This dysregulation leads to an imbalance of immune related molecules, including an overproduction of inflammatory compounds such as leukotriene E4 and an underproduction of anti-inflammatory mediators such as prostaglandin E2.

[2] A history of respiratory reactions to aspirin or others NSAIDs is sufficient to diagnose AERD in a patient that has both asthma and nasal polyps.

While AERD has been found to affect essentially all ethnicities, it is less common in parts of Asia where nasal polyps caused by type 2 inflammation are relatively more rare.

[5] While disease progression varies, most commonly the first symptom is rhinitis (inflammation or irritation of the nasal mucosa), which may manifest as sneezing, runny nose, or congestion.

Factors that affect reaction severity include NSAID dosage, underlying asthma control, leukotriene modifier usage and the state of the patient's nasal polyps.

[5] In addition to aspirin, patients also react to other NSAIDs such as ibuprofen, and to any medication that inhibits the cyclooxygenase-1 (COX-1) enzyme, although paracetamol (acetaminophen) in low doses is generally considered safe.

[5] Nonetheless, recent studies do find that these types of drugs, e.g. acetaminophen and celecoxib, may trigger adverse reactions in these patients; caution is recommended in using any COX inhibitors.

[12] In addition to aspirin and NSAIDs, consumption of even small amounts of alcohol also produces uncomfortable respiratory reactions in many patients.

Allergic reaction to the superantigen of Staphylococcus aureus, chronic viral infection and autoimmune mechanisms have been theorized, among others, though there is not sufficient evidence to support any specific theory.

These two components feed into each other in a highly complex negative cycle of increasing inflammation and dysregulation that is still under active research.

[7][14] AERD is associated with an aberrant arachidonic acid metabolism that leads to changes in levels of two major classes of eicosanoids, specifically certain cysteinyl leukotrienes (cysLTs) and prostaglandins.

AERD patients exhibit a seemingly paradoxical response to COX-1 inhibition, as it leads to greatly increased PGD2 and LTE4 levels, instead of the expected decrease in PGD2 and relative lack of change in LTE4.

However, given that COX-1 catalyzes the formation of PGE2, a leading explanation is that patients have an increased dependence on PGE2 and its corresponding receptor (EP2) to prevent inflammatory mediator release from mast cells.

Platelets, which express LTC4S and generate LTC4 when attached to 5-LO-expressing leukocytes (including eosinophils), are also implicated in disease pathogenesis as well as acute aspirin-induced exacerbations.

These cytokines lead to increased eosinophil recruitment, excessive mucus production via goblet cells, and promotion of TH2 and immunoglobulin E responses.

These responses cause the epithelial cells to release more cytokines and inflammatory molecules, creating a feed-forward negative cycle of increasing inflammation.

[17] Diagnosis of AERD can be difficult, as symptoms develop over time and can often be attributed to allergies, common asthma, and/or nonallergic rhinitis.

AERD is generally diagnosed based on a patient's medical history, however an oral aspirin challenge at a specialized facility is considered the most definitive method of diagnosis.

[18] Urinary LTE4 concentration is generally around 3 to 5 times higher in patients with AERD that it is in those with aspirin-tolerant asthma, and increases 2 to 30 fold during an aspirin challenge test.

There is evidence supporting four different long-term pharmacological treatments to this end: intra-nasal corticosteroids, aspirin desensitization and therapy, a range of biologic medicines, and antileukotrienes.

[26] Risk of adverse advents such as bleeding or gastrointestinal side effects is relatively high with daily aspirin therapy.

[19] This is borne out in studies on AERD patients—compared against standard of care and biologic medicines, aspirin therapy has a significantly higher rate of adverse outcomes.

[25] Various novel biologic monoclonal antibody medications that have come to market in recent years have been used to treat AERD including dupilumab, mepolizumab, omalizumab, and benralizumab.

However, due to the high cost and systemic nature of biologics, some patients whose symptoms are sufficiently controlled with other treatments may prefer to avoid them or not qualify under stricter prescription guidelines.

[34] Often functional endoscopic sinus surgery is required to remove nasal polyps,[35] although they typically recur, particularly if aspirin desensitization is not undertaken.

EPA and DHA are precursors for anti-inflammatory compounds that modulate leukotrienes, prostaglandins and thromboxanes that have been implicated in AERD pathogenesis.