- Patho/Etiology
- NSAID hypersensitivity reactions are non-allergic, idiosyncratic reactions that can be broadly divided into two main categories: those mediated by COX-1 inhibition and those that are immune-mediated (Type I or Type IV hypersensitivity).
- COX-1 Inhibition (Cross-Reactive): Most common mechanism. Inhibition of the COX-1 enzyme shunts arachidonic acid metabolism toward the 5-lipoxygenase pathway.
- This leads to overproduction of pro-inflammatory cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄).
- Concurrently, there is a decrease in anti-inflammatory prostaglandins like PGE2.
- This imbalance drives bronchoconstriction, increased vascular permeability, and eosinophilic inflammation.
- Immune-Mediated (Selective): Less common and drug-specific; involves a single NSAID or structurally similar ones.
- Type I (IgE-mediated): Classic immediate hypersensitivity leading to urticaria, angioedema, or anaphylaxis.
- Type IV (T-cell mediated): Delayed reactions (e.g., maculopapular rash, SJS/TEN).
- Clinical Presentation & Types
- NSAID-Exacerbated Respiratory Disease (NERD): Also known as Samter’s Triad. Classic triad of asthma, chronic rhinosinusitis with nasal polyps, and respiratory symptoms (bronchospasm) upon ingestion of COX-1 inhibiting NSAIDs. Symptoms typically appear 30 minutes to 3 hours after ingestion.
- NSAID-Exacerbated Cutaneous Disease (NECD): Acute urticaria and/or angioedema in patients with a history of chronic spontaneous urticaria.
- NSAID-Induced Urticaria/Angioedema (NIUA): Development of urticaria/angioedema in patients without a history of chronic urticaria.
- Single NSAID-Induced Urticaria/Angioedema/Anaphylaxis (SNIUAA): An IgE-mediated reaction to a single NSAID, without cross-reactivity to other classes. Can progress to anaphylaxis.
- Diagnosis
- Clinical History: The most important initial tool is a detailed patient history, identifying the specific NSAID, timing, and nature of the reaction.
- Provocation Test (Drug Challenge): The gold standard for diagnosis, especially for cross-reactive types. This is performed in a controlled medical setting by administering escalating doses of the suspected NSAID (e.g., aspirin) to confirm hypersensitivity.
- Skin/Blood Tests: Generally not useful for cross-reactive (COX-1 mediated) hypersensitivity. Skin tests or specific IgE assays may be positive in rare, truly allergic (SNIUAA) cases.
- Differential Diagnostics
- Chronic Spontaneous Urticaria (CSU): NECD is an exacerbation of this underlying condition. In NIUA, there is no pre-existing urticaria.
- Food Allergy: NSAIDs can act as cofactors, lowering the threshold for an allergic reaction to a food that is otherwise tolerated. If a reaction occurs close to a meal, a food allergy should be considered.
- Anaphylaxis from other causes: If the presentation includes systemic symptoms, other triggers for anaphylaxis (foods, other drugs, insect stings) must be ruled out.
- Management
- Avoidance: The primary strategy is strict avoidance of the offending NSAID and all other cross-reacting COX-1 inhibitors (e.g., ibuprofen, naproxen, diclofenac).
- Safe Alternatives:
- Acetaminophen: Generally safe at low doses (<1000 mg), but high doses can weakly inhibit COX-1 and may trigger reactions in highly sensitive NERD patients.
- Selective COX-2 Inhibitors: Celecoxib is the preferred alternative for analgesia/anti-inflammatory needs as it does not significantly inhibit COX-1 and is usually well-tolerated. Weak COX-1 inhibitors can also be considered.
- NERD Management:
- Leukotriene Modifiers: Montelukast or zafirlukast can help manage underlying respiratory symptoms.
- Aspirin Desensitization: For patients who require aspirin for cardiovascular protection (e.g., post-MI) or to control severe NERD symptoms, desensitization followed by daily therapy is highly effective. This must be done in a specialized setting.
- ** biologics:** For severe disease, biologics targeting Type 2 inflammation may be used.