[Biologic therapy in patients with severe NSAID-exacerbated respiratory disease and previous aspirin desensitization : Results of a multicentric study]. / Biologikatherapie bei schwer erkrankten Patienten mit "NSAID-exacerbated respiratory disease" und stattgehabter ASS­Desaktivierung : Ergebnisse einer multizentrischen Studie.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type­2 inflammatory disease of the upper airways, with severe impairment of quality of life. Persons affected by NSAID-exacerbated respiratory disease (NERD) usually present with highly dynamic recurrence of polyps and disease despite prior treatment with sinus surgeries, oral corticosteroids, and aspirin desensitization (ATAD). Biologic therapy has fundamentally changed the choice of therapeutic concept; however, limited data exist on subgroups such as NERD patients. The aim of the current article is to report on a multicenter retrospective study on add-on therapy with dupilumab, omalizumab, and mepolizumab in patients with NERD. METHODS: This is a retrospective cohort study of patients (NERD+, status after ATAD) in three reference centers in Germany (Munich, Mainz, Berlin). Subjective and objective parameters were collected at 4, 8, and 12 months after biologic therapy initiation in accordance with current EPOS/EUFOREA (European Position Paper on Rhinosinusitis and Nasal Polyps/European Forum for Research and Education in Allergy and Airway Diseases) guidelines. Biologic agents were chosen depending on availability and patient characteristics. RESULTS: Treatment was commenced in 122 patients meeting the criteria for CRSwNP and NERD. The endoscopic polyp score, SNOT-22 questionnaire score, visual analogue scoring of total symptoms/severity of disease, and sense of smell (psychophysical testing with Sniffin'Sticks/Brief Smell Identification Test, B­SIT; Sensonics, Inc., Haddon Heights, NJ, USA) improved significantly after 4 and 12 months of add-on therapy (p < 0.0001). All three biologic agents significantly improved one or more disease parameter. Adverse events were not life threatening but led to change of biologic agent in 4 cases. Patients rated biologic therapy significantly better than ATAD, with improved long-term disease control. CONCLUSION: Add-on biologic therapy is effective, safe, and widely accepted among CRSwNP + NERD patients. Future studies might allow for personalized algorithms with sequential surgery, ATAD, and/or biologic therapy.

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.

Aspirin-exacerbated respiratory disease: Updates in the era of biologics.

OBJECTIVE: Aspirin-exacerbated respiratory disease (AERD) is a chronic respiratory condition characterized by severe chronic rhinosinusitis with nasal polyps (CRSwNP), eosinophilic asthma, and respiratory reactions to cyclooxygenase inhibitors. The management of AERD has evolved recently with the availability of respiratory biologics for treatment of severe asthma and CRSwNP. The objective of this review is to provide an update on the management of AERD in the era of respiratory biologic therapy. DATA SOURCES: A literature review of pathogenesis and treatment of AERD, with a specific focus on biologic therapies in AERD, was performed through publications gathered from PubMed. STUDY SELECTIONS: Original research, randomized controlled trials, retrospective studies, meta-analyses, and case series of high relevance are selected and reviewed. RESULTS: Aspirin therapy after desensitization (ATAD) and respiratory biologic therapies targeting interleukin (IL)-4Rα, IL-5, IL-5Rα, and immunoglobulin E, all have some efficacy in the treatment of CRSwNP and asthma in patients with AERD. There are currently no head-to-head studies comparing ATAD vs respiratory biologic therapy, or specific respiratory biologics, for asthma and CRSwNP in patients with AERD. CONCLUSION: Advances in our understanding of the fundamental drivers of the chronic respiratory inflammation in asthma and CRSwNP have led to the identification of several potential therapeutic targets for these diseases that can be used in patients with AERD. Further study of the use of ATAD and biologic therapy, independently and together, will help to inform future treatment algorithms for patients with AERD.

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.

Relationship Between Alcohol Intolerance and Aspirin-Exacerbated Respiratory Disease (AERD): Systematic Review.

OBJECTIVE: Previous studies have suggested that patients with aspirin-exacerbated respiratory disease (AERD) have a high likelihood of alcohol intolerance. The purpose of this systematic review is to identify if there is sufficient evidence to confirm this correlation and the impact of medical therapy on subsequent alcohol tolerance. DATA SOURCES: PubMed, EMBASE, SCOPUS, EBSCO, Google Scholar, Cochrane Library, and Grey literature. We also performed snowballing on the identified observational studies (OS) for additional data. REVIEW METHODS: A systematic review was conducted from 1968 to 2022 to identify those studies describing AERD symptomatology triggered by alcohol intake. The primary outcome was to analyze the current literature for the association between alcohol intolerance and AERD symptoms. The secondary outcome looked for improvement in alcohol tolerance after aspirin desensitization or biological therapy. RESULTS: A total of 775 studies were identified and 40 abstracts were evaluated. From these, 5 studies met the inclusion criteria. Of the 5 manuscripts, there was 1 case-control, 2 cohort, and 2 cross-sectional studies. A total of 522 participants with AERD and a history of alcohol consumption were included, with 52.8% reporting at least 1 sinopulmonary exacerbation after alcohol intake. One of 3 studies noted improvement in alcohol tolerance after medical therapy with aspirin desensitization. CONCLUSION: The current literature suggests that patients with AERD have a high risk of alcohol intolerance. Additionally, aspirin desensitization may improve alcohol tolerance in this patient population.

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.

Aspirin desensitization following endoscopic sinus surgery is effective in patients with nonsteroidal antiinflammatory drug exacerbated respiratory disease.

INTRODUCTION: Aspirin desensitization (AD) is effective in relieving asthma and sinonasal outcomes in patients with non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD). So far, only a limited number of studies evaluated the effect of AD prospectively in a controlled manner in N-ERD. It is also a current approach to recommend endoscopic sinus surgery (ESS) before AD. This study aimed to prospectively document the clinical effects of AD for 1 year in patients with N-ERD who underwent ESS in the presence of a control group. METHODS: The study included patients with N-ERD who underwent AD (group 1, n = 22) and patients with N-ERD in whom desensitization was indicated but was not performed (group 2, n = 21). All patients had ESS before enrollment in the study. Asthma and rhinosinusitis outcomes were assessed at baseline and after 1 year. RESULTS: The study included a total of 43 subjects (F/M:28/15, mean age: 44.7 ± 2.8 years). Fewer patients had nasal polyp recurrency in group 1 (5/22, 22.7%) than in group 2 (11/21, 52.3%) at the end of the first year (p = 0.035). Smell-test scores were preserved only in group 1 after 1 year. There were significant decreases in the use of both asthma and nasal medications only in group 1. CONCLUSION: Our results strongly support the use of AD for the improvement of both nasal and asthmatic outcomes in patients with N-ERD for 1 year. We also recommend patients undergo ESS before AD. Further controlled studies are necessary to evaluate whether this effect lasts longer.

A Review of Aspirin-exacerbated Respiratory Diseases and Immunological Efficacy of Aspirin Desensitization.

Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory disease. It is defined by asthma, chronic rhinosinusitis with nasal polyposis, and a hypersensitivity reaction to aspirin or nonsteroidal anti-inflammatory drugs. Aspirin desensitization (AD) has been confirmed as an effective treatment to control AERD inflammation through the modulation of immune responses. We aimed to review AERD with an overview of the epidemiology, pathophysiology, and treatment. We also discussed the effect of AD on immunological markers involved in AERD pathogenesis. A search of electronic databases on AERD was performed. We included five randomized clinical trials (RCTs) on AD. We also searched databases for recent studies that investigated the effect of AD on the immunological mechanisms of AERD. RCTs have demonstrated the therapeutic effectiveness of AD on the patients' quality of life, asthma symptom score, inhaled and oral steroid use, forced expiratory volume in 1 sec (FEV1), and inflammatory mediators. The clinical benefits of AD can occur though the regulation of innate and adaptive immune responses that are involved in the pathogenesis of AERD. In addition to the valuable effects of AD in RCTs, some side effects such as gastrointestinal bleeding, asthma exacerbation, or rash have been reported that should be considered for reaching an optimal protocol for AD.

Appraisal of the Real-World Effectiveness of Biologic Therapies in Aspirin-Exacerbated Respiratory Disease.

BACKGROUND: There are no head-to-head studies for patients with aspirin-exacerbated respiratory disease (AERD) comparing any of the 5 Food and Drug Administration-approved respiratory biologic therapies. OBJECTIVE: Explore outcomes in subjects with AERD using biologic therapies in a real-world clinic setting. METHODS: A retrospective pilot study was conducted for subjects with AERD who had been prescribed omalizumab (anti-IgE), mepolizumab (anti-IL-5), reslizumab (anti-IL-5), benralizumab (anti-IL-5 receptor alpha [anti-IL-5Rα]), or dupilumab (anti-IL-4 receptor alpha [anti-IL-4Rα]). Clinical outcomes pre- versus postinitiation of biologic therapy were explored including symptoms, 22-item sino-nasal outcome test scores, systemic corticosteroid and antibiotic prescriptions, and emergency room visits related to AERD. RESULTS: Of the 74 subjects, 58.1% (n = 43) had used 1 biologic, though many (41.9%, n = 31) trialed more than 1 biologic. Of the 50 subjects who had used anti-IL-4Rα therapy, 98% (49 of 50) still had this therapy prescribed at study completion compared with 48.6% (17 of 35) and 26.9% (7 of 26) of those who used anti-IgE and anti-IL-5 and anti-IL-5 receptor alpha (anti-IL-5/IL-5Rα) therapy, respectively. Among those on anti-IL-4Rα therapy, there was a significant reduction in median total 22-item sino-nasal outcome test scores (51 to 19, P = .0002), corticosteroid bursts (2 to 0, P < .0001), and median number of antibiotic courses for respiratory disease (1 to 0, P = .0469) prebiologic versus postbiologic initiation. No statistically significant difference in those outcomes was observed for individuals on anti-IgE or anti-IL-5/IL-5Rα therapy. CONCLUSIONS: Anti-IL-4Rα therapy led to significantly higher rates of clinical improvement in AERD when compared with anti-IL-5/IL-5Rα and anti-IgE biologic therapies. Prospective studies would help clarify best practices for the use of biologic therapies in AERD.

New concepts for the pathogenesis and management of aspirin-exacerbated respiratory disease.

PURPOSE OF REVIEW: The purpose of this review is to provide a comprehensive summary of the current understanding of the pathogenesis of aspirin-exacerbated respiratory disease (AERD), and an update on its management. RECENT FINDINGS: Elevated levels of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a newly described metabolite of arachidonic acid, have been identified in nasal polyps of AERD patients. In nasal polyps, activated basophils, and interleukin-5 -receptor-α-positive IL-5Rα+ plasma cells are associated with more severe nasal polyposis in AERD. Alveolar monocyte-derived macrophages and their persistent proinflammatory activation were suggested as putative factors contributing to AERD. Although not AERD-specific, three biological agents are now available for the management of both nasal polyposis and asthma. SUMMARY: A newly downstream product of 15-lipoxygenase, 15-Oxo-ETE, was recently found to be significantly elevated in nasal polyps from AERD patients. This eicosanoid metabolite likely originates from an interplay between epithelial cells and mast cells. Nasal polyp basophils, IL-5Rα+ plasma cells, and alveolar macrophages were identified as important contributors to inflammation in AERD. Besides traditional aspirin desensitization and treatment for AERD management, several biologics for treatment of asthma are available, including three that have been approved for nasal polyposis. These biologic agents show variable rates of success in controlling AERD symptoms.

Chronic Rhinosinusitis Outcomes of Patients With Aspirin-Exacerbated Respiratory Disease Treated With Budesonide Irrigations: A Case Series.

BACKGROUND: Pathophysiology-targeting treatments exist for aspirin-exacerbated respiratory disease (AERD) through aspirin desensitization and biologics, such as dupilumab. With increasing attention paid to these treatments, which may be associated with significant side effects and/or cost, there is little description of chronic rhinosinusitis with nasal polyps (CRSwNP) response to treatment with intranasal corticosteroids and saline irrigations in AERD. OBJECTIVE: To determine the effect of intranasal budesonide irrigations for the treatment of CRSwNP in AERD. METHODS: This is an observational study of 14 AERD patients presenting to a rhinology clinic for CRS who were treated with twice daily high volume, low pressure irrigations with 240 mL of saline to which a 0.5 mg/2 mL respule of budesonide was added. All participants completed a 22-item Sinonasal Outcome Test (SNOT-22) at enrollment and at follow up 1 to 6 months later. Polyp scores were also calculated at each time point. RESULTS: SNOT-22 scores ranged from 26 to 98 (median: 40.5) at enrollment and 3 to 85 (median: 38.5) at follow-up. Polyp scores ranged from 2 to 6 (median: 4) at enrollment at 0 to 6 (median: 2) at follow-up. Over the treatment period, change in SNOT-22 score ranged from -38 to 16 (median: -18) and change in polyp score ranged from -2 to 0 (median: -0.5). Approximately 57% of participants experienced at least 1 minimal clinically important difference in SNOT-22 score and 21% of participants had a SNOT-22 score <20 at follow-up. CONCLUSION: Medical management with intranasal corticosteroids and saline irrigations alone leads to significant improvement in sinonasal symptomatology in a subset of AERD.

Clinical evaluation and diagnosis of aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) is a condition composed of chronic rhinosinusitis with nasal polyposis and asthma that is defined by respiratory hypersensitivity reactions to the cyclooxygenase 1-inhibitory effects of nonsteroidal anti-inflammatory drugs. It is diagnosed in 5% to 15% of patients with asthma and is even more common in those with comorbid nasal polyposis. Diagnosis is confirmed after an aspirin challenge procedure, yet many patients present with all components and can reliably be diagnosed by history. Patients with AERD commonly experience severe uncontrolled nasal polyposis and require multispecialty evaluation to properly stage and treat this condition. The presence of nasal polyposis plays a large component in the diminished quality of life in patients with AERD. In the last decade, multiple new therapeutic areas have been approved for type 2 airway diseases, offering patients with AERD many more options for control. This makes an early and accurate diagnosis of AERD important in the care of the larger population of type 2 airway diseases.

Aspirin Actions in Treatment of NSAID-Exacerbated Respiratory Disease.

Non-steroidal Anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (N-ERD) is characterized by nasal polyposis, chronic rhinosinusitis, adult-onset asthma and hypersensitive reactions to cyclooxygenase-1 (COX-1) inhibitors. Among the available treatments for this disease, a combination of endoscopic sinus surgery followed by aspirin desensitization and aspirin maintenance therapy has been an effective approach. Studies have shown that long-term aspirin maintenance therapy can reduce the rate of nasal polyp recurrence in patients with N-ERD. However, the exact mechanism by which aspirin can both trigger and suppress airway disease in N-ERD remains poorly understood. In this review, we summarize current knowledge of aspirin effects in N-ERD, cardiovascular disease, and cancer, and consider potential mechanistic pathways accounting for the effects of aspirin in N-ERD.

Effectiveness of endoscopic sinus surgery and aspirin therapy in the management of aspirin-exacerbated respiratory disease.

Background: Aspirin therapy and/or type 2 (T2) biologics are used in the management of aspirin-exacerbated respiratory disease (AERD). Objective: To identify the number of patients with AERD who tolerated aspirin therapy, yet due to persistent symptoms, incorporated T2 biologic management. Methods: A retrospective review was performed between July 2016 and June 2019. Patients with AERD and who underwent endoscopic sinus surgery (ESS), aspirin desensitization (AD), and at least 6 months of aspirin therapy (ATAD) after AD, and who remained biologic-naive up through this timepoint were included in the study. Introduction of a T2 biologic while on ATAD was the primary outcome. The secondary outcome was a change in a validated patient-reported outcome measure for chronic rhinosinusitis score between the postoperative predesensitization timepoint, and the 6-month postdesensitization timepoint, presented as means and compared by using the Student's t-test. Results: A total of 103 patients met inclusion criteria. Two patients (1.9%) ultimately supplemented ATAD with a T2 biologic. The mean outcomes measure test score after 6 months of ATAD for patients who received biologics was 40.5 versus 15 in those who did not receive biologics (p = 0.02). The mean differences between the postoperative predesensitization test score and the 6-month postdesensitization test score for patients who went on to receive biologics was an increase of 13 versus a decrease of 10 for those patients who did not receive biologics (p = 0.12). Conclusion: ESS, coupled with AD and ATAD, was successful in the long-term management of the majority of the patients with AERD, which rarely required the incorporation of T2 biologics. Patient questionnaires, such as outcomes measure test score, may identify aspirin therapy failures and help guide the practitioner in deciding when to introduce T2 biologics into the patient's treatment regimen.

The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: A Work Group Report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.

Aspirin-exacerbated respiratory disease (AERD) is characterized by the clinical triad of chronic rhinosinusitis with nasal polyps, asthma, and an intolerance to medications that inhibit the cycloxgenase-1 enzyme. Patients with AERD on average have more severe respiratory disease compared with patients with chronic rhinosinusitis with nasal polyps and/or asthma alone. Although patients with AERD traditionally develop significant upper and lower respiratory tract symptoms on ingestion of cycloxgenase-1 inhibitors, most of these same patients report clinical benefit when desensitized to aspirin and maintained on daily aspirin therapy. This Work Group Report provides a comprehensive review of aspirin challenges, aspirin desensitizations, and maintenance aspirin therapy in patients with AERD. Identification of appropriate candidates, indications and contraindications, medical and surgical optimization strategies, protocols, medical management during the desensitization, and recommendations for maintenance aspirin therapy following desensitization are reviewed. Also included is a summary of studies evaluating the clinical efficacy of aspirin therapy after desensitization as well as a discussion on the possible cellular and molecular mechanisms explaining how this therapy provides unique benefit to patients with AERD.

AERD Associated Nasal Polyposis: Efficacy of Postoperative Antileukotriene Therapy in Comparison with Aspirin Desensitization. A Retrospective Study.

INTRODUCTION: AERD (aspirin-exacerbated respiratory disease) is a severe form of an inflammatory disease of the upper airway system. Therapy remains challenging due to a complex underlying pathophysiology. OBJECTIVE: To evaluate the efficacy of postoperative antileukotriene therapy concerning recurrence of nasal polyposis in patients with AERD and to compare it with AD (aspirin desensitization) over time. METHODS: In this retrospective study we analyzed AERD patients (N = 61) after functional endoscopic sinus surgery (FESS). Patients were treated at our institution postoperatively with topical mometasone (control group, N = 22), leukotriene-receptor-antagonists (montelukast [MT], N = 18) or underwent an aspirin desensitization (N = 21). Subjective parameters as assessed by SNOT (sinonasal outcome test) questionnaire and endoscopic endonasal examination (polyposis grading) were evaluated throughout a follow-up period of 6-9 and >12 (long-term) months after surgery. RESULTS: Endoscopic endonasal examinations 6-9 months after sinus surgery showed a good disease control in all 3 groups with significant reduction in polyp grading in the AD group. After a follow-up period of more than 12 months, MT and AD patients had significantly less polyp recurrences as compared to the topical treatment group. Subjective sinonasal symptoms revealed that hyposmia and nasal obstruction were prominent factors in all 3 groups throughout the follow-up period. MT group showed significant improvement in sinonasal symptoms over time. CONCLUSION: Postoperative treatment with leukotriene-receptor-antagonists and aspirin desensitization both significantly reduce nasal polyp recurrence. MT has a positive effect on subjective sinonasal outcomes and patients' quality of life over time.