Immune mechanisms of drug allergy

The majority of adverse reactions to drugs do not involve specific immunologic sensitization (Table 1). Such nonimmunologic reactions include side effects, toxicity, and other pharmacologic effects, and will not be addressed here. Historically, immunologic drug reactions have been described in the context of the Gell and Coombs system (Table 2). This model continues to be useful clinically in certain situations. Indeed, demonstrating the presence of specific IgE to penicillin in the context of an appropriate clinical history has impressive predictive value. This approach, however, has limited use when applied to other drug reactions. For example, the well-known pseudoallergic reactions to nonsteroidal anti-inflammatory drugs (NSAIDs), radiocontrast media, and opiates all may present clinically with immediate urticaria, angioedema, bronchospasm, gastrointestinal distress, and cardiovascular collapse indistinguishable from IgE-mediated anaphylaxis, yet they do not require sensitization and do not appear to be allergenic as haptens or complete antigens. Clinical serum sickness symptoms that have been generally attributed to the Gell and Coombs Type III (i.e., immune complex) mechanism also may be misleading. For example, cells from patients who have had classic serum sickness reactions (e.g., fever, arthralgia, or erythema multiforme) to the antibiotic cefaclor die in vitro when exposed to a metabolized form of the drug, whereas cells from patients without such a history do not die. 23 In addition, immune complexes associated with cefaclor-induced serum sickness have never been identified. This suggests that the serum sickness may be caused by a cytotoxic effect of the drug on cells rather than by an immunologic reaction to the drug. To improve our ability to address these clinical challenges in the future, we must extend our understanding of the mechanisms involved. By definition, a true hypersensitivity response to a drug requires the development of an immune response to that agent. Such an immune response must be similar to the immune response to any antigen. There are several unique aspects of drugs, however, which make their interaction with the immune system unusual. This article provides an overview of how immune responses develop to antigens and emphasizes the unique features pertinent to the development of drug hypersensitivity. The factors that potentially influence the development of drug allergy are summarized in Table 3. Unfortunately, little is understood regarding the immune response to drugs; thus, much of this overview is speculative. This article emphasizes several unique aspects of the immune response to drugs, and most importantly, their function as incomplete antigens (i.e., haptens), which cannot trigger hypersensitivity reactions until they become covalently linked to an appropriate carrier molecule. 13,25,35 Any theory regarding the mechanism of drug allergy must also explain the phenomenon that in contrast to the atopic diseases—allergic rhinitis, asthma, and atopic dermatitis—drug allergies develop with the same frequency in atopic and nonatopic individuals. 2,46 Although atopy is not a risk factor for the development of drug allergy, surprisingly, there may be a familial predisposition. 4 Any mechanism proposed for the development of hypersensitivity toward haptens must provide a mechanism for this genetic predisposition and the tendency to develop multiple drug sensitivities to what are often completely unrelated compounds.