Nsaid hypersensitivity

Non-steroidal anti-inflammatory drugs are among the most commonly prescribed pharmaceuticals worldwide, accounting for approximately 10% of global pharmacy sales (Wedi B 2017).

In principle, NSAIDs can all cause 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 most common.

Knowledge and management of NSAID hypersensitivity are thus of great clinical importance.

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

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

In the rarer immunological late reactions, versch. Mechanisms involving T cells (type IV reactions - SNIDR), cytotoxic T cells and NK cells are considered. Clinically, lichenoid drug exanthema, severe systemic drug reactions (SCAR) such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) and "drug reaction with eosinophilia and systemic symptoms" (DRESS) appear, which not infrequently become threatening due to acute tubulointerstitial nephritis.

According to the time of occurrence:

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

According to etiopathogenetic reaction form:

• Non-immunological trigger: Dysbalance in arachidonic acid metabolism. Arachidonic acid is provided by phospholipases from the phospholipids of the cell membranes of eosinophils, mast cells and leucocytes. Via lipoxygenases and cyclooxygenases (COX) two metabolic pathways are optionally taken, some of whose products have an antagonistic effect. Prostaglandins (e.g. prostaglandin E2) are produced via the leukotriene C4 (LTC4) cyclooxygenase metabolic pathway. Peptide leukotrienes (PLT) are formed via the lipoxygenase metabolic pathway. In contrast to prostaglandins, PLT have a bronchospastic and mucous-forming effect. Patients with NSAID hypersensitivity tend to produce PLT in excess, probably due to an increased activity of LTC4 synthetase (cause: possible polymorphism of the gene sequence of LTC4 synthetase on chromosome 5q). In patients with AIS, a "shifting" (unchecked change) to the lipoxygenase metabolic pathway was 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/angiogenetic edema).

According to recent nomenclature, the term NSAID hypersensitivity (also NSAID hypersensitivity/hypersensitivity/intolerance) covers 5 different entities:

• NECD: NSAID exacerbated cutaneous disease (worsening of underlying urticaria / angioedema by NSARs.
• NIUA: NSAIDs-induced urticaria-angioedema (urticaria/angioedema caused by NSAIDs).
• NERD: NSAIDs exacerbated respiratory disease (all respiratory hypersensitivity caused by NSAIDs)
• SNIDR: Single-NSAID-induced delayed reactions (true T-cell-mediated drug reactions)
• SNIUAA: Single-NSAID-induced urticaria/angioedema or anaphylaxis (very rare, true IgE-mediated allergic reactions to NSAIDs - e.g. diclofenac, ibuprofen)

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).

Careful anamnesis, skin tests, stationary placebo-controlled provocation procedures in emergency preparedness, laboratory tests (basophil activation test, usually only minor relevance). Nasal or bronchial provocations are also possible in case of respiratory reactions (Wedi B 2017). In the case of severe index reactions, a careful risk assessment must be performed. Cross-reactions must be excluded (concerns NSAIDs of the same drug group e.g. COX-1 inhibitors). Alternatively, avoidance tests are recommended.

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

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

Reaction pattern:

• skin type (pruritus, urticaria, angioedema)
• Respiratory type (cough, bronchial asthma, shortness of breath, rhinorrhoea, 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 respond with significantly lower dose than patients with NECD/NUA.
• Indications of cross-reactions
• >3 episodes on various NSAR implies a high probability of NSAR 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 genesis

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. Cortellini G et al (2017) Clinical approach on challenge and desensitization procedures with aspirin in patients with ischemic heart disease and nonsteroidal anti-inflammatory drughypersensitivity. Allergy 72: 498-506.
2. Grattan CE (2003) Aspirin sensitivity and urticaria. Clin Exp Dermatol 28:123-127.
3. Jenkins C et al (2004) Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 328:434.
4. Kim JE et al (2007) The prevalence of Samter's triad in patients undergoing functional endoscopicsinus surgery. Ear Nose Throat J 86:396-399.
5. 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.
6. Laidlaw TM et al (2016) Aspirin-Exacerbated Respiratory Disease--New Prime Suspects.
   N Engl J Med 374:484-488.
7. Wedi B (2017) Current diagnosis of NSAID hypersensitivity. Allergo J Int 26: 204-211
8. Wöhrl S (2018) NSAID Hypersensitivity - Recommendations on Diagnostics and Patient Management. Allergo J Int 27: 113-121