Aspirin-Exacerbated Respiratory Disease (AERD): Disease-Characteristics Report

Executive summary

Aspirin-exacerbated respiratory disease (AERD), increasingly termed NSAID-exacerbated respiratory disease (N-ERD), is a chronic, usually adult-onset inflammatory disorder of the unified upper and lower airway. It comprises asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and reproducible respiratory reactions to aspirin or other strong cyclooxygenase-1 (COX-1) inhibitors. It is a complex, multifactorial disease—not an IgE allergy to aspirin and not a Mendelian disorder. Current evidence supports dysregulated arachidonic-acid metabolism superimposed on epithelial and type-2 inflammation, with deficient protective prostaglandin-E signaling and excessive cysteinyl leukotriene and prostaglandin-D2 activity. Mast cells, eosinophils, platelets, basophils, ILC2s, plasma cells, macrophages, and airway epithelial cells form the principal cellular network. (badrani2021cellularinteractionsin pages 1-3, li2019aspirinexacerbatedrespiratory pages 1-3, sehanobish2022newconceptsfor pages 1-3)

AERD affects approximately 0.3–0.9% of the general US population, about 7% of adults with asthma, approximately 15% with severe asthma, and 8–26% of CRSwNP populations, depending on ascertainment. Diagnosis is clinical when the triad and repeated unequivocal reactions are present; otherwise, supervised aspirin provocation is the reference standard. No blood, urine, genomic, or omics test can currently replace challenge testing. Management is multidisciplinary and combines guideline-based asthma therapy, topical sinonasal corticosteroids and saline irrigation, leukotriene-pathway therapy, endoscopic sinus surgery when indicated, aspirin desensitization followed by maintenance aspirin in selected patients, and phenotype-directed biologics. (li2019aspirinexacerbatedrespiratory pages 1-3, sehanobish2021aspirinactionsin pages 1-2, levy2016contemporarymanagementof pages 1-2, sehanobish2022newconceptsfor pages 9-10)

The following table summarizes the central evidence.

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.

1. Disease information

Definition and terminology

The classic triad is:

1. Asthma, commonly adult-onset and eosinophilic;
2. CRSwNP, generally bilateral and recurrent; and
3. Acute upper and/or lower respiratory reactions to COX-1-inhibiting NSAIDs.

Reactions may include nasal obstruction, profuse rhinorrhea, conjunctival symptoms, cough, wheeze, bronchospasm, and occasionally laryngospasm, flushing, gastrointestinal symptoms, or hypotension. Although systemic reactions can resemble anaphylaxis, the canonical mechanism is pharmacologic COX-1 inhibition rather than drug-specific IgE. (li2019aspirinexacerbatedrespiratory pages 1-3, sehanobish2021aspirinactionsin pages 1-2)

Synonyms: aspirin-exacerbated respiratory disease; NSAID-exacerbated respiratory disease; N-ERD/NERD; Samter triad/Samter syndrome; aspirin triad; aspirin-sensitive asthma; aspirin-intolerant asthma; aspirin-induced asthma. “N-ERD” is mechanistically broader because cross-reactivity extends beyond aspirin to other strong COX-1 inhibitors.

Identifiers and ontology mapping

• MeSH: Asthma, Aspirin-Induced is the closest established descriptor.
• ICD-10-CM: no single code completely represents the syndrome. Knowledge bases should compose asthma (J45.-), CRSwNP/nasal polyp (J32.-/J33.-), and adverse-effect or allergy-status coding for aspirin/NSAIDs as appropriate. Coding an aspirin “allergy” alone loses the syndrome’s non-IgE mechanism.
• ICD-11: use compositional coding for asthma, chronic rhinosinusitis/nasal polyposis, and NSAID hypersensitivity; local browser releases should be checked because a universally used single AERD stem code is not established.
• OMIM/Orphanet: no well-established dedicated Mendelian disease entry is appropriate.
• MONDO: a stable dedicated identifier could not be verified from the retrieved authoritative literature; therefore it should be recorded as unconfirmed, not inferred.
• Suggested disease-level ontology parentage: complex respiratory disease → asthma phenotype + CRSwNP + nonallergic drug hypersensitivity.

The evidence in this report is predominantly aggregated disease-level literature. Primary evidence includes challenge-confirmed clinical cohorts, randomized or open-label intervention studies, surgical cohorts, nasal-polyp and blood specimens, ex-vivo assays, transcriptomics/single-cell analyses, and induced mouse models. It is not derived from an individual patient’s EHR.

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factors

AERD has no single initiating pathogen, toxin, or causal mutation. Disease susceptibility arises from an incompletely resolved interaction among airway epithelial dysfunction, chronic type-2 inflammation, altered eicosanoid metabolism, and pharmacologic exposure to COX-1 inhibitors. Aspirin does not ordinarily create the underlying chronic disease; rather, COX-1 inhibition exposes an already dysregulated lipid-mediator network and precipitates acute reactions. (badrani2021cellularinteractionsin pages 1-3, sehanobish2022newconceptsfor pages 1-3)

Genetic factors

Reported candidate associations involve LTC4S, ALOX5, CYSLTR1/CYSLTR2, PTGER2/PTGER4, HLA-DPB1, TBXA2R, MS4A2, ACE, and genes affecting epithelial integrity and immune-cell interactions. However, associations are population-dependent and often fail replication. For example, a two-stage Mexican Mestizo candidate-gene study found replicated association of MS4A2 rs573790 CC, but this is a susceptibility marker—not an ACMG-pathogenic causal variant and not clinically diagnostic. Accordingly:

• no causal gene, OMIM gene–disease relationship, pathogenic variant, inheritance pattern, carrier frequency, or penetrance estimate is established;
• routine WES, WGS, gene panels, single-gene testing, CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion testing are not indicated for AERD itself;
• no validated protective allele, founder mutation, anticipation, germline mosaicism, or consanguinity effect is known.

Demographic and environmental modifiers

Typical onset is in the third or fourth decade; women are more frequently affected, with a reported female:male ratio near 3:2, and may have earlier or more severe disease. Strong COX-1 inhibitors are the defining acute trigger. Alcohol commonly provokes upper-airway or bronchial symptoms in affected patients, although it is not required for diagnosis. General asthma modifiers—smoking, air pollution, viral infection, occupational irritants, obesity, and poor adherence—may worsen respiratory control, but convincing evidence that they specifically cause AERD is limited. (li2019aspirinexacerbatedrespiratory pages 1-3)

Protective factors and interaction

Avoiding strong COX-1 inhibitors prevents pharmacologic attacks but does not reliably halt asthma or polyp progression. Selective COX-2 inhibitors are usually better tolerated, but the first dose may warrant supervised administration in highly reactive patients. Leukotriene modifiers attenuate reactions and chronic symptoms. Aspirin desensitization creates a temporary pharmacologic tolerant state, maintained only by continuous aspirin exposure; interruption permits resensitization. There is insufficient evidence for a generally protective diet, exercise regimen, microbiome intervention, vitamin, or low-salicylate diet. Dietary salicylates are not equivalent to pharmacologic COX-1 inhibition, and restrictive diets have weak evidence. (sehanobish2021aspirinactionsin pages 1-2, levy2016contemporarymanagementof pages 1-2)

3. Phenotypes

Core phenotype inventory

The disease is heterogeneous: high-type-2, mixed, and lower-type-2 inflammatory clusters have been reported. Atopy is neither necessary nor sufficient. A tertiary-center questionnaire study found good/very-good patient-reported control in 83% for asthma, 58% for nasal polyposis, and only 33% for chronic middle-ear disease, illustrating that upper-airway and otologic morbidity may dominate quality of life. AERD CRSwNP generally has greater inflammation, worse baseline health-related quality of life, and more revision surgery than aspirin-tolerant CRSwNP. (sehanobish2021aspirinactionsin pages 1-2, levy2016contemporarymanagementof pages 1-2)

4. Genetic and molecular information

AERD should be represented as multifactorial/polygenic susceptibility with no clinically actionable causal genotype. Reported SNPs are germline association signals; they are not somatic driver variants, do not meet ACMG/AMP pathogenic classification for AERD, and should not be entered as causal alleles. No recurrent aneuploidy, copy-number disorder, translocation, inversion, or chromosomal syndrome is established.

Molecular modifiers include receptor abundance or signaling through PTGER2/EP2, PTGER4/EP4, CYSLTR1, CYSLTR2, OXGR1/GPR99, CRTH2/PTGDR2, IL4R, IL5RA, ST2/IL1RL1, and enzymes PTGS1/COX-1, PTGS2/COX-2, ALOX5/5-LO, LTC4S, HPGDS, but altered expression or activity is more securely established than pathogenic coding variants. Human studies report reduced COX expression/PGE2 production in polyps and deficient PGE2 production by bronchial fibroblasts; relevant primary studies include PMID 12743569 and 21397936. (sehanobish2022newconceptsfor pages 9-10)

Epigenetic and microRNA changes have been explored, but no methylation signature or miRNA panel is validated for diagnosis, prognosis, or treatment selection. No AERD-specific pharmacogenomic guideline from CPIC or PharmGKB is established.

5. Environmental, lifestyle, and infectious information

• Defining exposure: aspirin and nonselective NSAIDs that strongly inhibit COX-1.
• Alcohol: frequent non-NSAID symptom trigger; mechanism may involve mast-cell/lipid-mediator pathways, but estimates vary.
• Smoking/pollution/occupation: plausible asthma and CRS aggravators; evidence specific to AERD onset is insufficient.
• Diet: low-salicylate diets remain experimental and potentially burdensome; no routine recommendation is supported.
• Exercise: beneficial for general health and asthma when controlled, but not demonstrated to prevent AERD.
• Infection: no bacterium, virus, fungus, or parasite causes AERD. Respiratory infections can exacerbate asthma or sinus disease but do not explain COX-1 cross-reactivity.

6. Mechanism and pathophysiology

Integrated causal chain

Upstream chronic state: genetically and environmentally conditioned epithelial barrier/immune dysregulation → chronic sinonasal and bronchial inflammation → reduced protective PGE2 production or EP-receptor responsiveness plus increased 5-LO/LTC4S capacity → constitutively elevated cysteinyl leukotrienes and PGD2. (badrani2021cellularinteractionsin pages 1-3, sehanobish2022newconceptsfor pages 1-3, sehanobish2022newconceptsfor pages 9-10)

Acute trigger: aspirin/nonselective NSAID inhibits COX-1 → further loss of PGE2 restraint on eosinophils, mast cells, and 5-LO activity → abrupt amplification of LTC4/LTD4/LTE4 and PGD2 → CysLT-receptor-mediated vascular permeability, mucus secretion, sensory symptoms, and bronchial smooth-muscle contraction. (patel2026anarrativereview pages 2-4, sehanobish2021aspirinactionsin pages 1-2)

Cellular amplification: CysLTs and epithelial injury promote IL-33 release; IL-33 activates mast cells and ILC2s. TSLP stimulates mast-cell PGD2 production; PGD2 acting through CRTH2 recruits or activates eosinophils, basophils, Th2 cells, and ILC2s. ILC2/Th2-derived IL-4, IL-5, and IL-13 sustain eosinophilia, IgE/plasma-cell responses, goblet-cell metaplasia, mucus, edema, bronchial hyperresponsiveness, and polyp growth. Platelet–leukocyte aggregates contribute LTC4S activity and inflammatory recruitment. (badrani2021cellularinteractionsin pages 1-3, badrani2021cellularinteractionsin pages 8-9)

Tissue outcome: persistent epithelial inflammation, edema, extracellular-matrix remodeling and polyp formation in nasal/paranasal mucosa; bronchial hyperresponsiveness and variable airflow obstruction in lower airways; recurrent acute reactions upon COX-1 inhibition.

Biochemical and omics findings

• Lipidomics/metabolomics: elevated baseline and challenge-induced urinary LTE4; elevated PGD2 metabolites; low lipoxin A4; and increased 15-oxo-ETE in AERD nasal polyps. (sehanobish2022newconceptsfor pages 1-3)
• Transcriptomics: RNA-seq of nasal epithelium has identified altered leukotriene-metabolism and epithelial-response genes. (badrani2021cellularinteractionsin pages 8-9)
• Single-cell profiling: IL-5Rα expression is enriched on IgE/IgG4-expressing polyp plasma cells; activated basophils and IL-5Rα-positive plasma cells associate with severe polyposis. A 2024 study further reported a proliferative signature in nasal-polyp antibody-secreting cells, supporting local adaptive-immune activity rather than proving a causal autoantibody. (sehanobish2022newconceptsfor pages 1-3, badrani2021cellularinteractionsin pages 8-9)
• Macrophages: persistent pro-inflammatory activation of alveolar monocyte-derived macrophages is a proposed contributor. (sehanobish2022newconceptsfor pages 1-3)
• Spatial transcriptomics/CRISPR screens: no clinically mature AERD-specific result was identified.

Suggested annotations include GO:0006690 eicosanoid metabolic process; GO:0002540 leukotriene production involved in inflammatory response; GO:0006954 inflammatory response; GO:0042098 T-cell proliferation; GO:0032615 interleukin-12 production (use only where experimentally supported); and cell terms CL:0000097 mast cell, CL:0000771 eosinophil, CL:0000233 platelet, CL:0001069 group 2 innate lymphoid cell, CL:0000787 memory B cell, CL:0000786 plasma cell, CL:0000235 macrophage, CL:0002633 respiratory airway epithelial cell.

7. Anatomical structures affected

Primary sites are the nasal cavity, paranasal sinus mucosa, nasal polyps, and bronchial airways. Suggested UBERON mappings include UBERON:0001707 nasal cavity, UBERON:0001825 paranasal sinus, UBERON:0001988 nasal mucosa, UBERON:0002185 bronchus, and UBERON:0002048 lung. Disease is ordinarily bilateral/diffuse rather than unilateral; unilateral polyposis should prompt an alternative diagnosis. Secondary involvement may include the middle ear and Eustachian tube.

Affected tissues comprise pseudostratified respiratory epithelium, polyp stroma, submucosal vasculature, mucus glands, airway smooth muscle, and resident/infiltrating immune compartments. Relevant subcellular sites include plasma membrane receptors, cytosolic arachidonic-acid enzymes, nuclear transcriptional machinery, and secretory granules of mast cells/eosinophils; there is no defining mitochondrial, lysosomal, or protein-aggregation lesion. Increased sphenoid bone thickness has been reported, probably reflecting chronic inflammatory remodeling (PMID 32660262). (sehanobish2022newconceptsfor pages 9-10)

8. Temporal development

A typical sequence is persistent rhinitis/sinus symptoms, development of asthma, recurrent polyps, and recognition of NSAID reactions, although the order varies. Onset is generally insidious during the third–fourth decades rather than congenital or pediatric. The chronic component is lifelong and progressive/fluctuating; acute drug reactions are episodic. Polyps commonly recur after surgery without sustained anti-inflammatory treatment. Up to 40% of patients in some CRSwNP cohorts may develop or have aspirin sensitivity recognized during follow-up. (li2019aspirinexacerbatedrespiratory pages 1-3, levy2016contemporarymanagementof pages 1-2)

There is no formal staging system analogous to cancer staging. Practical severity domains are asthma control/exacerbations, systemic-corticosteroid burden, endoscopic polyp score, CT Lund–Mackay score, smell function, SNOT-22, prior surgery, and drug-reaction severity. Remission is usually treatment-induced and domain-specific; “cure” is uncommon. Important intervention windows include disease recognition before inadvertent NSAID exposure, postoperative control before rapid polyp regrowth, and biologic or aspirin-therapy escalation before repeated systemic steroid use.

9. Inheritance and population epidemiology

AERD prevalence is approximately 0.3–0.9% in the general US population, ~7% among adults with asthma, and ~15% among severe asthma, with estimates of 8–26% among CRSwNP and approximately 10% among nasal-polyp populations. Challenge-based studies generally detect more disease than history alone; roughly 12% may remain undiagnosed in some asthma settings. (badrani2021cellularinteractionsin pages 1-3, li2019aspirinexacerbatedrespiratory pages 1-3, sehanobish2021aspirinactionsin pages 1-2, levy2016contemporarymanagementof pages 1-2)

Incidence per 100,000 person-years is not reliably established. Women predominate at roughly 3:2. AERD occurs globally; apparent geographic or ethnic differences may reflect referral, NSAID use, diagnostic challenge availability, and genetic background. No robust geographic founder variant is known.

Inheritance is multifactorial/polygenic with incomplete and poorly quantified familial aggregation. Mendelian penetrance, carrier status, anticipation, mosaicism, and consanguinity are not applicable.

10. Diagnostics

Clinical criteria and reference testing

A confident clinical diagnosis requires asthma/variable airflow obstruction, objective CRSwNP or chronic eosinophilic sinus disease, and repeated convincing respiratory reactions to at least one—and preferably multiple—COX-1 inhibitors. Where exposure history is absent, ambiguous, or discordant, a supervised graded aspirin challenge is the reference standard. Oral challenge is most widely used; nasal lysine-aspirin and bronchial protocols are available in specialized settings. Challenge requires stable asthma, baseline spirometry, trained staff, and rescue capability. (li2019aspirinexacerbatedrespiratory pages 1-3, sehanobish2022newconceptsfor pages 9-10)

Tests should include:

• spirometry with bronchodilator response and serial FEV1 during challenge;
• nasal endoscopy for bilateral polyps;
• sinus CT for extent and surgical planning—not for aspirin sensitivity itself;
• CBC with differential, total IgE, and FeNO for inflammatory phenotyping, not confirmation;
• urinary LTE4 as an adjunctive research/specialty biomarker.

A 2022 meta-analysis included 3,376 participants—1,354 N-ERD, 1,420 aspirin-tolerant asthma, and 602 healthy controls. Baseline uLTE4 was higher in N-ERD than aspirin-tolerant asthma (SMD 0.80, 95% CI 0.72–0.89); it rose after aspirin challenge in N-ERD (SMD 0.56, 95% CI 0.26–0.85) but not meaningfully in aspirin-tolerant asthma (SMD 0.12, 95% CI −0.08–0.33). Heterogeneous assays and thresholds prevent stand-alone diagnosis. (patel2026anarrativereview pages 2-4)

Pathology and differential diagnosis

Polyps usually show marked eosinophilic/type-2 inflammation, edema, epithelial abnormalities, mast cells and plasma cells, but histology is not specific. Differential diagnoses include aspirin-tolerant eosinophilic CRSwNP with asthma, IgE-mediated single-NSAID allergy, NSAID-induced urticaria/angioedema without airway disease, allergic fungal rhinosinusitis, eosinophilic granulomatosis with polyangiitis, cystic fibrosis, primary ciliary dyskinesia, immunodeficiency, and unilateral neoplasm.

There is no population, newborn, carrier, prenatal, or genetic screening program. Targeted case-finding among adults with severe asthma plus recurrent bilateral polyps is appropriate.

11. Outcome and prognosis

AERD generally does not have a defined disease-specific reduction in life expectancy, 5-year survival, or mortality rate. Its major burden is morbidity: severe asthma, systemic corticosteroid exposure, repeated sinus surgery, persistent anosmia, sleep disruption, middle-ear disease, restricted analgesic options, emergency care, and impaired work/social functioning. Compared with aspirin-tolerant asthma or CRSwNP, patients have more corticosteroid use, hospitalizations, lower FEV1, severe recurrent polyposis, and poorer quality of life. (sehanobish2021aspirinactionsin pages 1-2, levy2016contemporarymanagementof pages 1-2)

Poor prognostic features include severe or uncontrolled asthma, high polyp burden, prior revision surgery, persistent eosinophilia/type-2 inflammation, high urinary LTE4, inadequate topical therapy, and failure or intolerance of aspirin maintenance. No biomarker has sufficient validation to predict individual progression. Prognosis improves substantially with coordinated allergy/pulmonology/otolaryngology care, although responses to aspirin therapy and biologics remain heterogeneous.

12. Treatment and real-world implementation

Baseline algorithm

1. Confirm asthma, CRSwNP, and the NSAID-reaction phenotype.
2. Avoid strong COX-1 inhibitors until evaluated; provide written drug-safety guidance and suitable analgesic alternatives.
3. Optimize inhaled corticosteroid-containing asthma treatment, bronchodilators, intranasal corticosteroid, saline irrigation, and short systemic-steroid courses only when necessary.
4. Add a leukotriene receptor antagonist such as montelukast or 5-LO inhibitor zileuton, especially around challenge/desensitization.
5. Perform endoscopic sinus surgery for obstructive/uncontrolled disease and to improve topical drug access.
6. For persistent disease, choose aspirin desensitization/maintenance, biologic therapy, or both according to asthma/polyp severity, bleeding and gastrointestinal risk, aspirin need, prior response, cost, pregnancy plans, and patient preference.

Suggested NCIt mappings include corticosteroid therapy, leukotriene-receptor antagonist therapy, monoclonal-antibody therapy, aspirin desensitization, endoscopic sinus surgery, and supportive care; exact NCIt concept IDs should be validated against the current NCIt release rather than inferred.

Aspirin desensitization and aspirin therapy after desensitization

Desensitization followed by uninterrupted daily aspirin can reduce sinonasal symptoms, polyp recurrence, systemic steroid use, asthma morbidity, emergency visits, and repeat surgery in selected patients, especially when performed after adequate sinus surgery. Review-level evidence suggests reduction in polyp recurrence in more than 70% of treated patients, although protocols, doses, and outcome definitions vary. (sehanobish2021aspirinactionsin pages 1-2, sehanobish2022newconceptsfor pages 9-10)

A 2023 Chilean prospective cohort of 12 patients treated with sinus surgery, desensitization, and maintenance aspirin found sustained SNOT-22 improvement (p=0.002), reduced polyp score (p=0.001), only three small recurrences, and a 6.6-point Lund–Mackay reduction (p<0.001) at one year. Adverse effects occurred in 75%, most often abdominal pain (66.7%), but no participant discontinued during follow-up. This small uncontrolled study supports feasibility, not comparative superiority.

Contraindications or cautions include active peptic ulceration, bleeding disorder, anticoagulation conflicts, uncontrolled asthma, pregnancy, inability to adhere, and prior severe aspirin toxicity. Loss of doses can reverse tolerance.

Biologics

None is uniquely AERD-approved; use follows severe-asthma and/or CRSwNP indications.

• Dupilumab blocks IL-4Rα and therefore IL-4/IL-13 signaling. In a 2023 open-label study, after six months 23% (7/30) achieved complete aspirin tolerance and 33% (10/30) tolerated higher doses. Total polyp score changed by −2.68±1.84, asthma-control score by +2.34±3.67, and smell score by +11.16±9.54 (all p<0.001). Increased tolerance was associated with lower uLTE4 and reduced eotaxin-1, CCL17, IL-5, IL-17A, and IL-6. The abstract conclusion states: “Dupilumab improves aspirin hypersensitivity in over 50% of patients.” (schneider2023dupilumabincreasesaspirin pages 14-14, schneider2023dupilumabincreasesaspirin pages 13-14)
• Omalizumab neutralizes free IgE. In a double-blind randomized crossover trial of 16 challenge-confirmed patients, aspirin-challenge uLTE4 exposure fell from a median 80.8 on placebo to 51.1 during omalizumab (p<0.001); 10/16 (62.5%) tolerated cumulative aspirin doses up to 930 mg. This demonstrates that IgE-pathway modulation can suppress reactions even though AERD is not a conventional aspirin-specific IgE allergy.
• Mepolizumab and benralizumab target IL-5 or IL-5Rα and can improve eosinophilic asthma and CRSwNP, but AERD response is variable. A 2023 perioperative series reported that mepolizumab did not reliably prevent polyp regrowth; this cautions against assuming that eosinophil depletion controls every AERD pathway.
• Tezepelumab, targeting TSLP, reduced annualized exacerbations by 83% (95% CI 66–91) in the aspirin/NSAID-sensitive subgroup of the 2024 NAVIGATOR severe-asthma analysis. This is hypothesis-supporting subgroup evidence, not an AERD-specific prospective trial.

Expert reviews emphasize that there is no definitive evidence that biologics must always precede aspirin desensitization or vice versa. Dupilumab often provides the broadest simultaneous benefit for smell, polyps, and asthma, whereas aspirin therapy is inexpensive and may be particularly valuable after surgery or when aspirin is required for cardiovascular indications. Choice should be individualized. (sehanobish2022newconceptsfor pages 1-3)

Current experimental approaches and trials

Retrieved AERD-specific ClinicalTrials.gov records include dupilumab mechanism/efficacy studies NCT03595488, NCT04442256, and NCT05031455; thromboxane-receptor antagonist ifetroban safety NCT02216357; low-salicylate diet NCT01540032/NCT01778465; nasal microbiome NCT04375293; genetics/genomics NCT04261582; microRNA NCT01631773; IL-5R signaling in upper-airway cells NCT05672030; sleep after sinonasal surgery NCT03627481; and aspirin therapy/SARS-CoV-2 susceptibility NCT05797597. These records include small mechanistic trials and observational studies and do not establish routine care.

A 2023 translational study found that the GLP-1R agonist liraglutide reduced lysine-aspirin-induced airway resistance and platelet activation/recruitment in an AERD-like mouse model and attenuated thromboxane-agonist activation in platelets from 31 patients with AERD and 11 controls. This supports the platelet–GLP-1R axis as a candidate target but not off-label clinical treatment. (badrani2021cellularinteractionsin pages 1-3)

Gene therapy, cell therapy, RNA therapeutics, CRISPR treatment, and transplantation have no established role.

13. Prevention

Primary prevention: no intervention is known to prevent initial disease development. There is no vaccine or validated genetic/lifestyle prevention program.

Secondary prevention: recognize the combination of adult-onset asthma, recurrent bilateral polyps, anosmia, and NSAID or alcohol reactions; confirm uncertain cases before inadvertent exposure. Maintain a precise medication record distinguishing cross-reactive COX-1 intolerance from single-drug IgE allergy.

Tertiary prevention: avoid unplanned strong COX-1 exposure; use a medical-alert plan; optimize inhaled and topical therapy; control polyps early; use leukotriene modifiers around planned challenge; consider surgery, biologics, or aspirin desensitization to reduce recurrence and steroid toxicity. Patients who have been desensitized require continuous prescribed aspirin and instructions for missed doses. Standard immunizations are appropriate for asthma health but do not prevent AERD.

14. Other species and natural disease

No well-characterized naturally occurring veterinary equivalent of the full human AERD triad was identified in dogs, cats, livestock, or wildlife. Consequently, there is no established breed/VBO association, zoonotic transmission, cross-species natural epidemiology, or veterinary carrier state. Aspirin pharmacology and orthologous eicosanoid genes are conserved, but this does not establish naturally occurring AERD. The condition is noninfectious and nontransmissible.

15. Model organisms and experimental systems

The principal in-vivo system is an induced murine AERD-like model, commonly involving allergic airway inflammation/eosinophilia followed by lysine-aspirin challenge. It can reproduce acute airway-resistance increases, mast-cell activation, platelet recruitment, IL-33 dependence, PGD2/CysLT release, and response to pathway inhibition. Murine work supports a sequence in which LTE4 promotes epithelial IL-33, followed by mast-cell activation and acute bronchoconstriction. (badrani2021cellularinteractionsin pages 1-3)

Genetic knockouts or pathway perturbations involving PGE synthase/EP receptors, leukotriene receptors, IL-33/ST2, mast cells, platelets, or ILC2s are mechanistic models rather than complete disease replicas. Ex-vivo systems include patient platelets, eosinophils, mast cells, nasal epithelial cultures, polyp explants, fibroblasts, and peripheral blood; omics systems include bulk RNA-seq, single-cell RNA-seq, metabolomics, and lipid mediator profiling. (badrani2021cellularinteractionsin pages 8-9, sehanobish2022newconceptsfor pages 9-10)

Limitations are substantial: mice do not spontaneously develop the full adult-onset sequence of asthma, bilateral recurrent polyposis, and human NSAID intolerance; induced sensitization and aspirin dosing differ from clinical disease; and no model captures long-term surgery–polyp recurrence or heterogeneous biologic response. No validated zebrafish, Drosophila, C. elegans, yeast, iPSC, or organoid model currently recapitulates the complete syndrome.

Evidence-quality conclusions and key gaps

The strongest clinical evidence supports challenge-based diagnosis, uLTE4 as an adjunct rather than replacement biomarker, coordinated upper/lower-airway treatment, postoperative aspirin desensitization in selected patients, and use of asthma/CRSwNP-approved biologics. The most important 2023–2024 developments are dupilumab-associated improvement in aspirin tolerance, the tezepelumab signal in NSAID-sensitive severe asthma, GLP-1R/platelet translational findings, and single-cell evidence of proliferative antibody-secreting cells in AERD polyps. These advances refine endotyping but do not yet provide a curative treatment or definitive molecular diagnostic. (sehanobish2022newconceptsfor pages 1-3, schneider2023dupilumabincreasesaspirin pages 14-14, schneider2023dupilumabincreasesaspirin pages 13-14)

Major unresolved questions include why the syndrome begins in adulthood, which epithelial or immune abnormalities are initiating rather than secondary, how to select aspirin therapy versus a specific biologic, whether combination therapy modifies natural history, and which biomarkers predict durable remission. There remain no validated causal variants, protective variants, AERD-specific mortality estimates, population incidence rates, or natural animal disease models.

References

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8. (patel2026anarrativereview pages 2-4): Preena Ketan Patel, Aagat Sharma Khatiwada, Peter J Andrews, Glenis K Scadding, and Alfonso Luca Pendolino. A narrative review of recent developments in aspirin therapy after desensitization in nsaids-exacerbated respiratory disease. Journal of Inflammation Research, Volume 19:1-23, Aug 2026. URL: https://doi.org/10.2147/jir.s620047, doi:10.2147/jir.s620047. This article has 0 citations and is from a peer-reviewed journal.

9. (schneider2023dupilumabincreasesaspirin pages 13-14): Sven Schneider, Katharina Poglitsch, Christina Morgenstern, Tamara Quint, Katharina Gangl, Christoph Sinz, Tina Bartosik, Nicholas James Campion, David Tianxiang Liu, Lukas David Landegger, Aldine Tu, Victoria Stanek, Marianne Rocha-Hasler, Christine Bangert, and Julia Eckl-Dorna. Dupilumab increases aspirin tolerance in nsaid-exacerbated respiratory disease. The European Respiratory Journal, 61:2201335, Dec 2023. URL: https://doi.org/10.1183/13993003.01335-2022, doi:10.1183/13993003.01335-2022. This article has 43 citations.

10. (schneider2023dupilumabincreasesaspirin pages 14-14): Sven Schneider, Katharina Poglitsch, Christina Morgenstern, Tamara Quint, Katharina Gangl, Christoph Sinz, Tina Bartosik, Nicholas James Campion, David Tianxiang Liu, Lukas David Landegger, Aldine Tu, Victoria Stanek, Marianne Rocha-Hasler, Christine Bangert, and Julia Eckl-Dorna. Dupilumab increases aspirin tolerance in nsaid-exacerbated respiratory disease. The European Respiratory Journal, 61:2201335, Dec 2023. URL: https://doi.org/10.1183/13993003.01335-2022, doi:10.1183/13993003.01335-2022. This article has 43 citations.

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