DHR is a delayed-type hypersensitivity reaction that occurs to weeks, with an average of 22 days, after starting a medication Antiepileptics (carbamazepine, phenytoin, phenobarbital, lamotrigine) are the most common cause of DHR Other medications that commonly cause DHR are trimethoprimsulfamethoxazole, minocycline, dapsone, sulfasalazine, and abacavir There appears to be a genetic susceptibility for developing DHR to certain medications For example, HLA-A*31:01 is associated with an increased risk of DHR following exposure to carbamazepine in children Other associations with DHR include human herpesvirus-6 (HHV6), in which reactivation has been detected in cases of DHR Though the exact role of HHV6 in the pathogenesis of DHR is still unclear, some evidence suggests that HHV6 reactivation creates immune dysregulation that causes DHR, while others suggest that DHR-induced immune dysregulation allows for HHV6 reactivation The main differential diagnosis for DHR includes a cutaneous-limited morbilliform drug eruption, Kawasaki disease, and viral exanthem The presence of fever, facial edema, lymphadenopathy, and laboratory abnormalities distinguishes DHR from a cutaneous-limited morbilliform eruption The absence of conjunctivitis and mucous membrane involvement suggests DHR rather than Kawasaki disease The initiation of a potential high-risk medication weeks before rash onset increases the likelihood that an eruption is DHR rather than a viral exanthem FIGURE 68.4 This morbilliform eruption presented several days after starting ampicillin therapy (Reprinted with permission from Elder DE, Elenitsas R, Rubin AI, et al Atlas and Synopsis of Lever’s Histopathology of the Skin 3rd ed Philadelphia, PA: Lippincott Williams & Wilkins; 2012.) The most important treatment for DHR is stopping the culprit medication Oral steroids can typically quickly stop progression of the disease by treating systemic inflammation Steroids should be tapered over several weeks to prevent a rebound of the reaction PUSTULAR Acute generalized exanthematous pustulosis (AGEP) is a less commonly seen drug eruption in children It presents with widespread erythema overlaid with numerous pinpoint, superficial, sterile pustules ( Fig 68.5 ) The pustules are fragile and easily ruptured, leaving superficial areas of desquamation over the background of erythema The eruption frequently starts on the face or within skin folds before rapidly spreading to the rest of the body Fever is usually present, while mucous membrane involvement is not seen AGEP presents within a few days of starting the triggering medication, usually an antibiotic In one study, pristinamycin, aminopenicillins, and quinolones were the most common causes of AGEP, but cephalosporins, macrolides, clindamycin, tetracycline, and terbinafine are other causes The differential diagnosis for AGEP includes DHR and pustular psoriasis Careful inspection for pustules or for areas of desquamation, indicating ruptured pustules, in addition to laboratory evaluation, will help distinguish AGEP from DHR Eliciting either a personal or family history of psoriasis or a history of a high-risk medication can help favor a diagnosis of either pustular psoriasis or AGEP, respectively AGEP generally resolves with desquamation within to 10 days after stopping the drug Topical steroids and oral antihistamines can provide symptomatic relief if needed FIGURE 68.5 Erythema caloricum: back (Courtesy of Benjamin Barankin, MD, Edmonton, Alberta, Canada In: Stedman’s Medical Dictionary for the Health Professions and Nursing 7th ed Wolters Kluwer: Philadelphia, PA; 2012.) VESICULOBULLOUS Fixed Drug Fixed drug eruption generally appears as a sharply demarcated erythematous to dusky, edematous oval, or circular plaque ( Fig 68.6 ) The plaques may become bullous Lesions can appear anywhere, but the lips, face, hands, feet, and genitals are commonly affected They often leave hyperpigmentation that may take months to resolve Although usually solitary, multiple or very large lesions may form in fixed drug eruption following repeated exposure to the triggering medication The lesions can be pruritic, burning, or asymptomatic Initially, lesions appear within weeks of starting a medication, but with repeated exposure, onset can occur in minutes to hours Sulfonamides, particularly trimethoprim-sulfamethoxazole, are the most common causes of fixed drug eruption in children ( Fig 68.7 ), though NSAIDs and tetracycline are also frequent causes Some foods and food additives have also been reported to cause fixed drug reactions Fixed drug eruption can often be confused for arthropod bites, urticaria, or EM The history of recurrence in the exact same location with prominent postinflammatory hyperpigmentation is more suggestive of a fixed drug eruption rather than arthropod bites Similarly, fixed drug eruption is typically not as pruritic as arthropod bites As noted above, urticaria is transient, so individual lesions resolve within 24 hours, with any residual pigmentation or purpura resolving within days rather than the months that fixed drug eruption hyperpigmentation may last As compared to EM, the lesions of fixed drug eruption are larger and fewer and occur in a different distribution Stopping and avoiding the causative medication allows for resolution of the fixed drug eruption and prevents recurrence A fixed drug eruption does not progress to more severe drug eruptions, like DHR or Stevens–Johnson syndrome (SJS) If needed, a topical steroid can treat pruritus