Aspirin-Exacerbated Respiratory Disease

Complex MONDO:0008834 Pathograph 16 Show in embeddings browser Asthma

An adult-onset, chronic inflammatory disease of the unified upper and lower airway defined by the triad of eosinophilic asthma, chronic rhinosinusitis with bilateral nasal polyposis, and reproducible respiratory reactions to aspirin and other strong cyclooxygenase-1 (COX-1) inhibitors. The reaction is pharmacologic rather than IgE-mediated: patients carry a chronically dysregulated arachidonic-acid network — constitutively elevated cysteinyl leukotriene production, driven in part by markedly increased bronchial LTC4 synthase expression, together with loss of the restraining prostaglandin E2 (PGE2) signal on inflammatory cells — and COX-1 inhibition removes the residual PGE2 brake, releasing an abrupt surge of cysteinyl leukotrienes; mast cell activation supplies a parallel prostaglandin D2 arm that is both eosinophil-recruiting and directly bronchoconstrictive. Because the underlying disease is present before any NSAID exposure, avoiding NSAIDs prevents acute reactions but does not arrest the asthma or the polyp disease.

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1
Inheritance
9
Pathophys.
6
Phenotypes
2
Gaps
16
Pathograph
5
Medical Actions
1
Deep Research
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Classifications

Harrison's Part
RESPIRATORY
👪

Inheritance

1
Multifactorial
AERD is a complex multifactorial disease. No causal gene, Mendelian inheritance pattern, penetrance estimate or clinically actionable genotype is established; reported candidate-gene associations (LTC4S, ALOX5, CYSLTR1, PTGER2 among others) are population-dependent susceptibility signals that frequently fail replication and should not be curated as causal alleles.
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Discussions and Knowledge Gaps

2
What makes the AERD airway overexpress LTC4 synthase in the first place, and why does the disease begin in adulthood rather than childhood?
KNOWLEDGE GAP aerd_initiating_lesion
Attached to
pathophysiology#Bronchial LTC4 Synthase Overexpression
The LTC4 synthase excess and the EP2 deficit are both well documented as present in established disease, but neither has been shown to be the initiating lesion, and no causal genetic variant explains them. Without an initiating event the model cannot say why a previously healthy adult develops AERD, nor identify a window for prevention.
By what mechanism does continuous high-dose aspirin suppress the chronic inflammation it acutely provokes?
KNOWLEDGE GAP aerd_desensitization_mechanism
Attached to
treatments#Aspirin desensitization followed by maintenance aspirin
Desensitization is clinically effective and the tolerant state is maintained only while aspirin continues, but the randomized trial that demonstrated symptomatic benefit found no accompanying change in serum IL-10, IFN-gamma or TGF-beta. The mediator through which maintenance aspirin acts is therefore unresolved, which is why response cannot yet be predicted or monitored biochemically.
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Pathophysiology

9
Bronchial LTC4 Synthase Overexpression
The defining upstream lesion is a markedly increased number of cells expressing LTC4 synthase, the terminal enzyme of cysteinyl leukotriene synthesis, in the bronchial mucosa. Counts are roughly fivefold higher than in aspirin-tolerant asthma and eighteenfold higher than in normal subjects, while 5-lipoxygenase, FLAP, LTA4 hydrolase, COX-1 and COX-2 staining are indistinguishable between groups. This gives the AERD airway an enzymatic capacity for cysteinyl leukotriene overproduction that aspirin-tolerant asthmatic airways lack, and it is the reason the same COX-1 inhibition produces bronchoconstriction only in these patients.
mast cell CL:0000097 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mast cell (CL:0000097). CL:0000097 is a cell type from the Cell Ontology. eosinophil CL:0000771 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves eosinophil (CL:0000771). CL:0000771 is a cell type from the Cell Ontology.
leukotriene biosynthetic process GO:0019370 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased leukotriene biosynthetic process (GO:0019370). GO:0019370 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Constitutive Cysteinyl Leukotriene Overproduction Excess terminal synthase capacity raises baseline cysteinyl leukotriene output in the airway.
COX-1 Inhibition Unmasking Reaction Permissive rather than initiating: COX-1 inhibition lifts PGE2 restraint in everyone, but only an airway carrying this excess terminal synthase capacity converts that into a marked cysteinyl leukotriene surge. This edge is what makes the acute reaction a property of the primed airway rather than of the drug.
Show evidence (3 references)
PMID:9466979 SUPPORT Human Clinical
"Counts of cells expressing the terminal enzyme for cys-LT synthesis, LTC4 synthase, were fivefold higher in AIA biopsies"
Directly quantifies the LTC4 synthase overexpression that defines this node.
PMID:9466979 SUPPORT Human Clinical
"Immunostaining for 5-lipoxygenase, its activating protein (FLAP), LTA4 hydrolase, cyclooxygenase (COX)-1, and COX-2 did not differ."
Establishes that the enzymatic abnormality is specific to LTC4 synthase rather than a general upregulation of eicosanoid enzymes.
PMID:30884882 SUPPORT Human Clinical
"These IFN-γ differentiated eosinophils also have significantly increased levels of LTC4 synthase (LTC4S), possibly explaining the increased levels of Cys-LTs in AERD."
Identifies infiltrating eosinophils as one cellular source of the raised LTC4 synthase activity.
Loss of Prostaglandin E2 Restraint
PGE2 normally brakes cysteinyl leukotriene production by airway inflammatory cells through the EP2 receptor. In AERD this brake is defective at the receptor level: the proportion of neutrophils, mast cells, eosinophils and T cells expressing EP2 is significantly reduced in aspirin-sensitive compared with non-aspirin-sensitive rhinosinusitis, even though global mucosal EP2 expression on epithelial and goblet cells is elevated in both. The defect is therefore a cell-type-specific loss of PGE2 responsiveness in the effector leukocytes, not a global absence of the receptor.
mast cell CL:0000097 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mast cell (CL:0000097). CL:0000097 is a cell type from the Cell Ontology. eosinophil CL:0000771 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves eosinophil (CL:0000771). CL:0000771 is a cell type from the Cell Ontology. neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
prostaglandin E receptor activity GO:0004957 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased prostaglandin E receptor activity (GO:0004957). GO:0004957 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Constitutive Cysteinyl Leukotriene Overproduction Reduced EP2-mediated inhibition permits sustained cysteinyl leukotriene output at baseline.
Show evidence (2 references)
PMID:16461132 SUPPORT Human Clinical
"the percentages of neutrophils, mast cells, eosinophils, and T cells expressing EP(2), but not EP(1), EP(3), or EP(4), were significantly reduced (P < or = .04) in the aspirin-sensitive compared with nonaspirin-sensitive patients"
Localizes the EP2 deficit specifically to inflammatory cells in aspirin-sensitive patients.
PMID:17508965 SUPPORT In Vitro
"mast cells from AERD patients produced significantly more cys-LTs (6.9 +/- 2.0 ng/10(6) cells) than normal and ATA subjects"
Demonstrates the excess cysteinyl leukotriene output of AERD mast cells that PGE2 normally restrains.
Constitutive Cysteinyl Leukotriene Overproduction
The combination of excess LTC4 synthase capacity and a defective PGE2 brake leaves the AERD airway producing cysteinyl leukotrienes (LTC4, LTD4, LTE4) continuously, before and independent of any drug exposure. Baseline cysteinyl leukotriene concentrations in bronchoalveolar lavage fluid are elevated and correlate uniquely with bronchial LTC4 synthase cell counts, which is what ties the enzymatic lesion to the mediator excess.
mast cell CL:0000097 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mast cell (CL:0000097). CL:0000097 is a cell type from the Cell Ontology.
leukotriene metabolic process GO:0006691 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased leukotriene metabolic process (GO:0006691). GO:0006691 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
IL-33-Dependent Mast Cell Activation Cysteinyl leukotrienes drive epithelial IL-33 expression, which in turn activates airway mast cells.
Eosinophilic Airway Inflammation and Polyp Formation Sustained cysteinyl leukotriene signaling supports the chronic eosinophilic inflammation and polyp growth.
Show evidence (1 reference)
PMID:9466979 SUPPORT Human Clinical
"Enhanced baseline cys-LT levels in bronchoalveolar lavage (BAL) fluid of AIA patients correlated uniquely with bronchial counts of LTC4 synthase+ cells"
Links elevated baseline cysteinyl leukotrienes to the LTC4 synthase lesion in the same patients.
IL-33-Dependent Mast Cell Activation
AERD nasal polyps show markedly increased epithelial expression of the alarmin IL-33 compared with aspirin-tolerant polyps. In the ptges-null mouse model, deleting LTC4 synthase abolishes the raised IL-33 and sharply reduces eosinophilia and baseline mast cell product secretion, placing IL-33 downstream of cysteinyl leukotrienes; lysine-aspirin challenge of the same mice then induces IL-33-dependent mast cell activation and bronchoconstriction. This is the step that converts a lipid-mediator excess into an innate type 2 cellular response.
mast cell CL:0000097 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mast cell (CL:0000097). CL:0000097 is a cell type from the Cell Ontology. group 2 innate lymphoid cell CL:0001069 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves group 2 innate lymphoid cell (CL:0001069). CL:0001069 is a cell type from the Cell Ontology.
mast cell activation GO:0045576 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased mast cell activation (GO:0045576). GO:0045576 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Eosinophilic Airway Inflammation and Polyp Formation Activated mast cells and ILC2s sustain the type 2 cytokine milieu driving eosinophilia and polyp growth.
Mast Cell Prostaglandin D2 Release Mast cell activation is what releases prostaglandin D2, opening the second mediator arm.
Show evidence (2 references)
PMID:26342029 SUPPORT Human Clinical
"patients with AERD have markedly increased epithelial expression of the alarmin-like cytokine IL-33 in nasal polyps, as compared with polyps from aspirin-tolerant control subjects"
Establishes the raised epithelial IL-33 in human AERD polyps.
PMID:26342029 SUPPORT Model Organism
"Deletion of leukotriene C4 synthase, the terminal enzyme needed to generate cysLTs, eliminates the increased IL-33 content of the ptges(-/-) lungs and sharply reduces pulmonary eosinophilia and basal secretion of MC products."
Mouse genetic evidence placing IL-33 causally downstream of cysteinyl leukotrienes.
Platelet-Adherent Leukocyte Transcellular Synthesis
A second, independent route to the same cysteinyl leukotriene excess. Platelet-adherent eosinophils, neutrophils and monocytes are markedly more frequent in AERD than in aspirin-tolerant controls, and the adherent platelets themselves carry more than half of peripheral blood granulocyte LTC4 synthase activity. Because platelets supply the terminal synthase to leukocytes that lack it, this is transcellular biosynthesis rather than a change in any single cell's own program, and it explains part of the cysteinyl leukotriene burden that bronchial LTC4 synthase counts alone do not.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology. neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology. eosinophil CL:0000771 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves eosinophil (CL:0000771). CL:0000771 is a cell type from the Cell Ontology.
leukotriene biosynthetic process GO:0019370 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased leukotriene biosynthetic process (GO:0019370). GO:0019370 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Constitutive Cysteinyl Leukotriene Overproduction Platelet-supplied LTC4 synthase activity adds to the airway's cysteinyl leukotriene output independently of bronchial mucosal enzyme counts.
Show evidence (2 references)
PMID:30884882 SUPPORT Human Clinical
"They noted that platelet-adherent eosinophils, neutrophils, and monocytes were markedly increased in AERD patients relative to aspirin-tolerant controls and that urinary LTE4 correlates strongly with the frequency of platelet-adherent neutrophils, eosinophils, and monocytes."
Establishes the excess of platelet-adherent leukocytes in AERD and its correlation with the urinary cysteinyl leukotriene end-product.
PMID:30884882 SUPPORT Human Clinical
"Moreover, their experiments found that adherent platelets expressed more than half of the peripheral blood granulocyte LTC4S activity"
Quantifies the platelet contribution to granulocyte LTC4 synthase activity, which is what makes the synthesis transcellular.
Mast Cell Prostaglandin D2 Release
The second mediator arm alongside the cysteinyl leukotrienes. Activated mast cells release prostaglandin D2, which both recruits eosinophils and Th2 cells to the respiratory epithelium and is itself strongly bronchoconstrictive. PGD2 is therefore not a bystander marker of mast cell activation but a parallel effector, and it is part of why the acute reaction is not fully abolished by leukotriene-pathway blockade alone.
mast cell CL:0000097 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mast cell (CL:0000097). CL:0000097 is a cell type from the Cell Ontology.
prostaglandin biosynthetic process GO:0001516 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased prostaglandin biosynthetic process (GO:0001516). GO:0001516 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Eosinophilic Airway Inflammation and Polyp Formation PGD2 recruits eosinophils and Th2 cells into the respiratory epithelium.
Acute Bronchoconstriction and Upper Airway Reaction PGD2 is directly bronchoconstrictive and contributes to the acute reaction alongside the cysteinyl leukotrienes.
Show evidence (1 reference)
PMID:30884882 SUPPORT Human Clinical
"activated mast cells release a host of inflammatory mediators such as prostaglandin D2 (PGD2), which induces inflammation of the respiratory epithelium through recruitment of eosinophils and Th2 cells and also harbors highly bronchoconstrictive properties"
Establishes PGD2 release from activated mast cells and its two effects, eosinophil/Th2 recruitment and bronchoconstriction.
COX-1 Inhibition Unmasking Reaction
Ingestion of aspirin or another strong COX-1 inhibitor removes the residual PGE2 restraint on 5-lipoxygenase activity in an airway already primed with excess LTC4 synthase, producing an abrupt surge of cysteinyl leukotrienes and the acute upper- and lower-airway reaction. Lysine-aspirin challenge releases additional cysteinyl leukotrienes into bronchoalveolar lavage fluid in aspirin-intolerant but not aspirin-tolerant asthmatics, and bronchial responsiveness to lysine-aspirin correlates exclusively with LTC4 synthase cell counts. This node is the acute, drug-triggered arm of the disease and is what diagnostic aspirin provocation deliberately elicits.
cyclooxygenase pathway GO:0019371 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cyclooxygenase pathway (GO:0019371). GO:0019371 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Acute Bronchoconstriction and Upper Airway Reaction The cysteinyl leukotriene surge acts on CysLT receptors to produce bronchospasm, mucus secretion and nasal symptoms.
Show evidence (2 references)
PMID:9466979 SUPPORT Human Clinical
"Lysine-aspirin challenge released additional cys-LTs into BAL fluid in AIA patients (200+/-120 pg/ml, n = 8) but not in ATA patients"
Shows the acute cysteinyl leukotriene surge on COX-1 inhibition is specific to aspirin-intolerant patients.
PMID:9466979 SUPPORT Human Clinical
"Aspirin may remove PGE2-dependent suppression in all subjects, but only in AIA patients does increased bronchial expression of LTC4 synthase allow marked overproduction of cys-LT"
States the two-hit model in which COX-1 inhibition is permissive and LTC4 synthase excess is the determinant.
Acute Bronchoconstriction and Upper Airway Reaction
The clinical reaction following COX-1 inhibition — nasal obstruction, rhinorrhea, conjunctival symptoms, cough, wheeze and a fall in FEV1, and occasionally laryngospasm or hypotension. It is mediated by cysteinyl leukotrienes acting on CysLT receptors rather than by drug-specific IgE, which is why it reproduces with structurally unrelated strong COX-1 inhibitors and why selective COX-2 inhibitors are usually tolerated.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:26342029 SUPPORT Human Clinical
"involves overproduction of cysteinyl leukotrienes (cysLTs), activation of airway mast cells (MCs), and bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic PGE2"
Describes the acute bronchoconstrictive reaction and its mediator basis.
Eosinophilic Airway Inflammation and Polyp Formation
The chronic arm of the disease: persistent eosinophilic inflammation of the sinonasal and bronchial mucosa with oedema, extracellular-matrix remodelling and bilateral nasal polyp growth, together with bronchial hyperresponsiveness. This component is present independent of NSAID exposure and is what continues to progress in patients who simply avoid NSAIDs.
eosinophil CL:0000771 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves eosinophil (CL:0000771). CL:0000771 is a cell type from the Cell Ontology.
eosinophil chemotaxis GO:0048245 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased eosinophil chemotaxis (GO:0048245). GO:0048245 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:26342029 SUPPORT Human Clinical
"Aspirin-exacerbated respiratory disease (AERD), a severe eosinophilic inflammatory disorder of the airways"
Characterizes AERD as a severe eosinophilic airway inflammatory disorder.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Aspirin-Exacerbated Respiratory Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

6
Blood 1
Eosinophilia FREQUENT Increased total eosinophil count HP:0001880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eosinophilia, annotated with Increased total eosinophil count (HP:0001880). HP:0001880 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30884882 SUPPORT Human Clinical
"The increased IFN-γ has also been shown to stimulate differentiation of eosinophils through interferon consensus sequence binding protein, a transcription factor, leading to a dramatic upregulation in the number of infiltrating eosinophils"
Documents the marked increase in infiltrating eosinophils in AERD and the mechanism driving it.
Head and Neck 3
Nasal polyposis OBLIGATE HP:0100582 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nasal polyposis (HP:0100582). HP:0100582 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25282015 SUPPORT Human Clinical
"Aspirin-exacerbated respiratory disease (AERD) is manifested by adult-onset asthma, nasal polyposis, chronic rhinosinusitis, and aspirin sensitivity."
Names nasal polyposis as a defining manifestation of AERD.
Chronic rhinosinusitis VERY_FREQUENT Chronic sinusitis HP:0011109 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic sinusitis (HP:0011109). HP:0011109 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25282015 SUPPORT Human Clinical
"Aspirin-exacerbated respiratory disease (AERD) is manifested by adult-onset asthma, nasal polyposis, chronic rhinosinusitis, and aspirin sensitivity."
Names chronic rhinosinusitis as a defining manifestation of AERD.
Anosmia FREQUENT HP:0000458 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anosmia (HP:0000458). HP:0000458 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36549708 SUPPORT Human Clinical
"olfactory performance improved (University of Pennsylvania Smell Identification Test: +11.16±9.54, p<0.001) in all patients after therapy"
Olfactory dysfunction is a measured, treatment-responsive feature of the N-ERD cohort.
Other 2
Adult-onset asthma OBLIGATE HP:0002099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthma (HP:0002099). HP:0002099 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25282015 SUPPORT Human Clinical
"Aspirin-exacerbated respiratory disease (AERD) is manifested by adult-onset asthma, nasal polyposis, chronic rhinosinusitis, and aspirin sensitivity."
Names adult-onset asthma as a defining manifestation of AERD.
PMID:30884882 SUPPORT Human Clinical
"Generally, AERD manifests in the third or fourth decade of life"
Establishes the adult age of onset asserted in the entry description.
Aspirin-induced respiratory reaction OBLIGATE Aspirin-induced asthma HP:0012042 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aspirin- and NSAID-induced respiratory reaction, annotated with Aspirin-induced asthma (HP:0012042). HP:0012042 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26342029 SUPPORT Human Clinical
"bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic PGE2"
Describes the reproducible reaction to nonselective COX inhibitors that defines the hypersensitivity component.
💊

Medical Actions

5
Montelukast
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: montelukast CHEBI:50730 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses montelukast (CHEBI:50730). CHEBI:50730 is a therapeutic agent from Chemical Entities of Biological Interest.
A CysLT1 receptor antagonist. Together with corticosteroids, leukotriene modifiers are first-line therapy in AERD, which is what a cysteinyl leukotriene-driven disease predicts. Montelukast blocks the receptor rather than the synthesis, so it leaves the mediator excess in place and acts at the last step.
Mechanism Target:
INHIBITS Acute Bronchoconstriction and Upper Airway Reaction — CysLT1 receptor blockade prevents the cysteinyl leukotrienes already present from acting on the airway.
Show evidence (2 references)
PMID:30884882 SUPPORT Human Clinical
"Corticosteroids and leukotriene modifiers are the first line therapies used to treat AERD."
Establishes leukotriene modifiers as first-line AERD therapy.
PMID:30884882 SUPPORT Human Clinical
"FEV-1 showed a statistically significant improvement of 10.2% on average"
Quantifies the spirometric benefit reported in the montelukast randomized trial.
Zileuton
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: zileuton CHEBI:10112 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses zileuton (CHEBI:10112). CHEBI:10112 is a therapeutic agent from Chemical Entities of Biological Interest.
A 5-lipoxygenase inhibitor. Unlike montelukast it acts upstream, cutting cysteinyl leukotriene synthesis rather than blocking the receptor, so it reduces the mediator burden itself. A double-blind crossover trial reported a significant FEV1 rise within hours.
Mechanism Target:
INHIBITS Constitutive Cysteinyl Leukotriene Overproduction — Inhibiting 5-lipoxygenase blocks cysteinyl leukotriene synthesis upstream of the terminal synthase.
Show evidence (1 reference)
PMID:30884882 SUPPORT Human Clinical
"The zileuton arm showed a significant increase in the FEV-1 within hours (12.7% increase, p < 0.01)"
Quantifies the rapid spirometric benefit in the zileuton double-blind crossover trial.
Endoscopic sinus surgery
Action: endoscopic sinus surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is endoscopic sinus surgery (NCIT:C157836). NCIT:C157836 is a clinical intervention from the NCI Thesaurus. Ontology label: Endoscopic Sinus Surgery NCIT:C157836
Removal of polyps and opening of the sinuses. It reduces disease burden directly and creates the conditions for medical therapy to work; in current practice it is paired with post-operative aspirin desensitization rather than used alone, since polyps recur without sustained anti-inflammatory treatment.
Mechanism Target:
BYPASSES Eosinophilic Airway Inflammation and Polyp Formation — Surgery removes the polyp burden mechanically without altering the inflammation that produced it, which is why it is paired with medical therapy.
Show evidence (1 reference)
PMID:30884882 SUPPORT Human Clinical
"ASA desensitization, followed by either 325 mg twice a day or 650 mg twice a day post-endoscopic sinus surgery with polyp removal is now the standard of care for AERD patients"
Establishes surgery followed by aspirin desensitization as the current standard of care.
Aspirin desensitization followed by maintenance aspirin
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: aspirin CHEBI:15365 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses aspirin, annotated with acetylsalicylic acid (CHEBI:15365). CHEBI:15365 is a therapeutic agent from Chemical Entities of Biological Interest.
Graded aspirin administration under supervision induces a temporary pharmacologic tolerant state, maintained only by continuous daily aspirin; interruption permits resensitization. In a randomized double-blind placebo-controlled trial of 34 patients, desensitization followed by 625 mg twice daily for 6 months significantly reduced symptom scores and medication need. Notably the same trial found no accompanying change in serum IL-10, IFN-gamma or TGF-beta, so the clinical benefit is not explained by those systemic cytokines.
Mechanism Target:
INHIBITS Constitutive Cysteinyl Leukotriene Overproduction — Maintenance aspirin durably suppresses the cysteinyl leukotriene-driven chronic inflammation, reducing symptoms and polyp recurrence.
Show evidence (2 references)
PMID:26083948 SUPPORT Human Clinical
"Symptom scores and medication needs of patients with AERD who have undergone AD were significantly lower compared to the placebo group after 6 months"
Randomized placebo-controlled evidence that aspirin desensitization improves symptoms and reduces medication need.
PMID:26083948 SUPPORT Human Clinical
"no significant difference was observed in serum concentration of IL-10, IFN-γ, and TGF-β between two groups neither at baseline nor at the end of study"
The same trial found no systemic cytokine correlate, so the mechanism of benefit is not established by this study.
Dupilumab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dupilumab NCIT:C162455 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses dupilumab (NCIT:C162455). NCIT:C162455 is a therapeutic agent from the NCI Thesaurus.
An anti-IL-4 receptor alpha monoclonal antibody. In a 6-month open-label trial in confirmed N-ERD, dupilumab reduced polyp burden and improved asthma control and olfaction in all patients, and in a subset restored aspirin tolerance — 23% developed complete tolerance and a further 33% tolerated higher doses. Patients who gained tolerance showed falling urinary leukotriene E4, linking the clinical effect back to the cysteinyl leukotriene axis.
Mechanism Target:
INHIBITS Eosinophilic Airway Inflammation and Polyp Formation — Blocking IL-4 receptor alpha suppresses the type 2 cytokine signalling that sustains eosinophilic inflammation and polyp growth.
INHIBITS Constitutive Cysteinyl Leukotriene Overproduction — Patients gaining aspirin tolerance showed a significant fall in urinary leukotriene E4, indicating reduced cysteinyl leukotriene production.
Show evidence (2 references)
PMID:36549708 SUPPORT Human Clinical
"After 6 months of treatment with dupilumab, 23% of patients (n=7 of 30) developed complete aspirin tolerance and an additional 33% of patients (n=10 of 30) tolerated higher doses."
Quantifies the restoration of aspirin tolerance on dupilumab in confirmed N-ERD.
PMID:36549708 SUPPORT Human Clinical
"Patients with increased aspirin tolerance showed a significant decrease in urinary leukotriene E4 levels"
Ties the clinical gain in tolerance to a fall in the cysteinyl leukotriene end-product.
🌍

Environmental Factors

1
Aspirin and non-selective NSAID exposure
Ingestion of aspirin or another strong COX-1 inhibitor is the defining acute trigger. It does not cause the underlying chronic airway disease; it unmasks it.
Show evidence (1 reference)
PMID:26342029 SUPPORT Human Clinical
"bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic PGE2"
Identifies non-selective COX inhibitors as the exposure that provokes the acute reaction.
Mechanism Target:
TRIGGERS COX-1 Inhibition Unmasking Reaction — COX-1 inhibition removes the residual PGE2 restraint on cysteinyl leukotriene production, precipitating the acute reaction.
Show evidence (1 reference)
PMID:9466979 SUPPORT Human Clinical
"Aspirin causes bronchoconstriction in aspirin-intolerant asthma (AIA) patients by triggering cysteinyl-leukotriene (cys-LT) production, probably by removing PGE2-dependent inhibition."
States the triggering relationship between COX-1 inhibition and the cysteinyl leukotriene surge.
🔬

Biochemical Markers

1
Urinary leukotriene E4 (INCREASED)
Context: LTE4 is the stable urinary end-product of the cysteinyl leukotriene pathway and is the central AERD biomarker. It is consistently higher than in aspirin-tolerant asthma and rises further after aspirin challenge. It is not a stand-alone diagnostic test: assay and reporting heterogeneity are substantial, and the source below is explicit that an elevated value only shifts the odds when read alongside clinical features. It is also a treatment-response marker, falling in the dupilumab-treated patients who regained aspirin tolerance.
Pathograph Readouts
Readout Of Constitutive Cysteinyl Leukotriene Overproduction Positive Diagnostic
Urinary LTE4 reports the whole-body cysteinyl leukotriene burden produced by the LTC4 synthase excess and the failed PGE2 brake.
Show evidence (1 reference)
PMID:30884882 SUPPORT Human Clinical
"Increased levels of urinary LTE4 itself is not sufficient for diagnosis of AERD, but when elevated in the context of clinical parameters such as asthma exacerbations and nasal polyposis it nearly doubles the odds of AERD diagnosis"
States both the diagnostic signal and its limitation as a stand-alone test.
Show evidence (1 reference)
PMID:36549708 SUPPORT Human Clinical
"Patients with increased aspirin tolerance showed a significant decrease in urinary leukotriene E4 levels"
Shows urinary LTE4 tracking treatment response, supporting its use as a marker of the cysteinyl leukotriene burden.
🔬

Diagnosis

1
Aspirin provocation challenge
Supervised graded oral (or bronchial/nasal) aspirin provocation is the reference standard when the diagnosis is not already established by a history of repeated unequivocal reactions in a patient with the full triad. No blood, urine, genomic or omics test currently replaces challenge testing.
Show evidence (1 reference)
PMID:30884882 SUPPORT Human Clinical
"However, definitive diagnosis is only achieved through ASA provocation testing."
States that aspirin provocation is the only definitive diagnostic test, which is the claim being made.
📈

Progression

2
Sinonasal onset
Age: Third to fourth decade
Persistent rhinitis and chronic sinus symptoms typically come first, before the asthma or the recognised drug reactions.
Show evidence (1 reference)
PMID:30884882 SUPPORT Human Clinical
"Generally, AERD manifests in the third or fourth decade of life"
Establishes the adult decade of onset for the first phase.
Asthma and aspirin sensitivity
Age: Within about five years of the first respiratory symptoms
Asthma follows the initial respiratory tract symptoms after roughly two years, and aspirin sensitivity is recognised within about five years of onset. The lag matters clinically: a patient can be several years into the disease before the NSAID reaction identifies it.
Show evidence (1 reference)
PMID:30884882 SUPPORT Human Clinical
"On average, asthma developed in patients two years after the initial respiratory tract symptoms appeared, and ASA sensitivity developed within five years of onset"
Gives the observed interval between symptom onset, asthma, and recognised aspirin sensitivity.
📊

Prevalence

3
Adults with asthma
Point Prevalence 7150.0 per 100,000 >1 in 1,000
Pooled prevalence across all study designs in asthmatic populations, 7.15% (95% CI 5.26-9.03%), from a meta-analysis of 27 studies.
Show evidence (1 reference)
PMID:25282015 SUPPORT Human Clinical
"Among all studies in asthmatic patients, regardless of method, the prevalence of AERD was 7.15% (95% CI, 5.26% to 9.03%)"
Meta-analytic pooled prevalence of AERD among asthmatic patients.
Adults with severe asthma
Point Prevalence 14890.0 per 100,000 >1 in 1,000
Highest prevalence stratum in the same meta-analysis, 14.89% (95% CI 6.48-23.29%).
Show evidence (1 reference)
PMID:25282015 SUPPORT Human Clinical
"The prevalence of AERD was highest among patients with severe asthma (14.89% [95% CI, 6.48% to 23.29%])"
Meta-analytic prevalence of AERD in the severe-asthma stratum.
General population, United States
Point Prevalence 600.0 per 100,000 (300.0–900.0) >1 in 1,000
Review-level estimate of 0.3-0.9% of the general US population.
Show evidence (1 reference)
PMID:30884882 SUPPORT Human Clinical
"Aspirin exacerbated respiratory disease affects approximately 0.3⁻0.9% of the general population in the USA and approximately 7% of asthmatic patients."
Review reports the general-population prevalence range for AERD in the USA.
{ }

Source YAML

click to show 
name: Aspirin-Exacerbated Respiratory Disease
creation_date: "2026-08-27T16:00:00Z"
category: Complex
synonyms:
- NSAID-exacerbated respiratory disease
- N-ERD
- Samter triad
- aspirin triad
- aspirin-intolerant asthma
- aspirin-induced asthma
disease_term:
  preferred_term: Aspirin-exacerbated respiratory disease
  term:
    id: MONDO:0008834
    label: asthma, nasal polyps, and aspirin intolerance
parents:
- Asthma
description: >-
  An adult-onset, chronic inflammatory disease of the unified upper and lower
  airway defined by the triad of eosinophilic asthma, chronic rhinosinusitis
  with bilateral nasal polyposis, and reproducible respiratory reactions to
  aspirin and other strong cyclooxygenase-1 (COX-1) inhibitors. The reaction is
  pharmacologic rather than IgE-mediated: patients carry a chronically
  dysregulated arachidonic-acid network — constitutively elevated cysteinyl
  leukotriene production, driven in part by markedly increased bronchial LTC4
  synthase expression, together with loss of the restraining prostaglandin E2
  (PGE2) signal on inflammatory cells — and COX-1 inhibition removes the
  residual PGE2 brake, releasing an abrupt surge of cysteinyl leukotrienes; mast
  cell activation supplies a parallel prostaglandin D2 arm that is both
  eosinophil-recruiting and directly bronchoconstrictive. Because the underlying disease is present before any NSAID
  exposure, avoiding NSAIDs prevents acute reactions but does not arrest the
  asthma or the polyp disease.
classifications:
  harrisons_chapter:
  - classification_value: RESPIRATORY
    evidence:
    - reference: PMID:30884882
      reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "this classic triad of symptoms, eponymously named Samter's Triad, is known as aspirin exacerbated respiratory disease (AERD)"
      explanation: AERD is defined as an airway disease comprising asthma and sinonasal disease, placing it in Harrison's pulmonary Part.
prevalence:
- population: Adults with asthma
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 7150.0
  notes: >-
    Pooled prevalence across all study designs in asthmatic populations,
    7.15% (95% CI 5.26-9.03%), from a meta-analysis of 27 studies.
  evidence:
  - reference: PMID:25282015
    reference_title: "Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among all studies in asthmatic patients, regardless of method, the prevalence of AERD was 7.15% (95% CI, 5.26% to 9.03%)"
    explanation: Meta-analytic pooled prevalence of AERD among asthmatic patients.
- population: Adults with severe asthma
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 14890.0
  notes: Highest prevalence stratum in the same meta-analysis, 14.89% (95% CI 6.48-23.29%).
  evidence:
  - reference: PMID:25282015
    reference_title: "Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of AERD was highest among patients with severe asthma (14.89% [95% CI, 6.48% to 23.29%])"
    explanation: Meta-analytic prevalence of AERD in the severe-asthma stratum.
- population: General population, United States
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 600.0
  rate_low: 300.0
  rate_high: 900.0
  notes: Review-level estimate of 0.3-0.9% of the general US population.
  evidence:
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aspirin exacerbated respiratory disease affects approximately 0.3⁻0.9% of the general population in the USA and approximately 7% of asthmatic patients."
    explanation: Review reports the general-population prevalence range for AERD in the USA.
pathophysiology:
- name: Bronchial LTC4 Synthase Overexpression
  biological_scale: TISSUE
  description: >-
    The defining upstream lesion is a markedly increased number of cells
    expressing LTC4 synthase, the terminal enzyme of cysteinyl leukotriene
    synthesis, in the bronchial mucosa. Counts are roughly fivefold higher than
    in aspirin-tolerant asthma and eighteenfold higher than in normal subjects,
    while 5-lipoxygenase, FLAP, LTA4 hydrolase, COX-1 and COX-2 staining are
    indistinguishable between groups. This gives the AERD airway an enzymatic
    capacity for cysteinyl leukotriene overproduction that aspirin-tolerant
    asthmatic airways lack, and it is the reason the same COX-1 inhibition
    produces bronchoconstriction only in these patients.
  cell_types:
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  biological_processes:
  - preferred_term: leukotriene biosynthetic process
    term:
      id: GO:0019370
      label: leukotriene biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:9466979
    reference_title: "Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Counts of cells expressing the terminal enzyme for cys-LT synthesis, LTC4 synthase, were fivefold higher in AIA biopsies"
    explanation: Directly quantifies the LTC4 synthase overexpression that defines this node.
  - reference: PMID:9466979
    reference_title: "Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunostaining for 5-lipoxygenase, its activating protein (FLAP), LTA4 hydrolase, cyclooxygenase (COX)-1, and COX-2 did not differ."
    explanation: Establishes that the enzymatic abnormality is specific to LTC4 synthase rather than a general upregulation of eicosanoid enzymes.
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These IFN-γ differentiated eosinophils also have significantly increased levels of LTC4 synthase (LTC4S), possibly explaining the increased levels of Cys-LTs in AERD."
    explanation: Identifies infiltrating eosinophils as one cellular source of the raised LTC4 synthase activity.
  downstream:
  - target: Constitutive Cysteinyl Leukotriene Overproduction
    causal_link_type: DIRECT
    description: Excess terminal synthase capacity raises baseline cysteinyl leukotriene output in the airway.
  - target: COX-1 Inhibition Unmasking Reaction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - pharmacologic COX-1 inhibition
    - loss of the residual PGE2 restraint on 5-lipoxygenase activity
    description: >-
      Permissive rather than initiating: COX-1 inhibition lifts PGE2 restraint in
      everyone, but only an airway carrying this excess terminal synthase capacity
      converts that into a marked cysteinyl leukotriene surge. This edge is what
      makes the acute reaction a property of the primed airway rather than of the
      drug.
- name: Loss of Prostaglandin E2 Restraint
  biological_scale: CELLULAR
  description: >-
    PGE2 normally brakes cysteinyl leukotriene production by airway inflammatory
    cells through the EP2 receptor. In AERD this brake is defective at the
    receptor level: the proportion of neutrophils, mast cells, eosinophils and
    T cells expressing EP2 is significantly reduced in aspirin-sensitive
    compared with non-aspirin-sensitive rhinosinusitis, even though global
    mucosal EP2 expression on epithelial and goblet cells is elevated in both.
    The defect is therefore a cell-type-specific loss of PGE2 responsiveness in
    the effector leukocytes, not a global absence of the receptor.
  cell_types:
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  molecular_functions:
  - preferred_term: prostaglandin E receptor activity
    term:
      id: GO:0004957
      label: prostaglandin E receptor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:16461132
    reference_title: "Aspirin-sensitive rhinosinusitis is associated with reduced E-prostanoid 2 receptor expression on nasal mucosal inflammatory cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the percentages of neutrophils, mast cells, eosinophils, and T cells expressing EP(2), but not EP(1), EP(3), or EP(4), were significantly reduced (P < or = .04) in the aspirin-sensitive compared with nonaspirin-sensitive patients"
    explanation: Localizes the EP2 deficit specifically to inflammatory cells in aspirin-sensitive patients.
  - reference: PMID:17508965
    reference_title: "PGE suppresses excessive anti-IgE induced cysteinyl leucotrienes production in mast cells of patients with aspirin exacerbated respiratory disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "mast cells from AERD patients produced significantly more cys-LTs (6.9 +/- 2.0 ng/10(6) cells) than normal and ATA subjects"
    explanation: Demonstrates the excess cysteinyl leukotriene output of AERD mast cells that PGE2 normally restrains.
  downstream:
  - target: Constitutive Cysteinyl Leukotriene Overproduction
    causal_link_type: DIRECT
    description: Reduced EP2-mediated inhibition permits sustained cysteinyl leukotriene output at baseline.
- name: Constitutive Cysteinyl Leukotriene Overproduction
  biological_scale: TISSUE
  description: >-
    The combination of excess LTC4 synthase capacity and a defective PGE2 brake
    leaves the AERD airway producing cysteinyl leukotrienes (LTC4, LTD4, LTE4)
    continuously, before and independent of any drug exposure. Baseline
    cysteinyl leukotriene concentrations in bronchoalveolar lavage fluid are
    elevated and correlate uniquely with bronchial LTC4 synthase cell counts,
    which is what ties the enzymatic lesion to the mediator excess.
  cell_types:
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  biological_processes:
  - preferred_term: leukotriene metabolic process
    term:
      id: GO:0006691
      label: leukotriene metabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:9466979
    reference_title: "Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Enhanced baseline cys-LT levels in bronchoalveolar lavage (BAL) fluid of AIA patients correlated uniquely with bronchial counts of LTC4 synthase+ cells"
    explanation: Links elevated baseline cysteinyl leukotrienes to the LTC4 synthase lesion in the same patients.
  downstream:
  - target: IL-33-Dependent Mast Cell Activation
    causal_link_type: DIRECT
    description: Cysteinyl leukotrienes drive epithelial IL-33 expression, which in turn activates airway mast cells.
  - target: Eosinophilic Airway Inflammation and Polyp Formation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - CysLT receptor signaling on airway inflammatory cells
    - type 2 cytokine production
    description: Sustained cysteinyl leukotriene signaling supports the chronic eosinophilic inflammation and polyp growth.
- name: IL-33-Dependent Mast Cell Activation
  biological_scale: CELLULAR
  description: >-
    AERD nasal polyps show markedly increased epithelial expression of the
    alarmin IL-33 compared with aspirin-tolerant polyps. In the ptges-null mouse
    model, deleting LTC4 synthase abolishes the raised IL-33 and sharply reduces
    eosinophilia and baseline mast cell product secretion, placing IL-33
    downstream of cysteinyl leukotrienes; lysine-aspirin challenge of the same
    mice then induces IL-33-dependent mast cell activation and
    bronchoconstriction. This is the step that converts a lipid-mediator excess
    into an innate type 2 cellular response.
  cell_types:
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  - preferred_term: group 2 innate lymphoid cell
    term:
      id: CL:0001069
      label: group 2 innate lymphoid cell
  biological_processes:
  - preferred_term: mast cell activation
    term:
      id: GO:0045576
      label: mast cell activation
    modifier: INCREASED
  evidence:
  - reference: PMID:26342029
    reference_title: "Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with AERD have markedly increased epithelial expression of the alarmin-like cytokine IL-33 in nasal polyps, as compared with polyps from aspirin-tolerant control subjects"
    explanation: Establishes the raised epithelial IL-33 in human AERD polyps.
  - reference: PMID:26342029
    reference_title: "Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Deletion of leukotriene C4 synthase, the terminal enzyme needed to generate cysLTs, eliminates the increased IL-33 content of the ptges(-/-) lungs and sharply reduces pulmonary eosinophilia and basal secretion of MC products."
    explanation: Mouse genetic evidence placing IL-33 causally downstream of cysteinyl leukotrienes.
  downstream:
  - target: Eosinophilic Airway Inflammation and Polyp Formation
    causal_link_type: DIRECT
    description: Activated mast cells and ILC2s sustain the type 2 cytokine milieu driving eosinophilia and polyp growth.
  - target: Mast Cell Prostaglandin D2 Release
    causal_link_type: DIRECT
    description: Mast cell activation is what releases prostaglandin D2, opening the second mediator arm.
- name: Platelet-Adherent Leukocyte Transcellular Synthesis
  biological_scale: CELLULAR
  description: >-
    A second, independent route to the same cysteinyl leukotriene excess.
    Platelet-adherent eosinophils, neutrophils and monocytes are markedly more
    frequent in AERD than in aspirin-tolerant controls, and the adherent
    platelets themselves carry more than half of peripheral blood granulocyte
    LTC4 synthase activity. Because platelets supply the terminal synthase to
    leukocytes that lack it, this is transcellular biosynthesis rather than a
    change in any single cell's own program, and it explains part of the
    cysteinyl leukotriene burden that bronchial LTC4 synthase counts alone do
    not.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  biological_processes:
  - preferred_term: leukotriene biosynthetic process
    term:
      id: GO:0019370
      label: leukotriene biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They noted that platelet-adherent eosinophils, neutrophils, and monocytes were markedly increased in AERD patients relative to aspirin-tolerant controls and that urinary LTE4 correlates strongly with the frequency of platelet-adherent neutrophils, eosinophils, and monocytes."
    explanation: Establishes the excess of platelet-adherent leukocytes in AERD and its correlation with the urinary cysteinyl leukotriene end-product.
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, their experiments found that adherent platelets expressed more than half of the peripheral blood granulocyte LTC4S activity"
    explanation: Quantifies the platelet contribution to granulocyte LTC4 synthase activity, which is what makes the synthesis transcellular.
  downstream:
  - target: Constitutive Cysteinyl Leukotriene Overproduction
    causal_link_type: DIRECT
    description: Platelet-supplied LTC4 synthase activity adds to the airway's cysteinyl leukotriene output independently of bronchial mucosal enzyme counts.
- name: Mast Cell Prostaglandin D2 Release
  biological_scale: CELLULAR
  description: >-
    The second mediator arm alongside the cysteinyl leukotrienes. Activated mast
    cells release prostaglandin D2, which both recruits eosinophils and Th2 cells
    to the respiratory epithelium and is itself strongly bronchoconstrictive.
    PGD2 is therefore not a bystander marker of mast cell activation but a
    parallel effector, and it is part of why the acute reaction is not fully
    abolished by leukotriene-pathway blockade alone.
  cell_types:
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  biological_processes:
  - preferred_term: prostaglandin biosynthetic process
    term:
      id: GO:0001516
      label: prostaglandin biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "activated mast cells release a host of inflammatory mediators such as prostaglandin D2 (PGD2), which induces inflammation of the respiratory epithelium through recruitment of eosinophils and Th2 cells and also harbors highly bronchoconstrictive properties"
    explanation: Establishes PGD2 release from activated mast cells and its two effects, eosinophil/Th2 recruitment and bronchoconstriction.
  downstream:
  - target: Eosinophilic Airway Inflammation and Polyp Formation
    causal_link_type: DIRECT
    description: PGD2 recruits eosinophils and Th2 cells into the respiratory epithelium.
  - target: Acute Bronchoconstriction and Upper Airway Reaction
    causal_link_type: DIRECT
    description: PGD2 is directly bronchoconstrictive and contributes to the acute reaction alongside the cysteinyl leukotrienes.
- name: COX-1 Inhibition Unmasking Reaction
  biological_scale: ORGANISM
  description: >-
    Ingestion of aspirin or another strong COX-1 inhibitor removes the residual
    PGE2 restraint on 5-lipoxygenase activity in an airway already primed with
    excess LTC4 synthase, producing an abrupt surge of cysteinyl leukotrienes
    and the acute upper- and lower-airway reaction. Lysine-aspirin challenge
    releases additional cysteinyl leukotrienes into bronchoalveolar lavage fluid
    in aspirin-intolerant but not aspirin-tolerant asthmatics, and bronchial
    responsiveness to lysine-aspirin correlates exclusively with LTC4 synthase
    cell counts. This node is the acute, drug-triggered arm of the disease and
    is what diagnostic aspirin provocation deliberately elicits.
  biological_processes:
  - preferred_term: cyclooxygenase pathway
    term:
      id: GO:0019371
      label: cyclooxygenase pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:9466979
    reference_title: "Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lysine-aspirin challenge released additional cys-LTs into BAL fluid in AIA patients (200+/-120 pg/ml, n = 8) but not in ATA patients"
    explanation: Shows the acute cysteinyl leukotriene surge on COX-1 inhibition is specific to aspirin-intolerant patients.
  - reference: PMID:9466979
    reference_title: "Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aspirin may remove PGE2-dependent suppression in all subjects, but only in AIA patients does increased bronchial expression of LTC4 synthase allow marked overproduction of cys-LT"
    explanation: States the two-hit model in which COX-1 inhibition is permissive and LTC4 synthase excess is the determinant.
  downstream:
  - target: Acute Bronchoconstriction and Upper Airway Reaction
    causal_link_type: DIRECT
    description: The cysteinyl leukotriene surge acts on CysLT receptors to produce bronchospasm, mucus secretion and nasal symptoms.
- name: Acute Bronchoconstriction and Upper Airway Reaction
  biological_scale: ORGANISM
  description: >-
    The clinical reaction following COX-1 inhibition — nasal obstruction,
    rhinorrhea, conjunctival symptoms, cough, wheeze and a fall in FEV1, and
    occasionally laryngospasm or hypotension. It is mediated by cysteinyl
    leukotrienes acting on CysLT receptors rather than by drug-specific IgE,
    which is why it reproduces with structurally unrelated strong COX-1
    inhibitors and why selective COX-2 inhibitors are usually tolerated.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:26342029
    reference_title: "Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "involves overproduction of cysteinyl leukotrienes (cysLTs), activation of airway mast cells (MCs), and bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic PGE2"
    explanation: Describes the acute bronchoconstrictive reaction and its mediator basis.
- name: Eosinophilic Airway Inflammation and Polyp Formation
  biological_scale: TISSUE
  description: >-
    The chronic arm of the disease: persistent eosinophilic inflammation of the
    sinonasal and bronchial mucosa with oedema, extracellular-matrix remodelling
    and bilateral nasal polyp growth, together with bronchial
    hyperresponsiveness. This component is present independent of NSAID exposure
    and is what continues to progress in patients who simply avoid NSAIDs.
  cell_types:
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  biological_processes:
  - preferred_term: eosinophil chemotaxis
    term:
      id: GO:0048245
      label: eosinophil chemotaxis
    modifier: INCREASED
  evidence:
  - reference: PMID:26342029
    reference_title: "Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aspirin-exacerbated respiratory disease (AERD), a severe eosinophilic inflammatory disorder of the airways"
    explanation: Characterizes AERD as a severe eosinophilic airway inflammatory disorder.
phenotypes:
- name: Adult-onset asthma
  category: Respiratory
  frequency: OBLIGATE
  description: >-
    Asthma, usually beginning in the third or fourth decade and often
    moderate-to-severe and eosinophilic, is one of the three defining components.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:25282015
    reference_title: "Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aspirin-exacerbated respiratory disease (AERD) is manifested by adult-onset asthma, nasal polyposis, chronic rhinosinusitis, and aspirin sensitivity."
    explanation: Names adult-onset asthma as a defining manifestation of AERD.
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generally, AERD manifests in the third or fourth decade of life"
    explanation: Establishes the adult age of onset asserted in the entry description.
- name: Nasal polyposis
  category: Respiratory
  frequency: OBLIGATE
  description: >-
    Bilateral nasal polyps, characteristically recurrent after endoscopic sinus
    surgery, are the second defining component.
  phenotype_term:
    preferred_term: Nasal polyposis
    term:
      id: HP:0100582
      label: Nasal polyposis
  evidence:
  - reference: PMID:25282015
    reference_title: "Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aspirin-exacerbated respiratory disease (AERD) is manifested by adult-onset asthma, nasal polyposis, chronic rhinosinusitis, and aspirin sensitivity."
    explanation: Names nasal polyposis as a defining manifestation of AERD.
- name: Chronic rhinosinusitis
  category: Respiratory
  frequency: VERY_FREQUENT
  description: >-
    Chronic inflammation of the sinonasal mucosa with facial pressure, nasal
    discharge and obstruction, typically more severe and more often requiring
    revision surgery than in aspirin-tolerant chronic rhinosinusitis.
  phenotype_term:
    preferred_term: Chronic sinusitis
    term:
      id: HP:0011109
      label: Chronic sinusitis
  evidence:
  - reference: PMID:25282015
    reference_title: "Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aspirin-exacerbated respiratory disease (AERD) is manifested by adult-onset asthma, nasal polyposis, chronic rhinosinusitis, and aspirin sensitivity."
    explanation: Names chronic rhinosinusitis as a defining manifestation of AERD.
- name: Aspirin-induced respiratory reaction
  category: Immunologic
  frequency: OBLIGATE
  description: >-
    Reproducible acute respiratory reactions to aspirin and other strong COX-1
    inhibitors, pharmacologic rather than IgE-mediated. This is the component
    that distinguishes AERD from aspirin-tolerant eosinophilic CRSwNP with
    asthma.
  phenotype_term:
    preferred_term: Aspirin- and NSAID-induced respiratory reaction
    term:
      id: HP:0012042
      label: Aspirin-induced asthma
  evidence:
  - reference: PMID:26342029
    reference_title: "Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic PGE2"
    explanation: Describes the reproducible reaction to nonselective COX inhibitors that defines the hypersensitivity component.
- name: Eosinophilia
  category: Hematologic
  frequency: FREQUENT
  description: >-
    Blood and tissue eosinophilia. Tissue eosinophil infiltration is driven in
    part by the raised IFN-gamma milieu characteristic of AERD, and the
    infiltrating eosinophils themselves carry increased LTC4 synthase, feeding
    back into the cysteinyl leukotriene excess.
  phenotype_term:
    preferred_term: Eosinophilia
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The increased IFN-γ has also been shown to stimulate differentiation of eosinophils through interferon consensus sequence binding protein, a transcription factor, leading to a dramatic upregulation in the number of infiltrating eosinophils"
    explanation: Documents the marked increase in infiltrating eosinophils in AERD and the mechanism driving it.
- name: Anosmia
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Loss of the sense of smell is common and frequently severe, and improves
    measurably with effective anti-inflammatory therapy.
  phenotype_term:
    preferred_term: Anosmia
    term:
      id: HP:0000458
      label: Anosmia
  evidence:
  - reference: PMID:36549708
    reference_title: "Dupilumab increases aspirin tolerance in NSAID-exacerbated respiratory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "olfactory performance improved (University of Pennsylvania Smell Identification Test: +11.16±9.54, p<0.001) in all patients after therapy"
    explanation: Olfactory dysfunction is a measured, treatment-responsive feature of the N-ERD cohort.
inheritance:
- name: Multifactorial
  description: >-
    AERD is a complex multifactorial disease. No causal gene, Mendelian
    inheritance pattern, penetrance estimate or clinically actionable genotype
    is established; reported candidate-gene associations (LTC4S, ALOX5,
    CYSLTR1, PTGER2 among others) are population-dependent susceptibility
    signals that frequently fail replication and should not be curated as causal
    alleles.
biochemical:
- name: Urinary leukotriene E4
  presence: INCREASED
  context: >-
    LTE4 is the stable urinary end-product of the cysteinyl leukotriene pathway
    and is the central AERD biomarker. It is consistently higher than in
    aspirin-tolerant asthma and rises further after aspirin challenge. It is not
    a stand-alone diagnostic test: assay and reporting heterogeneity are
    substantial, and the source below is explicit that an elevated value only
    shifts the odds when read alongside clinical features. It is also a
    treatment-response marker, falling in the dupilumab-treated patients who
    regained aspirin tolerance.
  readouts:
  - target: Constitutive Cysteinyl Leukotriene Overproduction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Urinary LTE4 reports the whole-body cysteinyl leukotriene burden produced
      by the LTC4 synthase excess and the failed PGE2 brake.
    evidence:
    - reference: PMID:30884882
      reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Increased levels of urinary LTE4 itself is not sufficient for diagnosis of AERD, but when elevated in the context of clinical parameters such as asthma exacerbations and nasal polyposis it nearly doubles the odds of AERD diagnosis"
      explanation: States both the diagnostic signal and its limitation as a stand-alone test.
  evidence:
  - reference: PMID:36549708
    reference_title: "Dupilumab increases aspirin tolerance in NSAID-exacerbated respiratory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with increased aspirin tolerance showed a significant decrease in urinary leukotriene E4 levels"
    explanation: Shows urinary LTE4 tracking treatment response, supporting its use as a marker of the cysteinyl leukotriene burden.
progression:
- phase: Sinonasal onset
  age_range: Third to fourth decade
  notes: >-
    Persistent rhinitis and chronic sinus symptoms typically come first, before
    the asthma or the recognised drug reactions.
  evidence:
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generally, AERD manifests in the third or fourth decade of life"
    explanation: Establishes the adult decade of onset for the first phase.
- phase: Asthma and aspirin sensitivity
  age_range: Within about five years of the first respiratory symptoms
  notes: >-
    Asthma follows the initial respiratory tract symptoms after roughly two
    years, and aspirin sensitivity is recognised within about five years of
    onset. The lag matters clinically: a patient can be several years into the
    disease before the NSAID reaction identifies it.
  evidence:
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On average, asthma developed in patients two years after the initial respiratory tract symptoms appeared, and ASA sensitivity developed within five years of onset"
    explanation: Gives the observed interval between symptom onset, asthma, and recognised aspirin sensitivity.
diagnosis:
- name: Aspirin provocation challenge
  description: >-
    Supervised graded oral (or bronchial/nasal) aspirin provocation is the
    reference standard when the diagnosis is not already established by a
    history of repeated unequivocal reactions in a patient with the full triad.
    No blood, urine, genomic or omics test currently replaces challenge testing.
  evidence:
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, definitive diagnosis is only achieved through ASA provocation testing."
    explanation: States that aspirin provocation is the only definitive diagnostic test, which is the claim being made.
treatments:
- name: Montelukast
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    A CysLT1 receptor antagonist. Together with corticosteroids, leukotriene
    modifiers are first-line therapy in AERD, which is what a cysteinyl
    leukotriene-driven disease predicts. Montelukast blocks the receptor rather
    than the synthesis, so it leaves the mediator excess in place and acts at the
    last step.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: montelukast
      term:
        id: CHEBI:50730
        label: montelukast
  target_mechanisms:
  - target: Acute Bronchoconstriction and Upper Airway Reaction
    treatment_effect: INHIBITS
    description: CysLT1 receptor blockade prevents the cysteinyl leukotrienes already present from acting on the airway.
  evidence:
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corticosteroids and leukotriene modifiers are the first line therapies used to treat AERD."
    explanation: Establishes leukotriene modifiers as first-line AERD therapy.
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FEV-1 showed a statistically significant improvement of 10.2% on average"
    explanation: Quantifies the spirometric benefit reported in the montelukast randomized trial.
- name: Zileuton
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    A 5-lipoxygenase inhibitor. Unlike montelukast it acts upstream, cutting
    cysteinyl leukotriene synthesis rather than blocking the receptor, so it
    reduces the mediator burden itself. A double-blind crossover trial reported a
    significant FEV1 rise within hours.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: zileuton
      term:
        id: CHEBI:10112
        label: zileuton
  target_mechanisms:
  - target: Constitutive Cysteinyl Leukotriene Overproduction
    treatment_effect: INHIBITS
    description: Inhibiting 5-lipoxygenase blocks cysteinyl leukotriene synthesis upstream of the terminal synthase.
  evidence:
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The zileuton arm showed a significant increase in the FEV-1 within hours (12.7% increase, p < 0.01)"
    explanation: Quantifies the rapid spirometric benefit in the zileuton double-blind crossover trial.
- name: Endoscopic sinus surgery
  therapeutic_modality: SURGERY
  description: >-
    Removal of polyps and opening of the sinuses. It reduces disease burden
    directly and creates the conditions for medical therapy to work; in current
    practice it is paired with post-operative aspirin desensitization rather than
    used alone, since polyps recur without sustained anti-inflammatory treatment.
  treatment_term:
    preferred_term: endoscopic sinus surgery
    term:
      id: NCIT:C157836
      label: Endoscopic Sinus Surgery
  target_mechanisms:
  - target: Eosinophilic Airway Inflammation and Polyp Formation
    treatment_effect: BYPASSES
    description: Surgery removes the polyp burden mechanically without altering the inflammation that produced it, which is why it is paired with medical therapy.
  evidence:
  - reference: PMID:30884882
    reference_title: "Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ASA desensitization, followed by either 325 mg twice a day or 650 mg twice a day post-endoscopic sinus surgery with polyp removal is now the standard of care for AERD patients"
    explanation: Establishes surgery followed by aspirin desensitization as the current standard of care.
- name: Aspirin desensitization followed by maintenance aspirin
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Graded aspirin administration under supervision induces a temporary
    pharmacologic tolerant state, maintained only by continuous daily aspirin;
    interruption permits resensitization. In a randomized double-blind
    placebo-controlled trial of 34 patients, desensitization followed by 625 mg
    twice daily for 6 months significantly reduced symptom scores and medication
    need. Notably the same trial found no accompanying change in serum IL-10,
    IFN-gamma or TGF-beta, so the clinical benefit is not explained by those
    systemic cytokines.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: aspirin
      term:
        id: CHEBI:15365
        label: acetylsalicylic acid
  target_mechanisms:
  - target: Constitutive Cysteinyl Leukotriene Overproduction
    treatment_effect: INHIBITS
    description: Maintenance aspirin durably suppresses the cysteinyl leukotriene-driven chronic inflammation, reducing symptoms and polyp recurrence.
  evidence:
  - reference: PMID:26083948
    reference_title: "Aspirin desensitization for patients with aspirin-exacerbated respiratory disease: A randomized double-blind placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptom scores and medication needs of patients with AERD who have undergone AD were significantly lower compared to the placebo group after 6 months"
    explanation: Randomized placebo-controlled evidence that aspirin desensitization improves symptoms and reduces medication need.
  - reference: PMID:26083948
    reference_title: "Aspirin desensitization for patients with aspirin-exacerbated respiratory disease: A randomized double-blind placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "no significant difference was observed in serum concentration of IL-10, IFN-γ, and TGF-β between two groups neither at baseline nor at the end of study"
    explanation: The same trial found no systemic cytokine correlate, so the mechanism of benefit is not established by this study.
- name: Dupilumab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    An anti-IL-4 receptor alpha monoclonal antibody. In a 6-month open-label
    trial in confirmed N-ERD, dupilumab reduced polyp burden and improved asthma
    control and olfaction in all patients, and in a subset restored aspirin
    tolerance — 23% developed complete tolerance and a further 33% tolerated
    higher doses. Patients who gained tolerance showed falling urinary
    leukotriene E4, linking the clinical effect back to the cysteinyl
    leukotriene axis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dupilumab
      term:
        id: NCIT:C162455
        label: Dupilumab
  target_mechanisms:
  - target: Eosinophilic Airway Inflammation and Polyp Formation
    treatment_effect: INHIBITS
    description: Blocking IL-4 receptor alpha suppresses the type 2 cytokine signalling that sustains eosinophilic inflammation and polyp growth.
  - target: Constitutive Cysteinyl Leukotriene Overproduction
    treatment_effect: INHIBITS
    description: Patients gaining aspirin tolerance showed a significant fall in urinary leukotriene E4, indicating reduced cysteinyl leukotriene production.
  evidence:
  - reference: PMID:36549708
    reference_title: "Dupilumab increases aspirin tolerance in NSAID-exacerbated respiratory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After 6 months of treatment with dupilumab, 23% of patients (n=7 of 30) developed complete aspirin tolerance and an additional 33% of patients (n=10 of 30) tolerated higher doses."
    explanation: Quantifies the restoration of aspirin tolerance on dupilumab in confirmed N-ERD.
  - reference: PMID:36549708
    reference_title: "Dupilumab increases aspirin tolerance in NSAID-exacerbated respiratory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with increased aspirin tolerance showed a significant decrease in urinary leukotriene E4 levels"
    explanation: Ties the clinical gain in tolerance to a fall in the cysteinyl leukotriene end-product.
environmental:
- name: Aspirin and non-selective NSAID exposure
  description: >-
    Ingestion of aspirin or another strong COX-1 inhibitor is the defining acute
    trigger. It does not cause the underlying chronic airway disease; it unmasks
    it.
  influences_mechanisms:
  - target: COX-1 Inhibition Unmasking Reaction
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      COX-1 inhibition removes the residual PGE2 restraint on cysteinyl
      leukotriene production, precipitating the acute reaction.
    evidence:
    - reference: PMID:9466979
      reference_title: "Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Aspirin causes bronchoconstriction in aspirin-intolerant asthma (AIA) patients by triggering cysteinyl-leukotriene (cys-LT) production, probably by removing PGE2-dependent inhibition."
      explanation: States the triggering relationship between COX-1 inhibition and the cysteinyl leukotriene surge.
  evidence:
  - reference: PMID:26342029
    reference_title: "Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic PGE2"
    explanation: Identifies non-selective COX inhibitors as the exposure that provokes the acute reaction.
discussions:
- discussion_id: aerd_initiating_lesion
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Bronchial LTC4 Synthase Overexpression
  prompt: >-
    What makes the AERD airway overexpress LTC4 synthase in the first place, and
    why does the disease begin in adulthood rather than childhood?
  rationale: >-
    The LTC4 synthase excess and the EP2 deficit are both well documented as
    present in established disease, but neither has been shown to be the
    initiating lesion, and no causal genetic variant explains them. Without an
    initiating event the model cannot say why a previously healthy adult
    develops AERD, nor identify a window for prevention.
- discussion_id: aerd_desensitization_mechanism
  kind: KNOWLEDGE_GAP
  attaches_to:
  - treatments#Aspirin desensitization followed by maintenance aspirin
  prompt: >-
    By what mechanism does continuous high-dose aspirin suppress the chronic
    inflammation it acutely provokes?
  rationale: >-
    Desensitization is clinically effective and the tolerant state is
    maintained only while aspirin continues, but the randomized trial that
    demonstrated symptomatic benefit found no accompanying change in serum
    IL-10, IFN-gamma or TGF-beta. The mediator through which maintenance
    aspirin acts is therefore unresolved, which is why response cannot yet be
    predicted or monitored biochemically.
📚

References & Deep Research

Deep Research

1
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Aspirin-Exacerbated Respiratory Disease (AERD): Disease-Characteristics Report
Edison Scientific Literature 17 citations 2026-08-27T16:27:40.312723

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.

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. (badrani2021cellularinteractionsin pages 1-3, li2019aspirinexacerbatedrespiratory pages 1-3, sehanobish2021aspirinactionsin pages 1-2) 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. (badrani2021cellularinteractionsin pages 1-3, sehanobish2022newconceptsfor pages 1-3, badrani2021cellularinteractionsin pages 8-9, sehanobish2022newconceptsfor pages 9-10) 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). (patel2026anarrativereview pages 2-4, sehanobish2022newconceptsfor pages 9-10) 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. (sehanobish2021aspirinactionsin pages 1-2, levy2016contemporarymanagementof pages 1-2, sehanobish2022newconceptsfor pages 9-10) 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. (schneider2023dupilumabincreasesaspirin pages 13-14) 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. (sehanobish2022newconceptsfor pages 9-10) 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. (badrani2021cellularinteractionsin pages 1-3) 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. (schneider2023dupilumabincreasesaspirin pages 14-14) 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. (badrani2021cellularinteractionsin pages 1-3, sehanobish2022newconceptsfor pages 1-3, badrani2021cellularinteractionsin pages 8-9) 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.

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

Phenotype Type, onset/course, frequency Functional impact Suggested HPO term
Adult-onset asthma Symptom/sign; usually begins in early-to-middle adulthood; episodic exacerbations on chronic disease; often moderate–severe Dyspnea, rescue medication, systemic steroids, ED visits and hospitalization HP:0002099 Asthma; HP:0002098 Respiratory distress; HP:0030828 Wheezing
Chronic rhinosinusitis Sign/symptom; chronic, progressive or fluctuating Facial pressure, discharge, impaired sleep and productivity HP:0011109 Chronic sinusitis
Bilateral recurrent nasal polyposis Physical manifestation; high penetrance within classic AERD; recurrent after surgery Nasal obstruction, repeated surgery, impaired sleep HP:0100582 Nasal polyposis
Hyposmia/anosmia Symptom; common and frequently severe Food enjoyment, safety, social and emotional effects HP:0004408 Abnormality of smell; HP:0000458 Anosmia
NSAID-induced rhinorrhea/congestion Acute provoked symptom, usually within minutes to hours Restricts analgesic choices; may require monitored challenge HP:0031417 Rhinorrhea; HP:0001742 Nasal obstruction
Bronchospasm/FEV1 fall Acute clinical/functional sign after COX-1 inhibition Potentially severe reaction HP:0025428 Bronchospasm; HP:0002783 Abnormal pulmonary function
Blood/tissue eosinophilia Laboratory/pathology abnormality; common but variable Correlates imperfectly with severity and biologic eligibility HP:0001880 Eosinophilia
Middle-ear inflammation/hearing symptoms Secondary manifestation; cohort frequency about 18%, with earlier reports exceeding one-quarter Poor control and hearing-related disability HP:0000389 Chronic otitis media; HP:0000365 Hearing impairment

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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  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.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 11
On topic 9
Off topic 0

All extracted references resolved successfully.