Drug-induced hypersensitivity syndrome (DIHS) is a potentially severe idiosyncratic drug reaction with systemic manifestations including fever, rash, and internal organ involvement, most typically hepatitis. The acronym DRESS, for drug reaction with eosinophilia and systemic symptoms, was proposed as a more specific term in 1996. However, because only 60%-70% of patients demonstrate eosinophilia, many have suggested using DIHS to avoid confusion. The specific underlying mechanisms of this condition are unknown, and they likely vary between patients and specific drugs. Defects in the detoxification of anticonvulsants and sulfonamides have been demonstrated in patients with DIHS, with higher prevalence in certain ethnic groups and human leukocyte antigen (HLA) types. Human herpesviruses 6 and 7 (HHV-6 / HHV-7), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) reactivation have also been demonstrated in many of these patients, although the pathogenic role of this viral reactivation, if any, is yet to be determined.

Clinically, symptoms develop 2-8 weeks after initiation of the responsible drug. If a patient is rechallenged with the drug, the reaction will occur within 24 hours. An exanthematous eruption is present in over 80% of cases and can worsen even after the withdrawal of the offending drug. Eosinophilia and/or a mononucleosis-like atypical lymphocytosis is commonly observed. The liver is the most commonly and severely affected visceral site. Myocarditis, interstitial pneumonitis, interstitial nephritis, encephalitis, myositis, pancreatitis, and thyroiditis have all been observed. Cutaneous and visceral involvement may persist for several months after discontinuation of the offending drug.

Some patients may experience multiple episodes of remission and relapse. Some instances of relapse have been associated with reactivation of HHV-6, HHV-7, EBV, or CMV.

Hypothyroidism and other autoimmune conditions such as pancreatitis, myocarditis, or type 1 diabetes may develop several months after the acute phase of the illness. Systemic lupus erythematosus, bullous pemphigoid, arthritis, alopecia, vitiligo, and sclerodermoid graft-versus-host disease (GVHD) have also been reported.

The most commonly implicated drug groups causing DIHS include anticonvulsants, sulfonamides, and NSAIDs. Anticonvulsants include phenytoin, carbamazepine, phenobarbital, and lamotrigine. DIHS secondary to anticonvulsants is occasionally referred to as anticonvulsant hypersensitivity syndrome. Sulfonamide-induced DIHS can have an earlier onset than hypersensitivity syndromes caused by other classes of antibiotics, appearing as early as 7-14 days after initiation of therapy. Minocycline, allopurinol, azathioprine, metronidazole, dapsone, antiretroviral agents (eg, abacavir), clopidogrel, and ticlopidine are other known causes of DIHS.

It is imperative to withdraw the suspect medication(s) as soon as possible, as there is a 10% mortality associated with complications of organ inflammation, with liver injury being the most common cause of mortality and myocarditis the second most common.