ABSTRACT
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623 The Hapten Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 Genetic Predisposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 The Danger Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
A Holistic Approach to Drug Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625 Is the Drug Inherently Immunogenic?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626 Is the Drug Inherently Reactive? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626 Is the Drug Biotransformed to Protein-Reactive Products? . . . . . . . . . . . . . 627 Have Signs Consistent with Drug Allergy Been Observed in Nonclinical Toxicology Studies? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627 What Effects Have Been Observed in Clinical Trials Suggestive of Drug Allergy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
A Phenomenology of Drug Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630
Drug allergy is essentially a colloquial term used to describe pathologies that seem to have an immunological basis. It is important to remember when discussing drug allergy that an uncertain fraction of this group of phenomena only resembles what would be considered immunologic reactions, and at this time there is great uncertainty concerning the size of the fraction. As will be discussed below, there are many pathologies that are grouped under the general heading of “immune-mediated drug hypersensitivity reactions” (IDHR). Consider, for example the classic drug allergy reaction anaphylaxis. A quick search on the term in many databases (such as the Physicians Desk Reference-the PDR) gives a clue to the problem. In the case of the PDR, the latest edition lists anaphylaxis as a drug-associated adverse reaction in 235 product labels. It is highly unlikely that all of these products have the ability to induce true anaphylaxis. Most likely, signs associated with anaphylaxis-basically shock-like reactions-were reported when the drug was administered. Why so many drugs have the ability to produce shock reactions, interpreted as anaphylaxis, is unknown. What is clear, however, is that in the absence of relatively specifi c biomarkers-such as anti-drug IgE antibodies-the diagnosis is likely incorrect. In order to understand why it is so diffi cult to correctly diagnose IDHR it
is necessary to understand the complex factors that seem to be involved in true drug allergy.
