affecting both the upper and lower airways.

Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease.

BACKGROUND: Dupilumab, a mAb targeting IL-4Rα, improves upper and lower airway symptoms in patients with aspirin-exacerbated respiratory disease (AERD), but the mechanisms leading to clinical improvement are not fully elucidated. OBJECTIVE: Our aim was to identify the mechanistic basis of clinical improvement in patients with AERD treated with dupilumab. METHODS: A total of 22 patients with AERD were treated with dupilumab for 3 months for severe asthma and/or chronic rhinosinusitis with nasal polyps. Clinical outcomes were assessed at baseline and at 1 and 3 months after initiation of dupilumab. Nasal fluid, urine, blood, and inferior turbinate scrapings were collected at the 3 time points for determination of mediator levels, cellular assays, and RNA sequencing. RESULTS: Participants had rapid improvement in clinical measures, including sense of smell, sinonasal symptoms, and lung function after 1 month of treatment with dupilumab; the improvements were sustained after 3 months of dupilumab. Baseline severity of smell loss was correlated with lower nasal prostaglandin E2 levels. Dupilumab increased nasal prostaglandin E2 level and decreased levels of nasal albumin, nasal and urinary leukotriene E4, and serum and nasal IgE. Transcripts related to epithelial dysfunction and leukocyte activation and migration were downregulated in inferior turbinate tissue after treatment with dupilumab. There were no dupilumab-induced changes in nasal eosinophilia. CONCLUSION: Inhibition of IL-4Rα in AERD led to rapid improvement in respiratory symptoms and smell, with a concomitant improvement in epithelial barrier function, a decrease in inflammatory eicosanoid levels, and an increase in the anti-inflammatory eicosanoid prostaglandin E2 level. The therapeutic effects of dupilumab are likely due to decreased IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells.

Aspirin-Exacerbated Respiratory Disease: A Unique Case of Drug Hypersensitivity.

This review of aspirin-exacerbated respiratory disease (AERD) describes the clinical characteristics and pathophysiology of disease, highlighting its similarities and unique differences in comparison to classic IgE mediated hypersensitivity as well as AERD as a chronic disease. There is a specific focus on the comparison of mediator production over time and the use of desensitization in each diagnosis that serves to aid the clinician in differentiating aspirin reactions in AERD from those related to true immediate hypersensitivity.

Aspirin desensitization and biologics in aspirin-exacerbated respiratory disease: Efficacy, tolerability, and patient experience.

BACKGROUND: Patterns of medication use and efficacy in aspirin-exacerbated respiratory disease (AERD) have not been well characterized, especially since the advent of respiratory biologics. Aspirin therapy after desensitization (ATAD) is efficacious for upper and lower respiratory symptoms for patients with AERD, though aspirin-related adverse effects can limit therapy. The optimal coordination of ATAD and respiratory biologics for the treatment of AERD remains unclear. OBJECTIVE: We aimed to characterize patterns of medication use and treatment experience with biologics and ATAD in AERD. METHODS: We surveyed 98 patients with AERD recruited from the Brigham and Women's Hospital AERD registry. Patients completed an online questionnaire describing their medication history and treatment experience. RESULTS: A total of 52 (53.0%) patients reported a history of use of one or more respiratory biologics (omalizumab, mepolizumab, reslizumab, benralizumab, or dupilumab), and 84 (85.7%) reported undergoing aspirin desensitization. There were 24 patients (24.4%) who reported concurrent use of a biologic and ATAD. Compared with those taking ATAD alone, patients taking a biologic and ATAD concurrently were less likely to report that aspirin was effective for their AERD symptoms (odds ratio, 0.161 [95% confidence interval, 0.03-0.76]; P =.02). Whereas patients reported varying efficacy with biologics, dupilumab had the highest odds of patients reporting it worked "very well" (odds ratio, 17.58 [95% confidence interval, 5.68-54.35]; P < .001). CONCLUSION: Biologics are emerging as a treatment option for AERD and are generally well tolerated. Biologic efficacy in AERD is variable by agent, though most patients taking dupilumab found it to be effective. Patients on a biologic in conjunction with ATAD may represent a more severe subset of AERD for which ATAD alone is insufficient.

Urine Leukotriene E4: Implications as a Biomarker in Chronic Rhinosinusitis.

OBJECTIVE: To provide a comprehensive state-of-the-art review of the emerging role of urine leukotriene E4 (uLTE4) as a biomarker in the diagnosis of chronic rhinosinusitis (CRS), aspirin-exacerbated respiratory disease (AERD), and asthma. DATA SOURCES: Ovid MEDLINE(R), Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. REVIEW METHODS: A state-of-the-art review was performed investigating the role of uLTE4 as a diagnostic biomarker, predictor of disease severity, and potential marker of selected therapeutic efficacy. CONCLUSIONS: uLTE4 has been shown to be a reliable and clinically relevant biomarker for CRS, AERD, and asthma. uLTE4 is helpful in ongoing efforts to better endotype patients with CRS and to predict disease severity. IMPLICATIONS FOR PRACTICE: Aside from being a diagnostic biomarker, uLTE4 is also able to differentiate aspirin-tolerant patients from patients with AERD and has been associated with objective disease severity in patients with CRS with nasal polyposis. uLTE4 levels have also been shown to predict response to medical therapy, particularly leukotriene-modifying agents.