Hypersensitivity to antipyretics: pathogenesis, diagnosis, and management

Antipyretics are commonly prescribed drugs and hypersensitivity occurs at rates of 0.01% to 0.3%. Hypersensitivity can be due to immune mechanisms that include type I to IV hypersensitivity. Type I hypersensitivity results from specific immunoglobulin E production following sensitisation on first exposure. Subsequent exposures elicit degranulation of mast cells, culminating an immediate reaction. Non-type I hypersensitivity is a delayed reaction that involves various effector cells, resulting in maculopapular rash, fixed drug eruptions, drug reaction with eosinophilia and systemic symptoms, and Stevens-Johnson syndrome/toxic epidermal necrolysis. Antipyretics also cause non-immune hypersensitivity via cyclooxygenase inhibition. Apart from hypersensitivity to parent compounds, hypersensitivity to excipient has been reported. Clinical manifestations of antipyretic hypersensitivity involve the skin, mucosa, or multiple organs. Diagnosis of hypersensitivity requires a detailed history taking and knowledge of any underlying disorders. Differential diagnoses include infection, inflammatory conditions, and antipyretics acting as co-factors of other allergens. Investigations include specific immunoglobulin E assays, lymphocyte transformation test, basophil activation test, and skin prick test. Lack of standardisation and a scarcity of available commercial reagents, however, limit the utility of these tests. A drug provocation test under close supervision remains the gold standard of diagnosis. A trial of the culprit drug or other structurally different antipyretics can be considered. Patients with confirmed hypersensitivity to antipyretics should consider either avoidance or desensitisation. Other theoretical options include subthreshold or low-dose paracetamol, cyclooxygenase-2 inhibitors, pre-medication with antihistamines with or without a leukotriene receptor antagonist, co-administration of prostaglandin E2 analogue, traditional Chinese medicine, or desensitisation if antipyretics are deemed desirable. Safety and efficacy of unconventional treatments warrant future studies.