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.
Our aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD.
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.
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.
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.

Aspirin exacerbated respiratory disease (AERD) is a condition caused by increased bronchoconstriction in people with asthma after taking aspirin or another NSAID. Molecular analysis of the human genome has opened up new perspectives on human polymorphisms and disease. This study was conducted to identify the genetic factors that influence this disease due to its unknown genetic factors. We evaluated research studies, letters, comments, editorials, eBooks, and reviews. PubMed/MEDLINE, Web of Sciences, Cochrane Library, and Scopus were searched for information. We used the keywords polymorphisms, aspirin-exacerbated respiratory disease, asthma, allergy as search terms. This study included 38 studies. AERD complications were associated with polymorphisms in ALOX15, EP2, ADRB2, SLC6A12, CCR3, CRTH2, CysLTs, DPCR1, DPP10, FPR2, HSP70, IL8, IL1B, IL5RA, IL-13, IL17RA, ILVBL, TBXA2R, TLR3, HLA-DRB and HLA-DQ, HLA-DR7, HLA-DP. AERD was associated with heterogeneity in gene polymorphisms, making it difficult to pinpoint specific gene changes. Therefore, diagnosing and treating AERD may be facilitated by examining common variants involving the disease.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a clinical entity with specific features that impacts significantly on patient quality of life (QoL). CRSwNP is often associated with asthma and is difficult to control and manage despite pharmacological and/or surgical treatment. Omalizumab, a monoclonal anti-IgE antibody, has emerged as a putative therapeutic option.
OBJECTIVE: To evaluate the effects of omalizumab on nasal polyp (NP) size and QoL assessed by Sino-Nasal Outcome Test-22 (SNOT-22) in patients with recalcitrant CRSwNP and mild asthma.
METHODS: A multicenter retrospective analysis of patient data from the Community of Valencia (Spain) was performed. Adult patients with recalcitrant CRSwNP and comorbid mild asthma receiving compassionate use of omalizumab were included. NP size measured by total nasal endoscopic polyp score (TPS) and QoL evaluated through the SNOT-22 questionnaire were assessed at baseline and monthly over 12 months. An ordinal regression model was built to analyze the results.
RESULTS: A total of 23 CRSwNP patients with a mean age (± SD) of 54.78 ± 9.46 years were included. Nineteen suffered from aspirin-exacerbated respiratory disease (AERD). In all patients, a significant and sustained reduction in TPS was observed over time, accompanied by improvements in QoL reflected in lower SNOT-22 scores. In the ordinal regression model, time but not total IgE, age or tissue eosinophilia impacted on NP size and SNOT-22 outcomes. Additionally, improvements in QoL were not explained by reductions in the size of polyps.
CONCLUSIONS: Omalizumab was effective for the treatment of patients with recalcitrant CRSwNP and mild asthma, even when AERD was present, by reducing NP size and improving QoL; treatment time was a key factor. SNOT-22 improvements were not explained by decreases in TPS, indicating that omalizumab may be effective in all patients, regardless of polyp size.

Refractory chronic rhinosinusitis (CRS) remains a significant burden for patients, often leaving them with few therapeutic options that provide low-morbidity, long-term, and meaningful symptomatologic and endoscopic disease improvement. Macrolides have long been thought to offer both an immunomodulatory and antimicrobial effect. Our objective was to evaluate the efficacy of low-dose, long-term azithromycin in a carefully selected high-risk population failing appropriate medical therapy of budesonide nasal irrigations (BNIs) and endoscopic sinus surgery (ESS).
A double-blind, randomized, placebo-controlled trial was completed in a single tertiary-care center assessing the addition of 250 mg azithromycin, 3 times per week for 16 weeks, in adults failing ESS and high-volume BNIs. Associated comorbidities, as well as symptomatologic, microbiologic, and serologic values, were systematically collected.
A total of 128 patients were enrolled and underwent ESS followed by BNI. At the 4-month post-ESS visit, 48 patients showed disease persistence and were randomized to azithromycin or placebo. Overall, azithromycin, when compared with placebo, did not show a statistically significant difference in disease clearance (54% vs 33%, respectively; p = 0.146), although patients with disease clearance who were on azithromycin showed significantly better 22-item Sino-Nasal Outcome Test score improvements than patients on placebo (18 vs -0.9, respectively; p = 0.046). In a subgroup analysis excluding aspirin-exacerbated respiratory disease (AERD) patients, azithromycin significantly improved disease clearance when compared with placebo (71% vs 35%, respectively; p = 0.031), with a number needed to treat of 3 (2.8).
Low-dose azithromycin is a therapeutic option with few side effects. Its use can show favorable clinical outcomes in this difficult-to-treat population, especially if patients are AERD-negative.

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.
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.
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.
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.
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.

Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner.Objectives: To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E4 overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design.Methods: We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20-79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a >18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E4 concentration versus time curve in the intent-to-treat population during an oral aspirin challenge.Measurements and Main Results: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E4 concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) than in the placebo phase (80.8 [interquartile range, 65.4-87.8]) (P < 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (P < 0.001).Conclusions: Omalizumab treatment inhibited urinary leukotriene E4 overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.

Rationale: Daily high-dose aspirin therapy benefits many patients with aspirin-exacerbated respiratory disease but provides no benefit for aspirin-tolerant patients with asthma. Type 2 inflammation characterizes aspirin-exacerbated respiratory disease.Objectives: To determine whether high-dose aspirin therapy changes biomarkers of type 2 inflammation in aspirin-exacerbated respiratory disease.Methods: Forty-two subjects with aspirin-exacerbated respiratory disease underwent an aspirin desensitization and were placed on high-dose aspirin (1,300 mg daily). Fifteen aspirin-tolerant subjects with asthma were also placed on high-dose aspirin. Biologic specimens and clinical parameters were collected at baseline and after 8 weeks on aspirin. Urinary eicosanoids, plasma tryptase and cytokine levels, platelet-leukocyte aggregates, and granulocyte transcripts were assessed.Measurements and Main Results: Eight weeks of high-dose aspirin decreased nasal symptoms and urinary prostaglandin E metabolite (P < 0.05) and increased urinary leukotriene E4 (P < 0.01) levels in subjects with aspirin-exacerbated respiratory disease, but not in those with aspirin-tolerant asthma. Urinary prostaglandin D2 and thromboxane metabolites decreased in both groups. Only in subjects with aspirin-exacerbated respiratory disease, exhaled nitric oxide (P < 0.05), plasma tryptase (P < 0.01), and blood eosinophil (P < 0.01) and basophil (P < 0.01) counts increased and plasma tryptase correlated with eosinophil counts (Pearson r = 0.514; P < 0.01) on aspirin. After correction for eosinophil counts, aspirin-induced changes in blood granulocyte transcripts did not differ between groups. Aspirin had no effect on platelet-leukocyte aggregates, platelet activation markers, or plasma cytokines in either group.Conclusions: High-dose aspirin therapy for 8 weeks paradoxically increases markers of type 2 inflammation in subjects with aspirin-exacerbated respiratory disease, despite reducing nasal symptoms. This effect of aspirin is unique to aspirin-exacerbated respiratory disease and not observed in subjects with aspirin-tolerant asthma.

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.
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.
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.
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.
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.

The high levels of eicosanoid production and the clinical efficacy of leukotriene-modifying pharmacotherapies for patients with aspirin-exacerbated respiratory disease (AERD) suggest that other interventions targeting arachidonic acid dysregulation may also improve disease control.
To assess the utility of a high omega-3/low omega-6 diet for the treatment of AERD.
Prospective, nonblinded dietary intervention in 10 adult patients with AERD at Brigham and Women\'s Hospital in Boston, MA. The primary objective was for subjects to reduce dietary omega-6 fatty acid consumption to less than 4 g/d and increase omega-3 intake to more than 3 g/d. The primary outcome was change in urinary leukotriene E4, with changes in other eicosanoids, platelet activation, lung function, and patient-reported questionnaires also assessed.
Of the 10 subjects who screened for the study, all 10 completed the dietary intervention. Urinary leukotriene E4 decreased by 0.17 ng/mg (95% CI, -0.29 to -0.04; P = .02) and tetranor prostaglandin D-M decreased by 0.66 ng/mg creatinine (95% CI, -1.21 to -0.11; P = .02). There was a 15.1-point reduction in the 22-item Sino-Nasal Outcome Test score (95% CI, -24.3 to -6.0; P = .01), a 0.27-point reduction in the 7-item Asthma Control Questionnaire score (95% CI, -0.52 to -0.03; P = .03), and no change in FEV1 % predicted (P = .92) or forced vital capacity % predicted (P = .74). All patients lost some weight over the 2-week intervention period, and there were no diet-associated adverse events.
A high omega-3/low omega-6 diet may be an appropriate adjunct treatment option for patients with AERD.

Aspirin desensitization is an effective treatment option for aspirin-exacerbated respiratory disease. Aspirin desensitization protocol modifications have improved the safety and efficiency of this procedure, yet some providers remain reluctant to perform it.
The primary objective of this study was to evaluate the safety and outcomes of outpatient aspirin desensitization procedures. A secondary objective was to assess clinical characteristics that might predict reaction severity during aspirin desensitization.
Two hundred seventy-five patients underwent aspirin desensitization at Scripps Clinic between January 2009 and August 2015. Baseline patient characteristics and reaction results were analyzed in the 167 patients who reacted during desensitization.
All of the 167 reactors, including 23 who were classified as severe reactors, were successfully desensitized in the outpatient setting. The average desensitization duration among reactors was 1.67 days, and the average duration for gastrointestinal reactors was 2.29 days. The mean baseline Sino-Nasal Outcome Test score was higher in severe reactors compared with nonsevere reactors (P = .05). Overall, patients receiving omalizumab had a similar reaction profile to those not receiving omalizumab.
Most patients undergoing aspirin desensitization will have symptoms. It remains difficult to predict the severity of these symptoms. However, desensitization can be done safely and efficiently in an appropriately equipped outpatient setting. This treatment option should be made available to all patients with aspirin-exacerbated respiratory disease. The Sino-Nasal Outcome Test score might be able to predict more severe reactions and merits further study. Eight of the 9 patients receiving omalizumab reacted during desensitization, suggesting that it does not block reactions during aspirin desensitization.