Cutaneous adverse drug eruptions (CADEs) may occur on an immunologic or a nonimmunologic basis. Of all adverse drug reactions (ADRs), nonimmunologic ADRs outnumber immunologic drug reactions. However, with regard to cutaneous adverse reactions, an immunologic etiology should be suspected. Important exceptions are pseudoallergic reactions, which are caused by direct mast cell release, complement activation, or alteration of arachidonic acid metabolism, clinically mimicking a true allergy. Common etiologic agents of pseudoallergic reactions include opiates, aspirin, vancomycin, and radiocontrast media.
Hypersensitivity drug reactions may be grouped according to the Gell-Coombs classification:
1. Type I—immunoglobulin E (IgE)-dependent reactions (urticaria, angioedema, and anaphylaxis). Type I reactions may be immediate or may take >72 hours to occur.
2. Type II—cytotoxic reactions: antibody against a fixed antigen (druginduced pemphigus and petechiae secondary to drug-induced thrombocytopenia).
3. Type III—immune-complex formation (vasculitis and serum sickness-like reaction [SSLR]).
4. Type IV—delayed-type hypersensitivity, cell-mediated mechanism exanthems, fixed drug eruption (FDE), lichenoid eruption, acute generalized exanthematous pustulosis (AGEP), erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS)/druginduced hypersensitivity syndrome (DIHS), and pseudolymphoma.
In a recent study, there were an estimated 635,982 CADE-related outpatient visits per year to United States outpatient clinics and emergency departments, with 2.26 CADEs per 1,000 persons. The incidence of CADEs increased with age, affecting ages 70 to 79 most significantly.1 ADRs occur in 6.7% of all hospitalized patients, with cutaneous drug reactions occurring in >2% of hospitalized patients.2
II. CLINICAL PRESENTATION
In addition to skin findings, drug reactions may be manifested as fever or as alterations of one or many organ systems (e.g., hemolysis, thrombocytopenia, and renal damage).
A. Exanthematous Eruptions
The most common type of cutaneous reaction.
Also described as morbilliform or maculopapular.
Usually appear after 1-2 weeks of the causative drug being started; sensitization may occur after the first exposure or may develop to an antigen that the patient has been intermittently exposed to for years.
A rash may also start within 4 to 7 days of the offending drug being stopped (some antibiotics, particularly semisynthetic penicillins and allopurinol, may produce a rash 2 or more weeks after initiation).
Lesions most often start first and clear first from the head and upper extremities. Lesions of the trunk and lower legs often follow in succession.
Once the eruption has started, cutaneous lesions will become more severe and widespread over the following several days to a week and will then clear over the next 7 to 14 days.
Multiple drugs are associated with an exanthematous eruption including the penicillins, sulfonamides, barbiturates, and seizure medications.
Amoxicillin-induced morbilliform eruptions are mediated by a T-cell immune reaction, which may explain the increased incidence of this eruption when a patient is infected with the Epstein-Barr virus (acute mononucleosis).3
B. Urticaria
The second most common type of cutaneous drug eruption.
Urticarial eruptions may be due to pseudoallergic, type I-, or type III-mediated reactions.
Characterized by multiple pruritic wheals, widely scattered on the body. Individual lesions last <24 hours.
Angioedema may accompany urticaria and may result in eyelid, lip, and mucous membrane swelling.
The differential diagnosis of urticaria includes urticarial lesions due to vasculitis and/or serum sickness.
Angiotensin-converting enzyme (ACE) inhibitors are frequent causes of angioedema, often without urticaria, with the reaction occurring within an hour or several months of its administration.
C. Serum Sickness-Like Reaction
Serum sickness-like eruptions consist of fever, a rash with usually urticarial features, and arthralgias occurring within 1 to 3 weeks of initiation of the drug. Lymphadenopathy and eosinophilia may also be found.
Two of the most common drugs to induce this reaction are cefaclor and minocycline.
Treat with a short course of oral corticosteroids if symptoms are severe.
D. Acute Generalized Exanthematous Pustulosis
Characterized by the sudden onset of fever, leukocytosis, and a generalized eruption of monomorphous sterile pustules on a background of edema and erythema.
Discontinuation of the drug is usually all that is necessary.
Desquamation will occur 2 weeks later.
The most common offending drugs are the β-lactam and macrolide antibiotics (Table 12-1).
E. Fixed Drug Eruption
Lesions develop 1 to 2 weeks after a first exposure; with subsequent exposures they may appear within 24 hours.
Round and sharply demarcated erythematous plaques with possible central erosions are found anywhere on the body, but tend to favor lips, face, hands, feet, and genitalia.
Lesions fade over several days, often leaving residual postinflammatory hyperpigmentation. A nonpigmented variant of FDE is of note as it is commonly caused after the administration of pseudoephedrine.
Upon readministration of the causative drug, the lesions recur at the exact same locations, with potential to involve additional sites at each readministration.
The presence of numerous lesions is referred to as generalized FDE, and it may be difficult to distinguish from EM or SJS (when the oral mucosa is also involved).
Differential diagnosis includes spider or arthropod bite reaction, and EM or SJS when many lesions are present, particularly at mucous membranes.
Common etiologic agents for FDE include sulfonamides, nonsteroidal anti-inflammatory drugs, barbiturates, tetracycline, and carbamazepine (Table 12-1).
TABLE 12-1 Clinical Presentation and Selected Drug Etiology, Workup, and Treatment
Clinical Presentation
Description
Time Interval
Common Etiologic Drugs
Workup and Treatment
Exanthematous reactions
Morbilliform or maculopapular with rash beginning and ending on face and upper extremities, torso and lower extremities follow
7-14 d after initiation
Allopurinol, aminopenicillins, anticonvulsants, cephalosporins, and sulfonamides
