NSAID hypersensitivity

Non-steroidal anti-inflammatory drugs are among the most frequently prescribed pharmaceuticals worldwide and account for around 10% of global pharmacy sales (Wedi B 2017). In principle, NSAIDs (NASAIDs) can all trigger a wide range of allergic reaction types, but non-immunological immediate reactions with cutaneous (urticaria/angioedema) and/or respiratory symptoms(rhinitis, bronchial asthma) and anaphylactic reactions are the most common. Knowledge and management of NSAID (NASAID) hypersensitivity are therefore of great clinical importance.

In the case of (non-immunologically) triggered cutaneous NSAIDs(NECD), immediate reactions to ibuprofen, diclofenac and acetylsalicylic acid are in the foreground.

Acetylsalicylic acid dominates the immediate respiratory reactions(NERD) (Kowalski ML et al. 2011). COX-2 inhibitors (celecoxib, etoricoxib, parecoxib) very rarely cause hypersensitivity reactions.

In the rarer immunological late reactions, various mechanisms involving T-cells are described. Mechanisms involving T-cells (type IV reactions - SNIDR), cytotoxic T-cells and NK-cells are considered. Clinical manifestations include lichenoid drug exanthema, severe systemic drug reactions (SCAR) such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) anddrug reaction with eosinophilia and systemic symptoms(DRESS), which often become threatening due to acute tubulointerstitial nephritis.

By time of onset:

• Immediate cutaneous and/or respiratory reactions (occurring within minutes or hours; by far the most common type of reaction)
• Delayed reactions (occurring within > 24 hours)

By etiopathogenetic type of reaction:

• Non-immunologic trigger: imbalance in arachidonic acid metabolism. Arachidonic acid is provided by phospholipases from the phospholipids of the cell membranes of eosinophils, mast cells and leukocytes. Via lipoxygenases and cyclooxygenases (COX), two metabolic pathways are optionally followed, the products of which partly have an antagonistic effect. Prostaglandins (e.g. prostaglandin E2) are formed via the leukotriene C4 (LTC4) cyclooxygenase metabolic pathway. Peptide leukotrienes (PLT) are formed via the lipoxygenase metabolic pathway. In contrast to prostaglandins, PLTs have a bronchospastic and mucus-forming effect. Patients with NSAID hypersensitivity tend to overproduce PLT, probably due to increased activity of LTC4 synthetase (cause: possible polymorphism of the LTC4 synthetase gene sequence on chromosome 5q). In patients with AIS, shifting to the lipoxygenase pathway has been described after administration of NSAIDs.
• Immunological triggering: true (rare) T-cell-mediated, type IV drug exanthema; true (very rare) IgE-mediated type I reactions (urticaria/angioedema).

According to more recent nomenclature, 5 different entities are summarized under the term NSAID hypersensitivity (also NSAID hypersensitivity/hypersensitivity/intolerance):

• NECD: NSAID exacerbated cutaneous disease (worsening of underlying urticaria/angioedema due to NSAIDs. Presumed mechanism: COX1 inhibition.
• NIUA: NSAIDs-induced urticaria-angioedema (urticaria/angioedema triggered by NSAIDs). Suspected mechanism: COX1 inhibition.
• NERD: NSAIDs exacerbated respiratory disease (all respiratory hypersensitivities triggered by NSAIDs). Presumed mechanism: COX1 inhibition.
• SNIDR: Single-NSAID-induced delayed reactions (true T-cell-mediated drug reactions). IgE-mediated. T cell-mediated (type IV reaction), cytotoxic T cells, NK cells.
• SNIUAA: Single-NSAID-induced urticaria/angioedema or anaphylaxis (very rare, true IgE-mediated allergic reactions to NSAIDs - e.g. diclofenac, ibuprofen). IgE-mediated.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the second most common trigger of a drug hypersensitivity reaction in adults and children. This group of drugs is also considered the second most common cause of drug-induced anaphylaxis. In the USA, the one-year incidence of adverse drug reaction (ADR) was reported to be 1.7% in relation to NSAID prescriptions (Blumenthal KG et al. 2017). Up to 2% of the adult general population is affected by acetylsalicylic acid hypersensitivity.

For previously known bronchial asthma, the prevalence of NSAID hypersensitivity is reported to be 4-11% (Kowalski ML et al. 2011). In children it is significantly lower at 5% (Jenkins C et al. 2004).

In previously known bronchial asthma and polyposis nasi, the prevalence of hypersensitivity to acetylsalicylic acid is 26% (formerly known as velvet triad, now known as NERD - Kim JE et al. 2007).

For previously known urticaria the prevalence of hypersensitivity to acetylsalicylic acid is 27-35% (Grattan CE 2003). In children the prevalence is 25% (Wedi B 2017).

The definitive mechanism of NSAID hypersensitivity (intolerance) has not been definitively clarified. Probably the NSAR-COX blockade leads to a massive overproduction of prostaglandin E2 (Laidlaw TM et al. 2016).

The oral provocation test is considered the gold standard for suspected hypersensitivity to non-steroidal anti-inflammatory drugs (Valesky EM et al 2020). It provides reliable results. Suspicion can be verified by administering the suspected trigger. Cross-reactivity and contractual treatment alternatives can be identified by administering alternative preparations. As the most common ADR symptoms with NSAIDs, in addition to pruritus and dyspnoea, are urticaria and angioedema (grade I), severe allergic symptoms must be taken into account in the tests. They develop in almost ¾ of all patients within 120 minutes of ingestion (on average around 30 minutes). In cases where patients only develop symptoms in response to high doses of ASA, for example, low-dose ASA (1 omg) can be administered if necessary.

Careful medical history, skin tests, inpatient placebo-controlled provocation procedures in emergency standby, laboratory tests (basophil activation test, usually of little relevance). In the case of respiratory reactions, nasal or bronchial provocation is also possible (Wedi B 2017). A careful risk assessment must be carried out in the event of a severe index reaction. Cross-reactions must be ruled out (concerns NSAIDs of the same drug group, e.g. COX-1 inhibitors). Alternatively, evasion tests are recommended.

Late reactions: Careful medical history, skin biopsy, epicutaneous testing, inpatient placebo-controlled provocation procedures (gold standard), laboratory tests (usually only of minor relevance, e.g. LTT). Alternatively, evasion tests are recommended.

Allergological medical history with the following questions (varies according to S. Wöhrl 2018)

Reaction pattern:

• Skin type (pruritus, urticaria, angioedema)
• Respiratory type (cough, bronchial asthma, shortness of breath, rhinorrhea, blockage of nasal breathing)
• True anaphylaxis (drop in blood pressure, loss of consciousness, emergency medical measures)

Number of episodes, triggering dose:

• Number of episodes
• Triggering dose (patients with NERD react with significantly lower doses than patients with NECD/NUA.
• Indications of cross-reactions
• >3 episodes on different NSAIDs NSAIDs implies a high probability of NSAID hypersensitivity.

Pre-existing underlying disease:

• Chronic spontaneous urticaria
• Bronchial asthma
• Nasal polyps
• Chronic rhinosinusitis

Differential diagnoses to be excluded:

• Urticaria/angioedema or asthma of other origin

In the case of confirmed NSAID hypersensitivity, a life-long leave of absence is recommended. In case of hypersensitivity to a COX-1 inhibitor, it is recommended to avoid all COX-1 inhibitors, as cross-reactions are likely. This also applies analogously to COX-2 inhibitors. Alternative alternative preparations are opioid analgesics such as tramadol and tilidine.

In case of an assured immediate respiratory reaction and chronic rhinosinusitis with nasal polyps, tolerance induction (adaptive deactivation) with acetylsalicylic acid is recommended (Beule A et al. S2k guideline rhinosinusitis;). Tolerance induction is successful in >90% of patients (Cortellini G et al. 2017). After tolerance induction a daily intake is necessary, otherwise the tolerance will disappear again after 2-5 days. It is therefore particularly suitable for patients with coronary heart disease who have a daily requirement of ASA (see also salicylate intolerance).

Avoidance of the NSAIDs in question. Evasion tests with clinically relevant dosage for an alternative therapy. Paracetamol is generally tolerated in cases of NSAID hypersensitivity.

Drug reactions to NSAIDs are described inconsistently as hypersensitivity, hypersensitivity, idiosyncrasy, intolerance. Internationally, the term hypersensitivity is most commonly used.

NSAIDs are not found in food. The benefit of a low-salicylate diet with proven hypersensitivity to acetylsalicylic acid has not been proven (Wedi B 2017).

Since the mechanism of non-immunological NSAID hypersensitivity is COX-1 inhibition, classical skin allergy tests will remain negative and cannot be recommended!

Oral provocation tests in increasing dosages (e.g. ASS 50-250-500-1000mg) are proof of this. For other NSAIDs the following applies: 1/10 -1/2-1/1/1 of the normal dosage.

Provocation tests should only be performed under stationary conditions!

1. Angeletti F et al. (2020) Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) - a retrospective study. J Dtsch Dermatol Ges 18:1405-1416.

2. Cortellini G et al. (2017) Clinical approach on challenge and desensitization procedures with aspirin in patients with ischemic heart disease and nonsteroidal anti-inflammatory drug hypersensitivity. Allergy 72: 498-506.
3. Grattan CE (2003) Aspirin sensitivity and urticaria. Clin Exp Dermatol 28:123-127.
4. Jenkins C et al. (2004) Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 328:434.
5. Kim JE et al. (2007) The prevalence of Samter's triad in patients undergoing functional endoscopic sinus surgery. Ear Nose Throat J 86:396-399.
6. Kowalski ML et al. (2011) Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA*. Allergy 66:818-29.
7. Laidlaw TM et al. (2016) Aspirin-Exacerbated Respiratory Disease--New Prime Suspects.
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8. Wedi B (2017) Current diagnostics of NSAID hypersensitivity. Allergo J Int 26: 204-211
9. Wöhrl S (2018) NSAID hypersensitivity -recommendations for diagnosis and patient management. Allergo J Int 27: 113-121