Aspirin triad: symptoms and treatment

Aspirin triad (international term: AERD - aspirin-exacerbated respiratory disease; also N-ERD) is a chronic inflammatory disease of the respiratory tract, which is characterized by three components: bronchial asthma, chronic rhinosinusitis with nasal polyps and severe intolerance to non-steroidal anti-inflammatory drugs, primarily cyclooxygenase-1 (COX-1) inhibitors - aspirin, ibuprofen, naproxen, etc. Reactions usually develop 30-180 minutes after taking NSAIDs and are manifested by nasal congestion, runny nose, wheezing, shortness of breath, sometimes cough, lacrimation, itching of the skin, and in severe cases - a drop in expiratory volume (FEV1) and an attack of suffocation. This is not an allergy in the classical sense, but a specific, “cross-reactive” intolerance associated with the biochemistry of eicosanoids. [1]

AERD occurs in people of all ages, but most often appears in adulthood (approximately 20-50 years of age), often several years after the onset of symptoms of chronic rhinosinusitis. A significant proportion of patients present with recurrent nasal polyps, decreased or lost sense of smell, and "alcohol sensitivity"—a rapid increase in nasal congestion and wheezing after small amounts of wine, beer, or strong alcohol. These characteristics help to suspect the diagnosis even at the initial consultation. [2]

The key to understanding AERD is an imbalance in arachidonic acid metabolism pathways: blocking COX-1 reduces the formation of protective prostaglandins (especially PGE2) and shifts the flow into the leukotriene pathway, leading to excess cysteinyl leukotrienes (LTC4/LTD4/LTE4) and bronchoconstriction, mucosal edema, and hypersecretion. Therefore, "antiallergic" drugs like antihistamines are often ineffective in aspirin-induced attacks, while targeting leukotrienes is more effective. [3]

It is important to distinguish AERD from other forms of NSAID intolerance (e.g., cutaneous - NECD/NIUA) and from true drug allergy to a single drug. This is done using clinical criteria, aspirin provocation tests (oral, intranasal), and, if possible, biomarkers. Correct classification determines which painkillers are acceptable for the patient, when biologics are needed, whether sinus surgery is advisable, and whether aspirin desensitization followed by aspirin therapy (ATAD) is indicated. [4]

Epidemiology

According to meta-analyses and reviews, AERD is detected in approximately 5-15% of adult patients with asthma, with the proportion reaching ~15% in the severe asthma cohort. Among patients with chronic rhinosinusitis with nasal polyps, AERD is more common than in those without polyps. In the general population, estimates are more modest – approximately 0.3-0.9%. The variability is explained by different detection methods and underdiagnosis. [5]

In patients with severe asthma phenotypes and nasal polyposis, AERD significantly impairs quality of life, including more exacerbations, courses of systemic steroids, and sinus surgeries. Real-world data show worse long-term outcomes in AERD compared to aspirin-tolerant asthma with comparable treatment, unless targeted approaches are used. [6]

Onset most often occurs in the 3rd to 5th decades of life; the "classic" triad is rare in children. An important epidemiological detail is alcohol-induced respiratory symptoms: they are observed in the majority of patients with AERD (50-80% in studies), which is significantly more common than in asthmatic patients without aspirin intolerance. This feature is useful in screening. [7]

Gender and ethnic predisposition are debated: in some series, women were more frequently encountered, as was the combination with eosinophilic inflammatory phenotypes. However, general conclusions are limited due to sample heterogeneity; modern clinical practice focuses primarily on the clinical phenotype (asthma + CRSwNP + response to NSAIDs) and biomarkers such as urinary LTE4. [8]

Reasons

The main trigger is COX-1 inhibitors (classic NSAIDs and aspirin). Even small doses (for example, 75-100 mg of aspirin) provoke a severe respiratory reaction in some patients. Unlike a true IgE-mediated allergy to a specific drug, the reaction in AERD is cross-reactive to all drugs that strongly block COX-1. [9]

Outside of medication, AERD flare-ups are often triggered by viral infections, exacerbations of rhinosinusitis, uncontrolled exposure to allergens, and alcohol (especially wine). The latter is associated with the phenolic and sulfite components of beverages and increased release of prostaglandin D2 and leukotrienes. Reactions often occur after just a few sips. [10]

Medication-induced underlying factors are also highlighted: long courses of systemic glucocorticoids, frequent antibiotics for uncontrolled CRS, and insufficient step-down asthma therapy. Inappropriate analgesic management (repeated use of over-the-counter NSAIDs) perpetuates the symptomatic cycle. Therefore, patient education is part of causal prevention. [11]

Finally, a small number of patients exhibit a combination of AERD with other types of NSAID intolerance (e.g., cutaneous reactions such as NECD). In such cases, accurate phenotyping according to modern classifications is necessary to select safe analgesics and develop desensitization/biological therapy strategies. [12]

Risk factors

The risk of AERD is higher in patients with CRSwNP (especially recurrent) and in individuals with severe eosinophilic asthma requiring high doses of inhaled steroids and frequent systemic courses. These phenotypes are associated with leukotriene hyperproduction and PGE2 signaling deficiency. [13]

Additional vulnerability markers include elevated urinary LTE4, blood/sputum eosinophilia, high FeNO, and marked olfactory impairment. In real-world practice, elevated uLTE4 correlates with the severity of polypous rhinosinusitis (based on the Lund-Mackay scale), although it does not replace a provocative test. [14]

Alcohol sensitivity is common: nasal congestion, sneezing, and wheezing occur in 50-80% of patients. This is a reliable "indirect" marker of AERD and an important point when collecting complaints. In some patients, biologic drugs reduce these reactions better than aspirin therapy (according to observational studies). [15]

Finally, a family history of chronic nasal polyposis, asthma, and NSAID intolerance increases the likelihood of AERD; no specific major gene has been identified, but a combination of genetic and environmental factors creates a “vulnerable” phenotype. [16]

Pathogenesis

The underlying mechanism is COX-1 inhibition, resulting in a decline in protective PGE2, which normally "calms" mast cells and eosinophils via the EP2 receptor. PGE2 deficiency releases the brake on the 5-lipoxygenase pathway and leads to an avalanche of production of cysteinyl leukotrienes (LTC4, LTD4, LTE4), which increase bronchoconstriction and vasoconstriction, mucosal edema, and mucus hypersecretion. [17]

Mast cells and the thromboxane pathway play an important role: aspirin administration increases the release of PGD2 and thromboxane in patients with AERD; TP receptors are a promising target (there are pilot studies with ifetroban). The contribution of platelet-leukocyte aggregates, which enhance the formation of leukotrienes, is also being studied. [18]

Urinary LTE4 levels are consistently higher in AERD than in tolerant asthma and correlate with disease severity; an increase is also observed with aspirin challenge. This marker will be part of future "biomarker-based" algorithms, although it does not yet replace clinical challenge. [19]

The result is chronic type-2 airway inflammation with eosinophilia, mucosal hyperplasia, polyp formation, and bronchial hyperreactivity. Therefore, the treatment strategy for AERD simultaneously includes asthma control using GINA, CRSwNP management using EPOS, leukotriene pathway blockade, surgical sinus debridement when indicated, and/or aspirin therapy after desensitization, as well as biologic agents targeting key components of T2 inflammation. [20]

Symptoms

A typical reaction to aspirin/NSAIDs develops within 30-180 minutes: sudden nasal congestion, profuse watery discharge, itching in the nose/eyes, chest "creaking," difficulty exhaling, wheezing, and a feeling of tightness in the chest. Sometimes coughing, watery eyes, facial flushing, and itchy skin may occur. At the peak of the reaction, a significant drop in FEV1 is possible. [21]

Interictal manifestations include persistent rhinosinusitis (persistent congestion, decreased sense of smell, headache/facial pressure), recurrent nasal polyps, and frequent sinus infections. Asthma is often poorly controlled with standard doses of inhaled steroids without targeted inflammation management. [22]

A typical "everyday" trigger is alcohol: nasal congestion and/or wheezing often appear after just a few sips, and the type of drink is almost irrelevant. Patients often attribute this to sulfites in wine, but the mechanism is more complex and involves the eicosanoid cascade. [23]

The onset of AERD can be gradual: first rhinosinusitis, then polyps and olfactory disturbances; against this backdrop, taking a "regular" painkiller suddenly causes a severe reaction. Therefore, ENT specialists and pulmonologists should inquire about NSAIDs and alcohol in patients with polyps and uncontrolled asthma. [24]

Forms and stages

The modern classification of NSAID intolerance distinguishes several cross-reactive forms: N-ERD (respiratory), NECD (exacerbation of skin symptoms in patients with chronic urticaria), NIUA (isolated urticaria/angioedema in previously healthy individuals), and SNIUAA - a true allergy to one NSAID. AERD/NERD is precisely the respiratory variant. [25]

Reactions are classified by severity as mild, moderate, and severe. Criteria include a drop in FEV1, the severity of respiratory failure, and the need for systemic steroids/emergency care. The severity of the underlying condition (asthma, polyposis, frequency of exacerbations) also determines the level of long-term risk. [26]

The course of the disease is persistent rhinosinusitis with polyps and recurrent bronchial exacerbations with occasional use of NSAIDs or alcohol. In some patients, regular aspirin therapy after desensitization leads to a controlled course with less frequent polyps; in others, biological agents play a leading role. [27]

The staging of an episode with NSAIDs conventionally includes an increase (30-120 minutes), a plateau (several hours) and regression under the influence of therapy; however, without targeted treatment (bronchodilators, anti-leukotriene agents, glucocorticoids), severe protracted reactions are possible. [28]

Complications and consequences

Without targeted therapy, AERD leads to frequent asthma exacerbations, systemic steroid cycles, and accelerated steroid dependence with typical adverse effects (osteoporosis, hyperglycemia, etc.). This is one of the major contributions of AERD to the disease burden. [29]

The ENT component is characterized by recurrent polyps: even after endoscopic surgery, the sinuses "overgrow" again, the sense of smell weakens, and quality of life (sleep, performance) declines. Repeat surgeries are possible, but without systematic inflammation control, the effect is incomplete. [30]

Alcohol-induced complications increase the risk of unscheduled visits, and avoiding an entire class of analgesics complicates pain management for associated conditions. Therefore, it is important for patients to proactively select safe alternatives (see table below) and have a diagnosis "passport." [31]

Finally, long-standing airway inflammation in AERD is associated with poorer long-term outcomes unless targeted approaches (ATAD, biologics, targeted ENT surgery) are used. A properly selected combination strategy fundamentally changes the prognosis. [32]

Diagnostics

The first step is a clinical hypothesis: asthma + CRSwNP + respiratory response to any "strong" COX-1 inhibitor (aspirin, ibuprofen, naproxen) within 30-180 minutes. It is important to collect a history of reactions to alcohol, the frequency of ENT exacerbations, and courses of systemic steroids. In parallel, assess asthma control (spirometry) and the severity of CRS (endoscopy/CT according to EPOS). [33]

The gold standard for confirmation is the aspirin challenge test (oral; in some centers, intranasal titration). The test is performed in emergency settings after asthma has stabilized. Criteria for a positive response (fall in FEV1, symptom scores) have been described, and new studies are refining thresholds for the intranasal test (e.g., T-VAS and cumulative dose). [34]

Biomarkers: Urinary LTE4 is elevated in AERD and correlates with CRS severity; it is useful in supporting diagnosis and monitoring response, but does not yet replace provocation (sensitivity/specificity vary). Several studies are investigating a panel of eicosanoid metabolites and tryptase to predict the decline in FEV1 during testing. [35]

It is important to differentiate AERD from other forms of NSAID hypersensitivity (NECD, NIUA, SNIUAA): the EAACI/ENDA 2024-2025 algorithms are helpful here, defining when skin/oral testing with alternative NSAIDs is appropriate and how to select "approved" analgesics. The asthma phenotype is also assessed using GINA and the CRS score according to EPOS for treatment planning. [36]

Table 1. What helps confirm AERD

Component	What are we looking for?	What is useful?
Clinic	Reaction to COX-1 NSAIDs in 30-180 minutes; asthma; CRSwNP; reactions to alcohol	Forms a preliminary diagnosis
Provocation	Oral or intranasal aspirin test	The "gold standard" of confirmation
Biomarkers	Urinary LTE4 (higher in AERD), eosinophils, FeNO	Support, severity stratification
Visualization/endoscopy	CT scan of the sinuses, endoscopy	Staging of CRS/polyposis, ENT strategy
[37]

Differential diagnosis

1. Other NSAID reactions:
   - NECD (exacerbation of urticaria/angioedema in patients with chronic urticaria) - predominantly cutaneous symptoms, without the respiratory triad.
   - NIUA - isolated urticaria/angioedema in previously healthy individuals.
   - SNIUAA - true allergy to a single NSAID (e.g., metamizole) without cross-reactivity. The EAACI/ENDA algorithms help differentiate scenarios and select safe substitutions. [38]

2. Severe eosinophilic asthma without NSAID intolerance is similar in phenotype (T2 inflammation), but there are no reactions to NSAIDs/alcohol; the aspirin test is negative. Tactics - according to GINA (biological drugs according to biomarkers). [39]

3. Chronic rhinosinusitis without polyps or allergic rhinitis lack the typical severe reactions to NSAIDs and the "alcohol" trigger; the pattern of complaints and endoscopy are different. In doubtful cases, provocation and uLTE4 are used. [40]

4. Polyposis without asthma (eosinophilic, fungal) - requires ENT staging and evaluation for AERD if there is a history of reactions to NSAIDs. Again, history, testing, and biomarkers are helpful. [41]

Treatment

A. The basics for everyone: avoid triggers and treat both "branches" of the disease

The first rule is to strictly avoid strong COX-1 inhibitors (aspirin, ibuprofen, naproxen, diclofenac). For pain relief: paracetamol in low-medium doses is tolerated by most (but reactions are possible at high doses), selective COX-2 inhibitors (celecoxib) are considered the best option and in studies practically did not cause respiratory reactions in AERD; meloxicam is worse tolerated than celecoxib. It is better to fix the selection of alternatives in the "passport-memo". In parallel - full step therapy of asthma according to GINA-2024 and management of CRS/polyps according to EPOS-2020/2023 (irrigation, intranasal steroids; short courses of systemic steroids - rarely and briefly). [42]

B. Antileukotriene agents

Given the central role of leukotrienes in AERD, it is logical to use:

• CysLT receptor antagonists (montelukast, zafirlukast) - reduce nasal and bronchial symptoms and increase tolerance to triggers.
• The 5-lipoxygenase inhibitor zilleton reduces the formation of leukotrienes "upstream" and produces a more pronounced effect in some patients, but requires monitoring of liver enzymes. These drugs are particularly useful as a background for desensitization and ATAD. [43]

C. Sinus surgery (ESS) - when indicated

Endoscopic sinus debridement reduces inflammation, improves delivery of intranasal medications, and increases the success of aspirin therapy (including after unsuccessful attempts). The best results are achieved with a combination of ESS + supportive care (nasal steroids, irrigation) + a targeted systemic strategy (ATAD/biologics). The decision is made by an ENT specialist in conjunction with an allergist/pulmonologist. [44]

D. Aspirin desensitization and aspirin therapy (ATAD)

After confirmation of AERD and, as a rule, after ESS, a desensitization protocol is performed with a transition to daily aspirin (usually 325-650 mg/day, then on an individual basis). Effects: reduced recurrence of polyps, improved sense of smell, reduced need for steroids and exacerbations. Disadvantages: the need for strict adherence (missing doses for >48-72 hours risks "loss" of desensitization), gastrointestinal side effects, and ineffectiveness in some patients. Contraindications: active ulcers/bleeding, planned pregnancy, severe intolerance to even tiny doses at the start. Today, there is an active debate about who should prefer ATAD and who should prefer biologics. [45]

E. Biologics (asthma and/or CRSwNP)

In patients with a severe T2 phenotype (eosinophils, high FeNO, frequent exacerbations; in CRSwNP - according to the EPOS/EUFOREA-2023 criteria) the following is used:

• Dupilumab (anti-IL-4Rα): proven effective in severe asthma and CRSwNP, including in subgroups with AERD; improves nasal breathing, sense of smell, and reduces exacerbations.
• Mepolizumab/Benralizumab (anti-IL-5/IL-5R): reduces asthma exacerbations with eosinophilia; has a moderate effect on CRS.
• Omalizumab (anti-IgE) - for allergic phenotype.
• Tezepelumab (anti-TSLP) – for severe asthma, regardless of eosinophil levels. The choice is based on the GINA-2024 phenotype and EPOS/EUFOREA-2023 indicators. It has been noted that in some patients, biologics are more effective in reducing "alcohol sensitivity" than ATAD. [46]

F. What's New and Controversial (2024-2025)

• The 2024-2025 reviews emphasize the lack of consensus on which is better to start first - ATAD or biologics; the emphasis is on personalization (taking into account the patient's phenotype, availability, tolerability, and goals).
• Pilot studies of thromboxane receptor blockers (ifetroban) have demonstrated biological activity in AERD; this is still early research, but an interesting direction.
• Intranasal aspirin tests are being explored as a safer alternative for verification.
• Biomarkers (uLTE4 and eicosanoid panels) are being studied for therapy selection and monitoring. [47]

Table 2. Comparison of options: “what does” each profile provide?

Situation	What to consider	Comments
Mild/moderate asthma, CRS under control	COX-1 avoidance, paracetamol/celecoxib; montelukast	Base + Trigger Minimization
Frequent ENT exacerbations and polyps	ESS + support (intranasal steroids)	Increases the success of ATAD and local therapy
Long-term polyp/olfactory monitoring is needed	ATAD after desensitization	Effects on the ENT component, requires commitment
Severe T2 asthma ± CRS	Biology (according to GINA/EPOS)	Reduces exacerbations; dupilumab improves CRS
Alcohol reactions are troubling	Dupilumab (observational data)	May reduce alcohol triggers better than ATAD
[48]

Table 3. Safe pain relievers for AERD

Class	Medicines	Security Comments
Paracetamol	Paracetamol	More commonly tolerated; high doses cause symptoms in some patients - select individually
Selective COX-2	Celecoxib	Most preferred; did not provoke respiratory reactions in AERD in controlled studies
Selective (partially)	Meloxicam, etoricoxib	Tolerability is lower than that of celecoxib; reactions are possible; test doses should be carried out under the supervision of a specialist.
Avoid	Aspirin, ibuprofen, naproxen, diclofenac, etc. COX-1	Cross-reactive respiratory reactions are typical
[49]

Prevention

Primary and routine. Strictly avoid COX-1 NSAIDs; always check the ingredients of combination cold/back pain medications. Carry a "passport" with your diagnosis and a list of approved analgesics (e.g., paracetamol, celecoxib). Manage asthma according to GINA (regular inhaled steroids, correct technique) and CRS according to EPOS (daily gargles, intranasal steroids). Limit alcohol or adjust drinks/doses to your individual tolerance. [50]

Specific. Discuss with your doctor aspirin desensitization (if indicated) and/or biologic agents in severe cases. After ESS, the success rate of ATAD is higher. Antileukotriene drugs can reduce the frequency and severity of respiratory reactions and are useful as a background measure. Always have a clear "action plan" in case of accidental NSAID ingestion (where to go, what to do). [51]

Forecast

With a properly selected combination strategy (COX-1 avoidance + asthma/CRS control + ESS when indicated + ATAD and/or biologics), most patients achieve sustainable control: fewer exacerbations, fewer courses of systemic steroids and repeat surgeries, improved sense of smell and quality of life. The choice between ATAD and biologics is now individualized; both approaches are effective in their respective niches. [52]

The main risks are undiagnosed NSAID intolerance (recurrent severe reactions), overreliance on systemic steroids, and the lack of a clear pain management plan. Collaboration between the ENT specialist, pulmonologist, and allergist and patient education (including a "drug intolerance passport") significantly improve long-term outcomes. [53]

FAQ

• 1) Can I not take any painkillers?

Yes, yes. Paracetamol (with individual dose adjustment) and celecoxib (a COX-2 selective medication) are suitable for most patients with AERD. Classic COX-1 NSAIDs (aspirin, ibuprofen, naproxen, etc.) are not suitable. It is best to discuss alternatives with a specialist and document them in writing. [54]

• 2) Which is better: aspirin therapy or “biologics”?

There's no single answer. ATAD has a stronger effect on the ENT component (polyps/olfactory function) in some patients, but it requires commitment and isn't suitable for everyone. Biologics reduce asthma exacerbations and improve CRS (especially dupilumab), and sometimes they're better at reducing alcohol-related reactions. The decision is personalized; ATAD is more successful after ESS. [55]

• 3) How is AERD confirmed?

Based on clinical findings and, if necessary, an aspirin test (oral/intranasal) under safe conditions. Urinary LTE4 is helpful as a biomarker of severity and in monitoring, but does not yet replace provocation. [56]

• 4) Why is alcohol so addictive for AERD?

In most patients, alcohol triggers an eicosanoid cascade, increasing the production of PGD2 and leukotrienes; reactions occur in 50-80% of patients and occur after just a few sips. Biological therapy can reduce these reactions. [57]

• 5) Is it possible to be “cured” forever?

AERD is a chronic condition, but with the right management, symptoms and flare-ups can be reliably controlled. A long-term plan (COX-1 avoidance, asthma/CRS management, ATAD, and/or biologics) allows for a full life, work, and exercise. [58]