A patient develops aspirin-exacerbated respiratory disease (AERD) characterized by severe bronchospasm after aspirin ingestion. What is the precise pathophysiologic mechanism linking aspirin to bronchospasm in these patients?

• A Aspirin induces IgE-mediated type I hypersensitivity against salicylate haptens on mast cell surfaces in the airway
• B Aspirin inhibits COX-1 in the airway, reducing prostaglandin E2 which normally inhibits arachidonic acid conversion to leukotrienes; excess arachidonate is diverted to 5-lipoxygenase pathway producing excess cysteinyl leukotrienes (LTC4, LTD4, LTE4) causing bronchoconstriction ✓
• C Aspirin directly activates TRPV1 channels on airway C-fibers, releasing substance P causing neurogenic bronchospasm
• D Aspirin inhibits histamine methyltransferase, increasing local histamine levels which bind H1 receptors on bronchial smooth muscle

Explanation

AERD (Samter's triad) involves a non-immunologic (pseudo-allergic, not IgE-mediated) reaction to COX-1 inhibitors including aspirin. The prevailing mechanism: COX-1 inhibition in mast cells and eosinophils reduces prostaglandin E2 (PGE2), which normally suppresses 5-lipoxygenase (5-LOX) activity via EP2 receptors. Loss of PGE2 removes inhibitory 'brake' on 5-LOX, causing increased synthesis of cysteinyl leukotrienes (LTC4, LTD4, LTE4). These are potent bronchoconstrictors that also stimulate mucus secretion and mast cell degranulation. These patients have upregulated cysteinyl leukotriene receptor CysLT1. Treatment includes leukotriene antagonists (montelukast) and aspirin desensitization.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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