| domain | current understanding/key statistic | evidence type | key source/date/DOI |
|---|---|---|---|
| Definition / prevalence | AERD (also called N-ERD; historically Samter triad) is the adult-onset syndrome of asthma, chronic rhinosinusitis with nasal polyps, and respiratory reactions to COX-1 inhibitors. Estimated prevalence is ~0.3–0.9% in the general US population and ~7% among people with asthma; prevalence is higher in severe asthma, and some cases are likely undiagnosed. (pqac-00000000, pqac-00000002, pqac-00000003) | Review synthesis of human epidemiology | Li et al., 2019, *Medical Sciences*, Mar 2019, DOI: 10.3390/medsci7030045; Badrani & Doherty, 2021, DOI: 10.1097/aci.0000000000000712 |
| Mechanism | Core model: COX-1 inhibition lowers protective prostaglandin signaling and is associated with exaggerated cysteinyl leukotriene and PGD2 pathways, epithelial alarmins (IL-33, TSLP), and type-2 cellular circuits involving mast cells, eosinophils, platelets, ILC2s, basophils, and IL-5Rα+ plasma cells. A newer candidate lipid signal, 15-Oxo-ETE, is elevated in AERD nasal polyps. (pqac-00000000, pqac-00000005, pqac-00000006, pqac-00000007) | Review of human tissue, biomarker, omics, and animal-model data | Sehanobish et al., Nov 2022, *Curr Opin Allergy Clin Immunol*, DOI: 10.1097/aci.0000000000000795; Badrani & Doherty, 2021, DOI: 10.1097/aci.0000000000000712 |
| Diagnosis | Aspirin/NSAID challenge remains the diagnostic standard. Urinary LTE4 is consistently higher in N-ERD/AERD than aspirin-tolerant asthma and tends to rise further after aspirin challenge, but assay/reporting heterogeneity limits stand-alone clinical use. Meta-analysis included 3,376 subjects (1,354 N-ERD, 1,420 ATA, 602 healthy controls); N-ERD vs ATA SMD 0.80 (95% CI 0.72–0.89). (pqac-00000001, pqac-00000007) | Systematic review/meta-analysis plus review synthesis | Marquette et al., Nov 2022, *Curr Allergy Asthma Rep*, DOI: 10.1007/s11882-022-01049-8 |
| Aspirin desensitization / maintenance | Established multimodal therapy, often paired with sinus surgery. Review-level evidence indicates benefit for sinonasal symptoms, reduced polyp recurrence, improved quality of life, and lower corticosteroid burden in selected patients; biomarkers such as baseline uLTE4/eosinophils may influence response or failure risk. (pqac-00000003, pqac-00000004, pqac-00000007) | Evidence-based review and cohort synthesis | Levy et al., Dec 2016, *Int Forum Allergy Rhinol*, DOI: 10.1002/alr.21826; Sehanobish et al., 2021, DOI: 10.3389/fimmu.2021.695815 |
| Dupilumab | Open-label 6-month study: 23% (7/30) developed complete aspirin tolerance and another 33% (10/30) tolerated higher doses; total polyp score, asthma control, and smell improved, with biomarker reductions including urinary LTE4 in those with increased tolerance. (pqac-00000009) | Human interventional trial | Schneider et al., Dec 2023, *Eur Respir J*, DOI: 10.1183/13993003.01335-2022 |
| Omalizumab | Randomized crossover placebo-controlled trial in 16 patients: omalizumab lowered aspirin-challenge urinary LTE4 exposure and 62.5% (10/16) achieved oral aspirin tolerance up to cumulative 930 mg in the omalizumab phase. (pqac-00000007) | Human randomized controlled trial | Hayashi et al., Jun 2020, *Am J Respir Crit Care Med*, DOI: 10.1164/rccm.201906-1215OC |
| Experimental: GLP-1R axis | Platelets are increasingly viewed as mechanistic contributors. In a murine AERD-like model, liraglutide inhibited lysine-aspirin-induced airway resistance and reduced platelet activation/recruitment; in human AERD platelets in vitro, liraglutide attenuated thromboxane receptor agonist-induced activation. This is mechanistically promising but not yet standard care. (pqac-00000000) | Mixed animal + human in vitro translational study | Foer et al., Oct 2023, *Journal of Immunology*, DOI: 10.4049/jimmunol.2300102 |
| Experimental: tezepelumab signal | In a severe asthma subgroup analysis, patients with aspirin/NSAID sensitivity had the largest reduction in annualized exacerbation rate with tezepelumab versus placebo: 83% (95% CI 66–91). This supports possible utility in AERD-like severe asthma phenotypes, but the evidence is subgroup rather than AERD-specific prospective trial evidence. (pqac-00000008) | Post hoc/subgroup analysis of phase 3 asthma trial | Carr et al., May 2024, *Advances in Therapy*, DOI: 10.1007/s12325-024-02889-8 |
| Model / evidence limitations | AERD is not a monogenic disorder and lacks a single definitive biomarker. Much mechanistic evidence comes from mixed sources—reviews, tissue studies, RNA-seq/single-cell data, in vitro assays, and murine aspirin-challenge models—so causal inference and treatment selection remain imperfect. Reviews also emphasize heterogeneity and variable response to biologics and aspirin therapy. (pqac-00000000, pqac-00000005, pqac-00000006) | Review synthesis across human, omics, in vitro, and animal studies | Badrani & Doherty, 2021, DOI: 10.1097/aci.0000000000000712; Sehanobish et al., Nov 2022, DOI: 10.1097/aci.0000000000000795 |


*Table: This table summarizes the main evidence domains for aspirin-exacerbated respiratory disease, emphasizing current understanding, key quantitative findings, and the level of supporting evidence. It is useful as a compact reference for epidemiology, mechanisms, diagnosis, and established versus emerging therapies.*