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.

Use of cephalosporins in patients with immediate penicillin hypersensitivity: cross-reactivity revisited.

A 10% cross-reactivity rate is commonly cited between penicillins and cephalosporins. However, this figure originated from studies in the 1960s and 1970s which included first-generation cephalosporins with similar side-chains to penicillins. Cephalosporins were frequently contaminated by trace amount of penicillins at that time. The side-chain hypothesis for beta-lactam hypersensitivity is supported by abundant scientific evidence. Newer generations of cephalosporins possess side-chains that are dissimilar to those of penicillins, leading to low cross-reactivity. In the assessment of cross-reactivity between penicillins and cephalosporins, one has to take into account the background beta-lactam hypersensitivity, which occurs in up to 10% of patients. Cross-reactivity based on skin testing or in-vitro test occurs in up to 50% and 69% of cases, respectively. Clinical reactivity and drug challenge test suggest an average cross-reactivity rate of only 4.3%. For third- and fourth-generation cephalosporins, the rate is probably less than 1%. Recent international guidelines are in keeping with a low cross-reactivity rate. Despite that, the medical community in Hong Kong remains unnecessarily skeptical. Use of cephalosporins in patients with penicillin hypersensitivity begins with detailed history and physical examination. Clinicians can choose a cephalosporin with a different side-chain. Skin test for penicillin is not predictive of cephalosporin hypersensitivity, while cephalosporin skin test is not sensitive. Drug provocation test by experienced personnel remains the best way to exclude or confirm the diagnosis of drug hypersensitivity and to find a safe alternative for future use. A personalised approach to cross-reactivity is advocated.