Drug Hypersensitivity Syndrome

• Drug hypersensitivity syndrome is an idiosyncratic adverse drug reaction that begins acutely in the first 2 months after initiation of the drug and is characterized by fever, malaise, and facial edema with lymphadenopathy or an exfoliative dermatitis. Synonym: Drug reaction (not rash) with eosinophilia and systemic symptoms (DRESS).
• Etiology. Most commonly: Allopurinol, antiepileptic drugs (phenytoin, carbamazepine, or phenobarbital; cross-sensitivity among the three drugs is common) and sulfonamides (antimicrobial agents, dapsone, or sulfasalazine). Less commonly: Minocycline, abacavir, gold salts, sorbinil, zalcitabine, calcium-channel blockers, ranitidine, thalidomide, or mexiletine. HHV-6 infection may be a risk factor.
• Some patients have a genetically determined inability to detoxify the toxic arene oxide metabolic products of anticonvulsant agents. Slow N-acetylation of sulfonamide and increased susceptibility of leukocytes to toxic hydroxylamine metabolites are associated with a higher risk of hypersensitivity syndrome.
• Skin Lesions.Early: Morbilliform eruption on the face, upper trunk, and the upper extremities; cannot be distinguished from an exanthematous drug eruption (Fig. 23-8). May progress to generalized exfoliative dermatitis/erythroderma, especially if the drug is not discontinued. Eruption becomes infiltrated with edematous follicular accentuation. Facial edema (especially periorbitally) is characteristic and may result in blister formation. Sterile pustules may occur. Eruption may become purpuric on legs. Scaling and/or desquamation may occur with healing.
• Distribution. Symmetric. Almost always on the trunk and extremities. Lesions may become confluent and generalized.
• Mucous Membranes. Cheilitis, erosions, erythematous pharynx, and enlarged tonsils.
• General Examination. Involvement of the liver, kidney, lymph nodes, heart, lungs, joints, muscles, thyroid, and brain also occurs.
• Eosinophilia (30% of cases). Leukocytosis. Mononucleosis-like atypical lymphocytes. Histology Skin. Lymphocytic infiltrate, dense and diffuse, or superficial and perivascular. ± Eosinophils or dermal edema. In some cases, bandlike infiltrate of atypical lymphocytes with epidermotropism, simulating cutaneous T-cell lymphoma.
• Proposed Diagnostic Criteria. (1) Cutaneous drug eruption, (2) hematologic abnormalities (eosinophilia ≥1500/µL or atypical lymphocytes), and (3) systemic involvement (adenopathies ≥2 cm in diameter or hepatitis [SGOT ≥2 N] or interstitial nephritis, or interstitial pneumonitis or carditis). Diagnosis is confirmed if three criteria are present. The European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) has also created criteria for hospitalized patients and a scoring system.
• Course and prognosis: Rash and hepatitis may persist for weeks after the drug is discontinued. In patients treated with systemic glucocorticoids, rash and hepatitis may recur as glucocorticoids are tapered. Lymphadenopathy usually resolves when the drug is withdrawn; however, rare progression to lymphoma has been reported. Patients may die from systemic hypersensitivity such as with eosinophilic myocarditis (10%). Clinical findings recur if the drug is given again.
• Management. Identify and discontinue the offending drug. Systemic. Prednisone (0.5 mg/kg per day) usually results in improvement of symptoms and laboratory parameters but may not prevent/treat end-organ dysfunction.
• Prevention. The individual must be aware of his or her specific drug hypersensitivity and that other drugs of the same class can cross-react. These drugs must never be readministered. Patient should wear a medical alert bracelet.