NSAID hypersensitivity

NSAID hypersensitivity refers to a range of adverse reactions to NSAIDs and includes the pseudoallergic reactions aspirin-exacerbated respiratory disease (AERD), NSAID-exacerbated cutaneous disease (NECD), and NSAID-induced urticaria/angioedema (NIUA), and the allergic reactions single NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA), and single NSAID-induced delayed hypersensitivity reaction (SNIDHR). The underlying mechanism involves an imbalance between proinflammatory leukotrienes and anti-inflammatory prostaglandins due to cyclooxygenase-1 (COX-1) inhibition (e.g., in AERD, NECD, and NIUA) or an immunologic allergic reaction (e.g., in SNIUAA and SNIDHR). Diagnosis is primarily based on history and clinical presentation and, in some cases, drug challenge testing. Treatment involves discontinuation of the offending NSAID, management of severe reactions (e.g., anaphylaxis), and desensitization for patients requiring continued NSAID use. Nasal polypectomy and/or aspirin desensitization may be necessary to manage symptoms in patients with AERD.

Epidemiology ^[1]

• NSAID hypersensitivity prevalence: up to 5.7% of the general population ^[1]
• Aspirin hypersensitivity prevalence: up to 2% of the general population ^[2]

Clinical features and pathophysiology ^[1]

The following conditions are triggered by exposure to aspirin or other NSAIDs.

Diagnosis is based on history and clinical presentation. In some cases, drug challenge testing is performed to confirm the diagnosis.

Drug challenge testing ^[3][4][6]

Perform diagnostic challenge testing under the guidance of an allergy and immunology specialist.

• Method: exposure to gradually increasing NSAID or aspirin doses (up to the therapeutic dose) in a controlled, monitored setting
• Indication: diagnosis cannot be confirmed by history and clinical presentation and continued NSAID use is required
• Contraindications
  • History of anaphylaxis
  • History of severe cutaneous adverse reactions (e.g., TEN, SJS)
  • Poorly controlled asthma
• Agent ^[6]
  • Nonaspirin NSAID: for patients who react to aspirin
  • Aspirin: for patients who react to another NSAID
• Modalities
  • Oral challenge (oral provocation testing): diagnostic gold standard
  • Nasal and/or inhalation challenge
  • IV challenge (rare)
• Findings: clinical features of the specific NSAID hypersensitivity condition (see “Overview”)

Additional findings ^[4]

The following findings may be used to support the diagnosis.

• AERD ^[4]
  • ↑ 24-hour urine leukotriene E₄
  • Eosinophilia
  • Sinus opacification (e.g., on CT maxillofacial with or without IV contrast)
• SNIDHR: patch testing ^[6]

Approach ^[4][6]

• Discontinue the causative agent.
• Stabilize the patient and provide immediate care for severe reactions, e.g.:
  • Management of anaphylaxis
  • Management of angioedema
  • Treatment of SJS and TEN
• Manage comorbid conditions and acute flares, e.g.:
  • Acute and chronic rhinosinusitis, e.g., intranasal and/or oral corticosteroids (see “Treatment of sinusitis”)
  • Asthma and acute exacerbation, e.g., bronchodilators, leukotriene-receptor antagonists (see “Stepwise asthma treatment”)
  • Acute and chronic urticaria, e.g., antihistamines, glucocorticoids (see “Management of urticaria”)
• Consider nasal polypectomy in selected patients with AERD. ^[4]
• Consult an allergy and immunology specialist for the consideration and initiation of NSAID desensitization.

Avoid the causative agent (and cross-reacting NSAIDs in some cases) if desensitization is not performed. ^[1][6]

NSAID desensitization ^[4][6]

• Indications
  • Continued NSAID use required ^[3]
  • Patients with AERD and all of the following:
    • Nasal polyp recurrence
    • Suboptimal symptom control despite symptomatic treatment
    • Need for frequent corticosteroids
• Procedure for oral desensitization ^[4]
  • Perform under medical supervision in a specialized facility with access to emergency treatment.
  • Begin with a low dose of the offending NSAID.
  • Gradually increase the dose over 1–3 days.
  • Once the target dose (e.g., 325 mg aspirin) is reached, continue daily administration to maintain desensitization. ^[4]
• Complications ^[4]
  • GERD and/or gastrointestinal ulcers
  • Bleeding (e.g., ecchymoses, epistaxis)