Aspirin Challenge-Induced Genome-Wide DNA Methylation Profile of Peripheral Blood Lymphocytes in Aspirin-Exacerbated Respiratory Disease.

Genetic variation and epigenetic factors are thought to contribute to the development of hypersensitivity to aspirin. DNA methylation fluctuates dynamically throughout the day. To discover new CpG methylation in lymphocytes associated with aspirin-exacerbated respiratory disease (AERD), we evaluated changes in global CpG methylation profiles from before to after an oral aspirin challenge in patients with AERD and aspirin-tolerant asthma (ATA). Whole-genome CpG methylation levels of peripheral blood mononuclear cells were quantified with an Illumina 860K Infinium Methylation EPIC BeadChip array and then adjusted for inferred lymphocyte fraction (ILF) with GLINT and Tensor Composition Analysis. Among the 866,091 CpGs in the array, differentially methylated CpGs (DMCs) were found in 6 CpGs in samples from all 12 patients with asthma included in the study (AERD, n = 6; ATA, n = 6). DMCs were found in 3 CpGs in the 6 ATA samples and in 615 CpGs in the 6 AERD samples. A total of 663 DMCs in 415 genes and 214 intergenic regions differed significantly in the AERD compared with the ATA. In promoters, 126 CpG loci were predicted to bind to 38 transcription factors (TFs), many of which were factors already known to be involved in the pathogenesis of asthma and immune responses. In conclusion, we identified 615 new CpGs methylated in peripheral blood lymphocytes by oral aspirin challenge in AERD but not in ATA. These findings indicate that oral aspirin challenge induces epigenetic changes in ILFs, specifically in AERD patients, possibly via changes in TF binding, which may have epigenetic effects on the development of AERD.

Mast Cells in Aspirin-Exacerbated Respiratory Disease.

PURPOSE OF REVIEW: Aspirin-exacerbated respiratory disease (AERD) is a syndrome of high type 2 inflammation and is known to critically involve mast cell activation. The mast cell is an important cell in the baseline inflammatory processes in the upper and lower airway by maintaining and amplifying type 2 inflammation. But it also is prominent in the hypersensitivity reaction to COX-1 inhibition which defines this condition. RECENT FINDINGS: Recent work highlights the mast cell as a focal point in AERD pathogenesis. Using AERD as a specific model of both high type 2 asthma and chronic sinusitis, the role of mast cell activity can be better understood in other aspects of airway inflammation. Further dissecting out the mechanism of COX-1-mediated mast cell activation in AERD will be an important next phase in our understanding of NSAID-induced hypersensitivity as well as AERD pathophysiology.

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.

Optimizing the timing of biologic and surgical therapy for patients with refractory chronic rhinosinusitis with nasal polyposis (CRSwNP).

INTRODUCTION: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is often treated with endoscopic sinus surgery (ESS); however, patients may require revision surgery due to recurrence. To date, no studies have compared outcomes for combined surgery and biologic therapy for CRSwNP compared with biologic therapy alone. METHODS: Retrospective case-control study of CRSwNP patients who underwent ESS while on dupilumab or mepolizumab (ESS-biologic cohort) compared with CRSwNP patients on biologic therapy (biologic-only controls). Cohorts were matched according to indication, aspirin-exacerbated respiratory disease (AERD), sinonasal outcome test-22 (SNOT-22), and total polyp scores. RESULTS: Sixteen patients underwent ESS while on biologic therapy (13 dupilumab and 3 mepolizumab). Sixteen patients were biologic-only controls. There were no significant differences between indication, baseline SNOT-22 scores, polyp scores, and AERD status between cohorts. Patients underwent surgery a median of 33 days after starting biologic therapy. After 12 months of follow-up, the total polyp score for the ESS-biologic cohort decreased from 4.73 to 0.09 compared with a decrease from 5.22 to 3.38 for the biologic-only controls (95% confidence interval [CI] of difference: -5.37 to -1.38, Cohen's d: 2.40, p = 0.005). In the ESS-dupilumab subanalysis, the ESS-dupilumab cohort had a significant reduction in polyp burden from 4.85 to 0.00 compared with 4.88 to 3.50 for the controls (95% CI of difference: -5.68 to -1.32, Cohen's d: -1.69, p = 0.009). CONCLUSION: In CRSwNP patients, combined ESS and biologic therapy results in a significant and sustained decrease in polyp burden compared with biologic therapy alone. Larger studies are warranted to further examine the impact of combined therapy.

Not just snot: Local inflammatory profiles in patients with aspirin-exacerbated respiratory disease differ from patients with aspirin-tolerant chronic rhinosinusitis.

KEY POINTS: IL-5, CCL2, and CXCL8 in sinus mucous are higher in patients with AERD relative to aspirin-tolerant patients with CRS These mediators are pleiotropic, leading to widescale inflammatory processes contributing to AERD AERD is not only a T2 disease but heterogeneous: this may explain the refractory nature of AERD.

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.

Nasal polyp antibody-secreting cells display proliferation signature in aspirin-exacerbated respiratory disease.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) causes nasal obstruction and olfactory dysfunction. Aspirin-exacerbated respiratory disease (AERD) is the triad of CRSwNP, asthma, and respiratory reactions to COX-1 inhibitors. Patients with AERD have elevated nasal IL-5 levels and high numbers of antibody-secreting cells (ASCs), including plasma cells and plasmablasts, in their polyp tissue; in addition, their nasal polyp (NP) IgE levels are correlated with disease severity and recurrence of nasal polyposis. OBJECTIVE: We sought to explore differences in the transcriptomic profile, activation markers, and IL-5Rα expression and function of NP ASCs from patients with AERD and CRSwNP. METHODS: NP tissue was collected from patients with AERD and CRSwNP and digested into single-cell suspensions. NP cells were analyzed for protein expression by mass cytometry. For IL-5Rα functional studies, plasma cells were purified and cultured in vitro with or without IL-5 and analyzed by bulk RNA sequencing. RESULTS: Compared with polyp tissue from patients with CRSwNP, polyp tissue from patients with AERD contained significantly more ASCs and had increased ASC expression of IL-5Rα. ASCs from patients with AERD expressed higher protein levels of B-cell activation and regulatory markers (CD40, CD19, CD32, and CD38) and the proliferation marker Ki-67. ASCs from patients with AERD also expressed more IL5RA, IGHE, and cell cycle- and proliferation-related transcripts (CCND2, MKI67, CDC25A, and CDC25B) than did ASCs from patients with CRSwNP. Stimulation of plasma cells from patients with AERD with IL-5 induced key cell cycle genes (CCND2 and PTP4A3), whereas IL-5 stimulation of ASCs from patients with CRSwNP induced few transcriptomic changes. CONCLUSION: NP tissue ASCs from patients with AERD express higher levels of functional IL-5Rα and markers associated with cell cycling and proliferation than do ASCs from patients with aspirin-tolerant CRSwNP.

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

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

Quantifying surgical completeness in patients with aspirin exacerbated respiratory disease.

BACKGROUND: Aspirin exacerbated respiratory disease (AERD) in patients who have had sinus surgery remains a management challenge. Aspirin desensitization and biologics are additional treatment options. It remains unclear if patients require a more comprehensive surgery prior to implementing such additional therapies. The purpose of this study was to quantify prior surgery completeness in AERD patients at a tertiary rhinology practice. METHODS: Paranasal sinus CT scans were reviewed by four academic rhinologists to assess surgery completeness. Using a published CT grading system, each sinus was graded on the completeness of surgery and middle turbinate reduction. A score out of 14 was calculated for each patient (7 per side). RESULTS: Sixty-one patients with AERD out of 141 available were included. Mean inter-rater agreement across all sinuses was moderate (k = 0.42). The mean completeness score was 6.7/14. The following procedures were rated as complete (means): uncinectomy (L: 84%, R: 82%, k = 0.44), maxillary (L: 83%, R: 77%, k = 0.32), middle turbinate reduction (L: 45%, R: 46%, k = 0.31), anterior ethmoid (L: 35%, R: 39%, k = 0.51), sphenoid (L: 36%, R: 35%, k = 0.4), posterior ethmoid (L: 30%, R: 30%, k = 0.48), frontal (L: 22%, R: 21%, k = 0.46). CONCLUSION: Prior surgery in AERD patients were mostly deemed incomplete. Uncinectomy and maxillary antrostomy are the most common procedures previously performed. It remains toe seen whether this would be considered 'adequate' surgery or more 'complete' surgery is required to achieve greater disease control.

Glucagon-like Peptide-1 Receptor Pathway Attenuates Platelet Activation in Aspirin-Exacerbated Respiratory Disease.

Platelets are key contributors to allergic asthma and aspirin-exacerbated respiratory disease (AERD), an asthma phenotype involving platelet activation and IL-33-dependent mast cell activation. Human platelets express the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R agonists decrease lung IL-33 release and airway hyperresponsiveness in mouse asthma models. We hypothesized that GLP-1R agonists reduce platelet activation and downstream platelet-mediated airway inflammation in AERD. GLP-1R expression on murine platelets was assessed using flow cytometry. We tested the effect of the GLP-1R agonist liraglutide on lysine-aspirin (Lys-ASA)-induced changes in airway resistance, and platelet-derived mediator release in a murine AERD model. We conducted a prospective cohort study comparing the effect of pretreatment with liraglutide or vehicle on thromboxane receptor agonist-induced in vitro activation of platelets from patients with AERD and nonasthmatic controls. GLP-1R expression was higher on murine platelets than on leukocytes. A single dose of liraglutide inhibited Lys-ASA-induced increases in airway resistance and decreased markers of platelet activation and recruitment to the lung in AERD-like mice. Liraglutide attenuated thromboxane receptor agonist-induced activation as measured by CXCL7 release in plasma from patients with AERD and CD62P expression in platelets from both patients with AERD (n = 31) and nonasthmatic, healthy controls (n = 11). Liraglutide, a Food and Drug Administration-approved GLP-1R agonist for treatment of type 2 diabetes and obesity, attenuates in vivo platelet activation in an AERD murine model and in vitro activation in human platelets in patients with and without AERD. These data advance the GLP-1R axis as a new target for platelet-mediated inflammation warranting further study in asthma.

The chronic rhinosinusitis practice parameter.

The Allergy-Immunology Joint Task Force on Practice Parameters has published the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines for the medical management of chronic rhinosinusitis with nasal polyposis (CRSwNP). The practice parameter provides evidence-based guidelines on the use of intranasal corticosteroids (INCS) and biologics for CRSwNP, and aspirin therapy after desensitization (ATAD) for the management of aspirin-exacerbated respiratory disease (AERD). Evidence on surgery was not assessed. Overall, the guidelines suggest INCS rather than no INCS (conditional recommendation, low certainty of evidence), biologics rather than no biologics (conditional recommendation, moderate certainty of evidence), and ATAD rather than no ATAD (conditional recommendation, moderate certainty of evidence). Patient-important outcomes are compared across the various INCS delivery modalities and across the different biologics and ATAD. Specific consideration points for shared decision making with patients are detailed in the guideline. These include delivery method and small treatment effect sizes for INCS, disease burden at presentation, variability in efficacy among biologics, cost issues for biologics, and adverse effects of aspirin and risks related to desensitization for ATAD. The guidelines also identify a need for randomized control trials directly comparing treatment modalities and further investigation into which outcomes are important for patients.

[Omalizumab Treats Aspirin-Induced Asthma Complicated With Nasosinusitis and Otitis Media:Report of One Case].

Omalizumab,as a biological agent targeting IgE,is a recombinant humanized monoclonal antibody and the first targeted drug approved for treating moderate-to-severe bronchial asthma.By reviewing one case of aspirin-induced asthma complicated with nasosinusitis and otitis media,we discussed the value of omalizumab in the treatment of asthma and its complications,aiming to provide a reference for clinical practice.

Sex, Ethnicity, Body Mass Index, and Environmental Exposures Associated With NSAID-Exacerbated Respiratory Disease Symptom Sequence.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has a triad of symptoms: nasal polyposis, asthma, and NSAID hypersensitivity. Little is known about symptom timing and disease progression. OBJECTIVE: The aim of this study is to characterize disease progression in N-ERD. METHODS: Patients with N-ERD were prospectively interviewed and classified into 4 groups based on their first symptom at initial N-ERD onset (asthma, nasal polyps, NSAID hypersensitivity, or all concurrently). Associations of patient characteristics with the 4 groups were examined, along with associations within the "asthma first" group. RESULTS: Patients (N = 240) were mostly female (68%) and self-identified as non-White (77%). Half (N = 119) reported asthma as the earliest symptom in the N-ERD triad. Compared with other groups, "asthma first" was associated with younger age of onset (25 years, standard error ±1.3, P < .001) and higher body mass index (BMI) (odds ratio [OR] = 1.3, 95% confidence interval [CI]: 1.06-1.7, P = .02). In this group, age of onset <20 years was associated with female sex, Latino ethnicity, and higher BMI (all P < .05). The "NSAID sensitivity first" group was significantly associated with male sex (OR = 3.3, 95% CI: 1.5-7.4, P = .004) and pollution exposure (OR = 4.4, 95% CI: 1.6-11.9, P = .003). At the initial presentation, 27% of patients were unaware of their N-ERD diagnosis. Black and Latino patients were more likely to be unaware of their N-ERD diagnosis compared with White (P = .003). The median diagnostic delay was 3 years (interquartile range: 0-5 years). CONCLUSIONS: In this cohort, N-ERD is highly variable in onset and progression, with sex, BMI, race and ethnicity, and environmental exposures significantly associated with disease patterns and diagnostic delay.

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.

Association Between Aspirin-Exacerbated Respiratory Disease and Atherosclerotic Cardiovascular Disease: A Retrospective Review of US Claims Data.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) consists of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and hypersensitivity to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). Asthma is associated with increased risk of atherosclerotic cardiovascular diseases (ASCVD). However, there is lack of data on association between AERD and ASCVD. OBJECTIVE: To investigate the relationship between AERD and subsequent risk of ASCVD. METHODS: An algorithm to find patients with AERD was generated and validated through chart review at our home institution. This algorithm was applied to a national insurance claims database to obtain data for a retrospective cohort study. Demographic and comorbidity data were obtained for propensity matching. Several methods of analysis were performed on the data. RESULTS: A total of 571 patients met criteria for AERD; 3909 met criteria for asthma, CRSwNP, and no allergy to aspirin or NSAIDs (group 1); and 75,050 met criteria for asthma, CRS without nasal polyps, and no allergy to aspirin or NSAIDs (group 2). After covariate adjustment, AERD was significantly associated with ASCVD, including severe ASCVD, over groups 1 and 2 regardless of asthma severity. CONCLUSION: Patients with AERD are at higher risk of ASCVD than patients with asthma and CRSwNP or CRS without nasal polyps, underscoring the need for early ASCVD screening and a consideration for aspirin desensitization or use of a nonaspirin antiplatelet agent in the setting of AERD and comorbid ASCVD.

Long-term clinical outcomes of aspirin-exacerbated respiratory disease: Real-world data from an adult asthma cohort.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a phenotype of severe asthma, but its disease course has not been well documented compared with that of aspirin-tolerant asthma (ATA). OBJECTIVES: This study aimed to investigate the long-term clinical outcomes between AERD and ATA. METHODS: AERD patients were identified by the diagnostic code and positive bronchoprovocation test in a real-world database. Longitudinal changes in lung function, blood eosinophil/neutrophil counts, and annual numbers of severe asthma exacerbations (AEx) were compared between the AERD and the ATA groups. Within a year after baseline, two or more severe AEx events indicated severe AERD, whereas less than two AEx events indicated nonsevere AERD. RESULTS: Among asthmatics, 353 had AERD in which 166 and 187 patients had severe and nonsevere AERD, respectively, and 717 had ATA. AERD patients had significantly lower FEV1%, higher blood neutrophil counts, and higher sputum eosinophils (%) (all p < .05) as well as higher levels of urinary LTE4 and serum periostin, and lower levels of serum myeloperoxidase and surfactant protein D (all p < .01) than those with ATA. In a 10-year follow-up, the severe AERD group maintained lower FEV1% with more severe AEs than the nonsevere AERD group. CONCLUSION AND CLINICAL RELEVANCE: We demonstrated that AERD patients presented poorer long-term clinical outcomes than ATA patients in real-world data analyses.