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.

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.

Differences in men and women suffering from CRSwNP and AERD in quality of life.

PURPOSE: While the overall impact of chronic rhinosinusitis (CRS) on patients' health is diverse, many affected individuals have a substantially impaired quality of life (QoL). The aim of this study was to evaluate the impact of sex-associated differences specifically in the subgroups of CRS with nasal polyps (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) by assessing QoL parameters in women and men separately. METHODS: In a retrospective single-center study, 59 patients with CRSwNP (39 males and 20 females) and 46 patients with AERD (18 males and 28 females) were included. Patient-reported outcome measures (PROM) evaluating QoL via the Sino-Nasal Outcome Test-20 German Adapted Version (SNOT-20 GAV) as well as the total polyp score (TPS) were analysed. RESULTS: There was no significant difference in TPS (p = 0.5550) and total SNOT-20 GAV scores (p = 0.0726) between male or female patients with CRSwNP or AERD. Furthermore, no significant sex differences were found within disease groups regarding the subcategories of the SNOT-20 GAV items. CONCLUSION: Thus, quality of life is severely impaired in patients suffering from various forms of CRS regardless of their sex.

Is otitis media with effusion associated with Samter's triad a new nosological entity? A preliminary report on inflammatory mediator production.

PURPOSE: Otitis media with effusion (OME) associated with Samter's triad (ST) is a difficult entity to treat. The aim of study was an investigation of the middle ear and nasal production of inflammatory mediators (IM) in patients with ST and analysing differences between them and controls. METHODS: Prospective case-control study. Nineteen patients with OME (five had allergic rhinitis, four had nasopharyngeal lymphoid hyperplasia, five had no evident sino-nasopharyngeal disease and five had confirmed ST) and 15 healthy participants were included. The concentrations of IM interleukin-1 beta (IL-1ß), interferon-alpha 2 (IFN-α2), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23 and IL-33 were measured in nasal and middle ear secretions. RESULTS: There was a difference that was close to a level of statistical significance only for IL-1ß levels in middle ear fluid (p = 0.052) between the ST subgroup and the other patients with OME. Also, we found a significant difference for IL-23 in nasal secretions between these subgroups (p = 0.040), whereas the difference in nasal fluid IL-33 was close to a level of statistical significance (p = 0.052). There was a significant difference in nasal concentrations of IL-1ß, IFN-α2, MCP-1, IL-8, IL-18 and IL-33 (p < 0.001, p = 0.005, p = 0.008, p = 0.011, p = 0.011 and p = 0.011, respectively) between the OME group and the healthy subjects. There were significant positive correlations between concentrations of IL-1ß, IFN-α2, IFN-γ, TNF-α, MCP-1, IL-17A, IL-18 and IL-33 (p < 0.001, p < 0.001, p = 0.002, p = 0.028, p < 0.001, p < 0.001, p < 0.001 and p < 0.001, respectively) in nasal and middle ear secretions. CONCLUSION: This preliminary report showed some differences in IM production between the patients with OME associated with ST and those without it. Our results suggest a uniformity of the production of nasal and middle ear IM and supported the concept of a united airway respiratory disease.

A trial of type 12 purinergic (P2Y12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, recurrent nasal polyposis, and respiratory reactions on ingestion of COX-1 inhibitors. Increased numbers of platelet-leukocyte aggregates are present in the sinus tissue and blood of patients with AERD compared with that of aspirin-tolerant patients, and platelet activation can contribute to aspirin-induced reactions. OBJECTIVE: We sought to determine whether treatment with prasugrel, which inhibits platelet activation by blocking the type 12 purinergic (P2Y12) receptor, would attenuate the severity of sinonasal and respiratory symptoms induced during aspirin challenge in patients with AERD. METHODS: Forty patients with AERD completed a 10-week, double-blind, placebo-controlled crossover trial of prasugrel. All patients underwent oral aspirin challenges after 4 weeks of prasugrel and after 4 weeks of placebo. The primary outcome was a change in the provocative dose of aspirin that would elicit an increase in Total Nasal Symptom Score (TNSS) of 2 points. Changes in lung function, urinary eicosanoids, plasma tryptase, platelet-leukocyte aggregates, and platelet activation were also recorded. RESULTS: Prasugrel did not significantly change the mean increase in TNSS of 2 points (79 ± 15 for patients receiving placebo and 139 ± 32 for patients receiving prasugrel, P = .10), platelet-leukocyte aggregates, or increases in urinary leukotriene E4 and prostaglandin D2 metabolite levels during aspirin-induced reactions in the study population as a whole. Five subjects (responders) reacted to aspirin while receiving placebo but did not have any reaction to aspirin challenge after the prasugrel arm. In contrast to prasugrel nonresponders (35 subjects), the prasugrel responders had smaller reaction-induced increases in TNSS; did not have significant aspirin-induced increases in urinary leukotriene E4, prostaglandin D2 metabolite, or thromboxane B2 levels; and did not display increases in serum tryptase levels during aspirin reactions on the placebo arm, all of which were observed in the nonresponders. CONCLUSION: In the overall study population, prasugrel did not attenuate aspirin-induced symptoms, possibly because it failed to decrease the frequencies of platelet-adherent leukocytes or to diminish aspirin-induced mast cell activation. In a small subset of patients with AERD who had greater baseline platelet activation and milder upper respiratory symptoms during aspirin-induced reactions, P2Y12 receptor antagonism with prasugrel completely inhibited all aspirin-induced reaction symptoms, suggesting a contribution from P2Y12 receptor signaling in this subset.

Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Prostaglandin (PG) D2 is the dominant COX product of mast cells and is an effector of aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: We evaluated the role of the innate cytokine thymic stromal lymphopoietin (TSLP) acting on mast cells to generate PGD2 and facilitate tissue eosinophilia and nasal polyposis in patients with AERD. METHODS: Urinary eicosanoid levels were measured in aspirin-tolerant control subjects and patients with AERD. Nasal polyp specimens from patients with AERD and chronic rhinosinusitis were analyzed by using quantitative PCR, Western blotting, and immunohistochemistry. Human cord blood-and peripheral blood-derived mast cells were stimulated with TSLP in vitro to assess PGD2 generation. RESULTS: Urinary levels of a stable PGD2 metabolite (uPGD-M) were 2-fold higher in patients with AERD relative to those in control subjects and increased further during aspirin-induced reactions. Peak uPGD-M levels during aspirin reactions correlated with reductions in blood eosinophil counts and lung function and increases in nasal congestion. Mast cells sorted from nasal polyps expressed PGD2 synthase (hematopoietic PGD2 synthase) mRNA at higher levels than did eosinophils from the same tissue. Whole nasal polyp TSLP mRNA expression correlated strongly with mRNA encoding hematopoietic PGD2 synthase (r = .75), the mast cell-specific marker carboxypeptidase A3 (r = .74), and uPGD-M (r = 0.74). Levels of the cleaved active form of TSLP were increased in nasal polyps from patients with AERD relative to those in aspirin-tolerant control subjects. Recombinant TSLP induced PGD2 generation by cultured human mast cells. CONCLUSIONS: Our study demonstrates that mast cell-derived PGD2 is a major effector of type 2 immune responses driven by TSLP and suggests that dysregulation of this innate system contributes significantly to the pathophysiology of AERD.

Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is manifested by adult-onset asthma, nasal polyposis, chronic rhinosinusitis, and aspirin sensitivity. Previously reported prevalence rates have been widely variable based on the population studied, method of diagnosis, and definition of aspirin sensitivity. OBJECTIVE: We sought to determine the prevalence of AERD among asthmatic adults. METHODS: A systematic review of databases was performed to identify all clinical trials published on or before June 16, 2013, that evaluated the prevalence of AERD. The studies were clustered into 7 different groups based on underlying disease (asthma, nasal polyps or chronic rhinosinusitis, or both), as well as on the methodology of prevalence determination. RESULTS: A total of 1770 articles were identified, with 27 considered appropriate for inclusion. Prevalence rates of AERD ranged from 5.5% to 12.4% based on study type. Among all studies in asthmatic patients, regardless of method, the prevalence of AERD was 7.15% (95% CI, 5.26% to 9.03%). The prevalence of AERD was highest among patients with severe asthma (14.89% [95% CI, 6.48% to 23.29%]). Among patients with nasal polyps and chronic rhinosinusitis, the prevalence was 9.69% (95% CI, 2.16% to 17.22%) and 8.7% (95% CI, -1.02% to 18.34%), respectively. CONCLUSION: AERD is a distinct and important subtype of asthma and polypoid sinus disease. The prevalence of AERD is 7% in typical adult asthmatic patients and twice that number in patients with severe asthma, which underscores the importance of recognizing this disorder. Early identification of this syndrome is critical in view of the increased morbidity and costs associated with asthma exacerbations and the option to treat patients with AERD with long-term aspirin treatment after desensitization.

Platelets in patients with aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory disease characterized clinically by the triad of asthma, nasal polyposis, and pathognomonic respiratory reactions after ingestion of aspirin. It is a distinct syndrome associated with eosinophilic infiltration of respiratory tissues and excessive production of cysteinyl leukotrienes. Despite the consistent clinical phenotype of the respiratory disease, the underlying pathogenesis of the disease remains unclear. In addition to their role in hemostasis, platelets have the capacity to influence the activation state and function of other immune cells during inflammation and to facilitate granulocyte recruitment into the tissues. Platelets also possess a repertoire of potent preformed mediators of inflammation that are released on activation and are a rich source of newly synthesized lipid mediators that alter vascular permeability and smooth muscle tone. Accordingly, platelet activity has been linked to diverse inflammatory diseases, including asthma. Both human and animal studies strongly suggest that platelet activity is uniquely associated with the pathophysiology of AERD. This article summarizes the evidence supporting an effector role for platelets in asthmatic patients in general and in patients with AERD in particular and considers the potential therapeutic implications.

Prostaglandin D2: a dominant mediator of aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin desensitization followed by high-dose aspirin therapy is routinely performed for patients with aspirin-exacerbated respiratory disease (AERD). Little is known about the contributions of mediators other than cysteinyl leukotrienes to aspirin reactions and to the therapeutic benefit of high-dose aspirin therapy. OBJECTIVE: We investigated differences in urinary eicosanoid metabolite levels and blood eosinophil counts in patients with AERD who tolerate and those who fail aspirin desensitization and also in patients with AERD who were successfully treated with high-dose aspirin therapy. METHODS: Twenty-nine patients with AERD were stratified into those who tolerated aspirin desensitization (group I) and those who did not (group II). Urine was analyzed for eicosanoid metabolites at baseline, during aspirin reactions, and during high-dose aspirin therapy. Blood was analyzed for cell differentials at baseline and during aspirin therapy. RESULTS: Basal prostaglandin D2 metabolite (PGD-M; 13.6 ± 2.7 vs 7.0 ± 0.8 pmol/mg creatinine [Cr], P < .05) and thromboxane metabolite (TX-M; 1.4 ± 0.3 vs 0.9 ± 0.1 pmol/mg Cr, P < .01) levels were higher in group II than in group I. During aspirin reactions, PGD-M levels remained unchanged, whereas TX-M levels (0.7 ± 0.1 pmol/mg Cr, P = .07) tended to decrease in group I. In contrast, PGD-M levels increased dramatically in group II (61.3 ± 19.9 pmol/mg Cr, P < .05), whereas TX-M levels did not change. The decrease in FEV1 inversely correlated with basal urinary levels of both leukotriene E4 and PGD-M. Blood eosinophil and basophil levels increased and urinary PGD-M levels (2.2 ± 0.8 pmol/mg Cr, P < .001) decreased on 2 months of high-dose aspirin therapy in group I. CONCLUSION: Failure to tolerate aspirin desensitization in a subset of patients with AERD is associated with prostaglandin D2 overproduction. The increase in blood eosinophil and basophil counts during high-dose aspirin therapy might reflect the functional consequences of decreased prostaglandin D2 release and the therapeutic benefit of aspirin.

Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is an inflammatory condition of the respiratory tract and is characterized by overproduction of leukotrienes (LT) and large numbers of circulating granulocyte-platelet complexes. LT production can be suppressed by prostaglandin E(2) (PGE(2)) and the cyclic AMP-dependent protein kinase A (PKA). OBJECTIVE: To determine if PGE(2)-dependent control of LT production by granulocytes is dysregulated in AERD. METHODS: Granulocytes from well-characterized patients with and without AERD were activated ex vivo and subjected to a range of functional and biochemical analyses. RESULTS: Granulocytes from subjects with AERD generated more LTB4 and cysteinyl LTs than did granulocytes from controls with aspirin-tolerant asthma and controls without asthma. When compared with controls, granulocytes from subjects with AERD had comparable levels of EP(2) protein expression and PGE(2)-mediated cAMP accumulation, yet were resistant to PGE(2)-mediated suppression of LT generation. Percentages of platelet-adherent neutrophils correlated positively with LTB4 generation and inversely with responsiveness to PGE(2)-mediated suppression of LTB(4). The PKA inhibitor H89 potentiated LTB4 generation by control granulocytes but was inactive in granulocytes from individuals with AERD and had no effect on platelet P-selectin induction. Both tonic PKA activity and levels of PKA catalytic gamma subunit protein were significantly lower in granulocytes from individuals with AERD relative to those from controls. CONCLUSIONS: Impaired granulocyte PKA function in AERD may lead to dysregulated control of 5-lipoxygenase activity by PGE(2), whereas adherent platelets lead to increased production of LTs, which contributes to the features of persistent respiratory tract inflammation and LT overproduction.

Inheritance of NSAID-Exacerbated Respiratory Disease.

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has been considered an acquired condition. Positive first-degree family history has been reported in 1% of cases. The geographic and genetic isolation of the Finnish population offers exceptional opportunities for inheritance studies. In this questionnaire study, we explored the familial aggregation of N-ERD in 66 Finnish families of patients with N-ERD. The majority of patients (67%) had a positive family history of NSAID intolerance, asthma, nasal polyposis, or N-ERD. Furthermore, 55% had a positive first-degree family history of asthma, 21% nasal polyposis, 20% NSAID intolerance, and 11% N-ERD. The prevalence of asthma, nasal polyposis, NSAID intolerance, and N-ERD among first-degree relatives was 13%, 5%, 4%, and 2%, respectively. We present the pedigrees of the 44 affected families. According to our findings, Finnish patients with N-ERD seem to have a genetic susceptibility to it.

Demographic and clinical profile of patients with chronic rhinosinusitis in Saudi Arabia.

OBJECTIVES: To determine the clinical features of patients with chronic rhinosinusitis at a tertiary hospital in Riyadh, Saudi Arabia. METHODS: A cross-sectional study was carried out at King Abdulaziz University Hospital, Riyadh, Saudi Arabia. We enrolled 660 male and female participants with medical records indicating a history of chronic rhinosinusitis between 2021 and 2022. Quantitative and descriptive analyses of age, gender, nationality, presence of polyps, aspirin sensitivity, presence of urticaria, asthma, and allergies were performed. RESULTS: Of the 660 enrolled patients, 60% (n=396) were male and 40% (n=264) were female. Additionally, 67.7% (447) had nasal polyps, 32% had a history of asthma, 10% had hypersensitivity to aspirin, 1.4% reported a history of urticaria, 9.7% reported allergies to medications, 7.9% reported food allergies, 26% reported multiple allergies, and 1.8% reported environmental allergies. CONCLUSION: Our study revealed the following: Samter's triad was present in 6.9% of participants with chronic rhinosinusitis; the greatest prevalence of chronic rhinosinusitis with nasal polyps was observed among those older than 50 years. The prevalence of urticaria was not significantly different among groups; a higher rate of environmental allergies was observed among those with CRSwNP than among those without nasal polyps; and a higher prevalence of aspirin hypersensitivity was observed among those with CRSwNP than among non-polyps group.

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.

Nonsteroidal Anti-inflammatory Drug (NSAID) Tolerance After Biological Therapy in Patients With NSAID-Exacerbated Respiratory Disease: A Randomized Comparative Trial.

BACKGROUND: There are no prospective studies comparing how biological therapies affect nonsteroidal anti-inflammatory drug (NSAID) tolerance in NSAID-exacerbated respiratory disease. OBJECTIVE: To study the induction of NSAID tolerance after biological therapy in patients with NSAID-exacerbated respiratory disease. METHODS: A prospective pilot study in a real-world clinic setting was conducted among subjects with severe asthma and type 2 inflammation. A random allocation of therapy was carried out: benralizumab, dupilumab, mepolizumab, or omalizumab. NSAID intolerance was confirmed by an oral challenge test (OCT) using acetyl-salicylic acid (ASA-OCT). The principal outcome was NSAID tolerance according to OCT before and after 6 months of each biological therapy (intragroup comparisons). As exploratory outcomes, we compared NSAID tolerance between biological therapies (intergroup comparisons). RESULTS: A total of 38 subjects were included; 9 received benralizumab, 10 dupilumab, 9 mepolizumab, and 10 omalizumab. There was an increase in the concentration needed to produce a reaction during ASA-OCT with omalizumab (P < .001) and dupilumab (P = .004) but not with mepolizumab and benralizumab. Omalizumab and dupilumab achieved the highest frequency of NSAID tolerance (omalizumab 60%, dupilumab 40%, mepolizumab 22%, and benralizumab 22%). CONCLUSIONS: Biological therapies for asthma are useful for inducing NSAID tolerance; however, in patients with type 2 inflammation and high levels of total IgE, atopy, and eosinophils, anti-IgE or anti-IL4/13 seem to be more effective than antieosinophilic therapies. Omalizumab and dupilumab increased ASA tolerance, whereas mepolizumab and benralizumab did not. Future trials will be able to clarify this finding.

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.

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 in nonsteroidal anti-inflammatory exacerbated respiratory disease: The first prospective cohort in Chile.

Background: Nonsteroidal anti-inflammatory exacerbated respiratory disease (N-ERD) is characterized by the Samter triad: chronic rhinosinusitis with nasal polyps, asthma, and nonallergic hypersensitivity to NSAIDs. Its diagnosis is based on a complete clinical history and an aspirin (ASA) challenge test. Medical treatments include biological drugs and ASA desensitization. Objective: This study aims to evaluate the clinical response of patients with N-ERD undergoing functional endoscopic surgery (FES), followed by ASA desensitization and maintenance treatment, being the first prospective cohort study carried out in Chile. Methods: We conducted 1-year follow-up of 12 patients with N-ERD treated with FES, desensitization, and maintenance with ASA. For each control, the medication score, sinonasal symptomatology (SNOT-22), PEF (peak expiratory flow), nasal polyposis (Lildholdt score), and the appearance of adverse effects were recorded. Computed tomography (CT) of the paranasal cavities was performed at baseline and at the 12-month follow-up to calculate the Lund-Mackay score. Results: Patients presented a reduction of SNOT-22 after the FES, which was maintained at 12 months (p = 0.002); the symptoms that showed the greatest reduction were feeling embarrassed and nasal obstruction. The Lildholdt score was also significantly reduced (p = 0.001); in only three patients, the nasal polyps recurred, and all were small. The PEF showed a slight nonsignificant increase of 3.3%. In total, 75% of patients had an adverse effect, the most frequent being abdominal pain (66.7%), but none of the 12 patients required discontinuation of aspirin treatment in 1-year follow-up. The Lund-Mackay score had a significant reduction of 6.6 points (p < 0.001). Conclusion: ASA desensitization is safe and effective in reducing upper and lower respiratory symptoms in patients with N-ERD and delays the reappearance of nasal polyps, although it is not exempt from adverse effects, with the vast majority being mild.

Dacryocystitis in a patient with Samter's triad.

Samter's triad, also known as aspirin-exacerbated respiratory disease, is characterized by nasal polyposis, bronchial asthma, and aspirin intolerance. Here, we present a case of a 36-year-old woman with a history of Samter's triad and recurrent dacryocystitis. After combined dacryocystorhinostomy and endoscopic sinus surgery, pathological specimens of the lacrimal sac showed respiratory fibrosis with chronic inflammation and eosinophilic infiltration. Our case demonstrates that Samter's triad is a potential etiology for inflammatory nasolacrimal duct obstruction.

Dupilumab as Add-on Therapy for Chronic Rhinosinusitis With Nasal Polyposis in Aspirin Exacerbated Respiratory Disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) affects 7% of asthmatics. Usual therapies are inadequate for asthma and/or nasal polyposis, leading to decreased quality of life. OBJECTIVE: Our objective was to evaluate the efficacy of dupilumab in AERD patients with uncontrolled, chronic rhinosinusitis with nasal polyposis (CRSwNP). METHODS: Patients 18 years and older with a physician diagnosis of AERD and sino-nasal outcome test 22 (SNOT 22) score ≥19 despite standard medical therapy were eligible for the study. Patients received one month of placebo dosing, followed by 6 months of dupilumab. Patients were blinded to the order of therapy. Wilcoxon-paired rank sum test was used to compare study outcomes at baseline and the completion of the study. RESULTS: Ten patients completed the study. The median baseline SNOT 22 score improved from 46 [IQR: 34 to 64.8] to 9.5 [IQR: 2.5 to 19] after 6 months of therapy (p = 0.0050). The median baseline Lund MacKay score improved from 21.5 [IQR: 17 to 23.3] to 4 [IQR: 1.2 to 6] after 6 months of therapy (p = 0.0050). There was also improvement in the following secondary outcomes: asthma control test (ACT), mini asthma quality of life questionnaire (AQLQ), and University of Pennsylvania Smell Identification test (UPSIT). Exhaled nitric oxide (FeNO), total serum IgE, 24-hour urinary leukotriene E4, and serum thymus and activation regulated cytokine (TARC) also decreased. There were no significant study-related adverse events. CONCLUSION: Dupilumab was highly effective as add-on therapy for CRSwNP in AERD, improving patient-reported outcomes, sinus opacification, and markers of T2 inflammation.

Pathomechanisms of AERD-Recent Advances.

The pathomechanisms behind NSAID-exacerbated respiratory disease are complex and still largely unknown. They are presumed to involve genetic predisposition and environmental triggers that lead to dysregulation of fatty acid and lipid metabolism, altered cellular interactions involving transmetabolism, and continuous and chronic inflammation in the respiratory track. Here, we go through the recent advances on the topic and sum up the current understanding of the background of this illness that broadly effects the patients' lives.