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

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

Lower serum 15-HETE level predicts nasal ILC2 accumulation during COX-1 inhibition in AERD.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D2, and low levels of prostaglandin E2. Further, 15-hydroxyeicosatetraenoic acid (15-HETE) levels may have predictive value in therapeutic outcomes of aspirin desensitization. Accumulation of nasal group 2 innate lymphoid cells (ILC2s) has been demonstrated during COX-1 inhibition in AERD, although the relationships between tissue ILC2 accumulation, reaction symptom severity, and novel lipid biomarkers are unknown. OBJECTIVE: We sought to determine whether novel lipid mediators are predictive of nasal ILC2 accumulation and symptom scores during COX-1 inhibitor challenge in patients with AERD. METHODS: Blood and nasal scraping samples from patients with AERD were collected at baseline and COX-1 inhibitor reaction and then processed for flow cytometry for nasal ILC2s and serum for lipidomic analysis. RESULTS: Eight patients with AERD who were undergoing aspirin desensitization were recruited. Of the 161 eicosanoids tested, 42 serum mediators were detected. Baseline levels of 15-HETE were negatively correlated with the change in numbers of airway ILC2s (r = -0.6667; P = .0428). Docosahexaenoic acid epoxygenase metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) was positively correlated with both changes in airway ILC2s (r = 0.7143; P = .0305) and clinical symptom scores (r = 0.5000; P = .0081). CONCLUSION: Low levels of baseline 15-HETE predicted a greater accumulation of airway ILC2s in patients with AERD who were receiving COX-1 inhibition. Further, increases in the cytochrome P pathway metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) were associated with increased symptoms and nasal ILC2 accumulation. Future studies to assess how these mediators might control ILC2s may improve the understanding of AERD pathogenesis.

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.

Mechanisms by which dupilumab normalizes eicosanoid metabolism and restores aspirin-tolerance in AERD: A hypothesis.

Aspirin-exacerbated respiratory disease (AERD) is associated with overproduction of proinflammatory cysteinyl leukotrienes (CysLTs), defective generation of anti-inflammatory prostaglandin E2 (PGE2), and reduced expression of the EP2 receptor for PGE2. Reduced PGE2 synthesis results from the downregulation of inducible COX-2. Because PGE2 signaling via EP2 inhibits the 5-lipoxygenase/leukotriene C4 synthase-dependent pathway, the deficient levels of both PGE2 and EP2 likely contribute to the excessive baseline production of cysteinyl leukotrienes in patients with AERD compared with in patients with aspirin-tolerant asthma. The COX-2 pathway is regulated by an autocrine metabolic loop involving IL-1ß, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. Previous studies reported that this metabolic loop is dysregulated in patients with AERD. When the downexpressed EP2 receptor is normalized, the entire loop returns to its normal function. Cotreatment of airway cells from healthy subjects with IL-4 and IFN-γ induces alterations in the metabolic loop similar to those seen in patients with AERD. In these patients, IL-4, which is produced in excess in airways of patients with AERD, likely contributes to the alteration of normal functioning of the autocrine metabolic loop involving IL-1ß, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. We hypothesized that by blocking IL-4 action, dupilumab normalizes EP2 expression and restores the normal functioning of the COX-2 pathway autocrine metabolic loop, thereby normalizing the synthesis of PGE2 and restoring aspirin tolerance.

Management of United Airway Disease Focused on Patients With Asthma and Chronic Rhinosinusitis With Nasal Polyps: A Systematic Review.

BACKGROUND: The clinical approach to upper and lower respiratory diseases from a joint perspective, known as united airways disease (UAD), is challenging for health care professionals owing to a paucity of specific studies. OBJECTIVE: This study reviews recent scientific evidence on the management of asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) from a UAD perspective. METHODS: A systematic search of PubMed, Scopus, and Web of Science was conducted for 9 research questions, and studies published from January 2015 to July 2021 were included. Quality assessment was performed with the Critical Appraisal Skills Programme. RESULTS: In total, 32 publications met the inclusion criteria. Control of type 2 inflammation in UAD (reported in 9 studies) was associated with biologic therapies, for which an impact on asthma, CRSwNP, and/or aspirin/nonsteroidal anti-inflammatory drug-exacerbated respiratory disease outcomes was described in 9 studies. However, there was a lack of scientific evidence on clinical and/or biochemical markers associated with response to biologics in patients with UAD. The benefit on corticosteroid reduction in patients receiving biologics was reported in 9 studies. Three publications reported a positive impact of surgery on asthma and/or CRSwNP outcomes, and the effect of biologics on reducing the need of surgery was consistent across 6 studies. CONCLUSIONS: Our results underscore an overall scarcity of scientific evidence on the treatment strategies for these frequent coexisting entities from an UAD approach but also identify several research gaps and unmet needs that should be addressed to ensure optimal diagnosis, management, and follow-up of these patients.

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.

Aspirin­induced asthma: a still evolving area of basic and clinical research.

The first modern description of respiratory syndrome of aspirin hypersensitivity was published over half of the century ago, but the pathogenesis of the disease is still elusive. Just a few years after discovery how aspirin works, Andrew Szczeklik and his co­workers described that asthmatics with aspirin hypersensitivity cross­react to the whole class of nonsteroidal anti­inflammatory drugs. It took rest of his life to seek for an answer on how this disease, nowadays referred to as N ­ERD, develops and how it can be treated. In the meantime, cysteinyl leukotrienes, leukotriene modifying drugs, and novel subpopulations of lymphocytes were discovered. This review on aspirin hypersensitivity documents a progress in our understanding of mechanisms of hypersensitivity to nonsteroidal anti­inflammatory drugs. Current concepts about origin of the disease integrate advances in the field of allergology and inflammatory mechanisms of asthma. However, pharmacological inhibition of prostaglandin biosynthesis by nonsteroidal anti­inflammatory drugs has a pivotal role in these investigations. Presented is a central role of prostaglandin E2 , a double­faced lipid immunoregulatory mediator whose deficiency is related to the administration of an anti­inflammatory drug. Discussed are cysteinyl leukotrienes, the most reliable biomarkers of aspirin hypersensitivity and cells of innate immunity capable of leukotrienes production. Involvement of blood platelets and recently described mucosal basophils are areas of ongoing studies in the disease. Aspirin hypersensitivity is an acquired condition; therefore, the search for genetic predisposition using classic association studies was inconclusive. There is a new hope to explain mechanisms of aspirin hypersensitivity by studies of innate lymphoid cells, which have a central role in the regulation of respiratory mucosa function in asthma.

Controversies in Allergy: Aspirin Desensitization or Biologics for Aspirin-Exacerbated Respiratory Disease-How to Choose.

Aspirin-exacerbated respiratory disease (AERD) can be a frustratingly complex syndrome to treat. Until recently, standard medical and surgical therapies for patients' asthma and chronic rhinosinusitis with nasal polyposis were the primary treatment modalities available, combined with either complete avoidance of all aspirin and nonsteroidal anti-inflammatory medications, or aspirin desensitization and initiation of high-dose aspirin therapy. There are now several targeted respiratory biologics added to the available armament for patients with AERD and choosing between this ever-growing list of options can be daunting for both patients and their clinicians. This review includes our understanding and interpretation of the existing data for each option, along with our own approach to weighing the pros and cons of each treatment for individual patients.

Steroid affected cytokines in aspirin-exacerbated respiratory disease.

BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) are among the most challenging rhinologic patients to treat. AERD has a complex inflammatory milieu of lipid mediators and cytokines. In this study we evaluated cytokine differences in the complex AERD environment at the mucus, epithelial, and tissue levels. METHODS: Samples were acquired at the time of sinus surgery from 21 patients (seven steroid-treated, 14 untreated) with aspirin challenge-confirmed AERD. Three methods (sponge adsorption, epithelial brushing, tissue biopsy) were used to acquire samples from the respective sinus sampling sites (mucus, polyp epithelium, and full-thickness polyp) of each patient. We measured and compared 16 cytokine concentrations in AERD patients with or without prednisone treatment using the Luminex platform. RESULTS: In most sampling sites, IL-5, IL-6, IL-10, IL-13, IL-33, CCL20, and TNF-α were detected at higher concentrations than IFN-γ, IL-1ß, IL-17A, IL-4, IL-22, IL-17E/IL25, and GM-CSF. Each sampling site had a different pattern of cytokine levels, and except for IL-5 and IL-25 there was no correlation among sampling methods for each cytokine tested. The most notable and significant decreases in cytokines from those treated with prednisone were observed in the epithelium for IL-5, IL-10, IL-33, and IFN-γ. CONCLUSIONS: In the epithelial samples, type 2-associated cytokines IL-5 and IL-33, the anti-inflammatory cytokine IL-10, and IFN-γ were lower in AERD patients treated with prednisone. This work serves as a basis to assess therapeutic-induced mucosal cytokine responses in AERD and indicates that the site of cytokine measurement is an important consideration when assessing results.

Safety, Outcomes, and Recommendations for Two-Step Outpatient Nonsteroidal Anti-Inflammatory Drug Challenges.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) outpatient challenge protocols are not standardized. They vary in clinical practice and can be time- and resource-intensive to perform. OBJECTIVE: To investigate the safety and outcomes of two-step outpatient NSAID challenges to evaluate patients with non-aspirin-exacerbated respiratory disease (AERD)-related NSAID hypersensitivity. METHODS: We conducted a retrospective study of patients with a history of NSAID allergy who underwent outpatient NSAID challenges under allergist supervision. Individuals with AERD were excluded. Patient demographics, NSAID reaction history, and drug challenge details and outcomes were collected. RESULTS: A total of 249 patients (mean age, 51.6 years; 63.5% female) underwent 262 NSAID challenges. Of these, 224 challenges were negative (85.5%). Thirty challenges resulted in an immediate reaction during the challenge procedure (11.5%) and eight resulted in delayed reactions (3.1%). Three individuals with immediate reactions required treatment with intramuscular epinephrine. Factors associated with a positive NSAID challenge included a prior reaction occurring within 5 years of drug challenge (odds ratio [OR] = 3.66; 95% confidence interval [CI], 1.67-8.44), a prior immediate reaction within 3 hours of NSAID ingestion (OR = 2.45; 95% CI, 1.12-5.57), a history of cross-reactive NSAID hypersensitivity to multiple NSAIDs (OR = 2.97; 95% CI, 1.23-6.91), and the presence of comorbid chronic spontaneous urticaria (OR = 2.95; 95% CI, 1.35-6.41). CONCLUSIONS: More than 85% of two-step non-AERD NSAID drug challenges were negative for an immediate or delayed reaction, which allowed patients to use at least one clinically indicated NSAID. Challenge reactions were generally mild. Two-step NSAID challenge protocols can be safely performed in the outpatient setting.

Long-term role of zileuton in the treatment of chronic rhinosinusitis in aspirin exacerbated respiratory disease.

BACKGROUND: Chronic rhinosinusitis (CRS) in the setting of Aspirin Exacerbated Respiratory Disease (AERD) have high rate of treatment failure and disease recurrence. OBJECTIVE: Evaluate the long-term effect of zileuton on sinonasal outcomes in patients with AERD. METHODS: AERD patients were reviewed and divided into two cohorts, depending if they were treated with zileuton during their clinical course. Demographic data, 22-item sinonasal outcome test (SNOT-22), Lund-Kennedy (LK) endoscopy score, duration of treatment, and number of sinus surgeries performed were collected. RESULTS: 40 AERD patients were included, with follow-up duration up to 10 years (avg of 5.2 years). All patients were treated with topical saline and budesonide irrigations, intranasal steroid spray, and montelukast. 19 patients had uncontrolled sinus disease requiring multiple steroid tapers and were switched from montelukast to zileuton (cohort 1, 47.5%) at some point in their treatment. 21 patients (cohort 2, 52.5%) never needed zileuton. The average duration of treatment with zileuton was 6 years. Patients who required zileuton had a worse SNOT-22 (32.1 vs 19, p = 0.117), worse LK score (8.1 vs 7.5, p = 0.504), and higher average number of surgeries (1.9 vs 1.6, p = 0.343). The outcomes in the zileuton cohort trended toward improvement, however these did not reach statistical significance with an improved SNOT-22 from 32.1 to 27.4 (p = 0.617) and LK score from 7.9 to 6.2 (p = 0.092); The addition of zileuton significantly lowered the number of surgeries needed to an average of 0.5 (p < 0.0001). CONCLUSION: Zileuton may help decrease the number of sinus surgeries needed in AERD.