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Pichler WJ (ed): Drug Hypersensitivity. Basel, Karger, 2007, pp 168–189 Drug Hypersensitivity Reactions: Classification and Relationship to T-Cell Activation Werner J. Pichler Division of Allergology, Department for Rheumatology and Clinical Immunology/Allergology, Inselspital, University of Bern, Bern , Switzerland A b s t r a c t gic reaction without detectable reactions of the The clinical characteristics of drug hypersensitivity reac- adaptive immune system. tions are very heterogeneous as drugs can actually elicit all Drug hypersensitivity reactions can become types of immune reactions. The majority of allergic reac- tions involve either drug-specific IgE or T cells. Their stimu- manifest in a great variety of clinical symptoms lation leads to quite distinct immune responses, which are and diseases, some of which are quite severe and classified according to Gell and Coombs. Here, an extension even fatal [2, 3] . The most common allergic reac- of this subclassification, which considers the distinct T-cell tions occur in the skin and are observed in about functions and immunopathologies, is presented. These 2–3% of hospitalized patients [4, 5] . Any drug is subclassifications are clinically useful, as they require differ- assumed to be able to elicit hypersensitivity reac- ent treatment and diagnostic steps. Copyright © 2007 S. Karger AG, Basel tions. Antibiotics and antiepileptics are the drugs most frequently causing them. The risk of sensi- tization and the severity of clinical symptoms de- pend on the state of immune activation of the in- Introduction dividual, the dose and duration of treatment, fe- male sex and the immunogenetic predisposition Drug-induced adverse reactions are common (in particular HLA-B alleles), while a pharmaco- and normally classified as type A reactions, genetic predisposition has rarely been detected which represent predictable side effects due a [see chapters of Hung et al., pp 105–114, and No- pharmacological action of the drug or type B re- lan et al., pp 95–104]. actions, which are not predictable and comprise Epicutaneous application of a drug clearly in- idiosyncratic reactions due to some individual creases the risk of a sensitization compared to predisposition (e.g. an enzyme defect), and hy- oral or parental treatments. It may be due to persensitivity reactions [1] . Drug hypersensitivi- the high density of dendritic cells in the skin. ty reactions account for about one sixth of all ad- Atopy – defined as the genetic predisposition to verse drug reactions. They comprise allergic and mount an IgE response to inhaled or ingested in- so-called pseudoallergic reactions. The latter is nocuous proteins – is normally not associated characterized by having the features of an aller- with a higher risk of drug hypersensitivity in general. However, an atopic predisposition may with other, structurally-related drugs, natural prolong the persistence of drug-specific IgE in course and prognosis. It requires knowledge of the serum [6] , and an ongoing IgE-mediated al- underlying immune mechanisms, and of how lergic inflammation may aggravate the symp- these mechanisms result in different forms of toms of an IgE-mediated drug hypersensitivity clinical disease. On the other hand, one has to be reaction. aware that a classification is a simplification of complex events occurring in vivo. The immune system often combines different approaches to Classification of Drug Hypersensitivity defend against a real or – as is the case with Reactions allergies – putative pathogen. On the other hand, in many hypersensitivity diseases a certain type Drug hypersensitivity reactions can cause many of immune reaction dominates the clinical pic- different diseases. To account for this heteroge- ture, even if the immune response is rather com- neity and to better explain the various clinical plex. pictures, Gell and Coombs [7] have classified In drug hypersensitivity, an additional level drug hypersensitivity as well as other immune re- of complexity derives from the p-i concept (phar- actions in four categories termed type I–IV reac- macological interaction with immune recep- tions: This classification relies on formation of tors), as drugs may act more like superantigens IgE antibodies, which bind to high-affinity IgE [discussed in the chapter by Gerber and Pichler, receptors on mast cells and basophilic leuko- pp 66–73]: cytes, on complement-fixing antibodies and on • The p-i concept postulates a bypassing of the T-cell reactions, which orchestrate different development of a normal immune response, as a forms of inflammations. One has to be aware that direct, pharmacological stimulation of memory these reactions are tightly connected, as for ex- and effector T cells is implied; ample the maturation of B cells to IgE- or IgG- • Therefore, it does not follow the normal rules producing plasma cells depends on the help of T of an immune response, which may already ex- cells. Moreover, this classification was devel- plain some as ‘bizarre’ classified clinical fea- opped in the 1960s, before any functional hetero- tures; geneity of T cells was known. In the meantime it • It could appear at the first encounter with has become clear that the immune system is not the drug, as no sensitization is required; only specific and has a kind of memory, but is • Those T cells which happen to be stimulated also well adapted to the type of challenge it faces, by drugs are assumed to actually have a peptide as for example the defense against intracellular specificity (to which they were primed); however, pathogens requires a different approach than the which peptides are recognized is unknown. defense against extracellular bacteria, etc. This It is unclear (a) whether the drug-induced discrimination seems to be regulated by different stimulation of peptide-specific T cells results in a types of T cells [8] . To better take into account different clinical picture, if the peptides, which this heterogeneity of T-cell functions, which are are recognized by the drug-stimulated T cells, are important to understand different forms of dis- present in the body; (b) whether the function of eases, the classification of Gell and Coombs has the stimulated T cells remains the same, if the T recently been revised [8] as discussed below. cell is stimulated by the drug or by its natural li- This modified and extended Gell and Coombs gand, a certain MHC-associated peptide, and (c) classification has an impact on classifying dis- whether the constant presence of the presumed ease severity, treatment, level of cross-reactivity natural ligand, the peptide, may contribute to the Drug Hypersensitivity Reactions: Classification and Relationship to T-Cell Activation 169 persistence of drug-allergic reactions over years Table 1. IgE-mediated drug allergies in spite of strict avoidance of the drug. Up to 50% of patients with IgE-induced anaphylaxis These questions are open and explain why the to certain drugs have no history of previous drug naming of type B reactions as ‘bizarre’ reactions exposure! is actually not so far fetched. Anaphylaxis occurs rapidly (<20 min), seldom later Asphyxia is probably the main cause of lethal anaphylaxis Antibody-Mediated Drug Hypersensitivity Reactions Cardiac arrest can be the sole symptom of an anaphylaxis (in particular in perioperative anaphylaxis) The hapten-like features of a drug allow the mod- In certain cases, desensitization procedures are possible ification of soluble and cell-bound proteins. For and may allow reuse of the drug example, a penicillin molecule could bind cova- lently to a lysine within a serum protein, but also to cell-bound proteins [see figure 2 in chapter of Torres et al., pp 190–203]. The ‘normal’ reaction dins, TNF- , etc.) are released, which cause the of the immune system to such modified proteins immediate symptoms and may start and facili- is the development of a humoral immune re- tate late allergic reactions. sponse, consisting of many distinct antibodies IgE-mediated reactions to drugs are usually with hapten specificity. Consequently, if a coor- thought to depend on the prior development of dinated humoral immune response develops an immune response to a hapten/carrier com- (based on T-cell help), one may conclude that the plex: B cells need to mature into IgE-secreting eliciting drug has hapten-like features forming plasma cells, and T cells help in this process by hapten-carrier complexes or is itself a protein interacting with B cells (i.e. CD40-CD40L in- bearing ‘foreign’ determinants [e.g. a chimeric teraction) and by releasing IL-4/IL-13, which antibody, see figure 1 in chapter of Pichler and are switch factors for IgE synthesis. This sensi- Campi, pp 151–165]. Indeed, as shown in table 1 , tization phase is asymptomatic and may have the majority of drugs able to elicit IgE-mediated occurred during an earlier drug treatment. allergies are known to be haptens, or they contain Upon renewed contact with the drug, a hapten- foreign antigenic structures ( fig. 1 ) [9] . carrier complex is formed again, which then cross-links preformed drug-specific IgE on Type I (IgE-Mediated) Allergies mast cells. The drug itself is normally too small The IgE system is geared to react to small amounts to cross-link two adjacent IgE molecules, and of antigens. It achieves this extraordinary sensi- needs to bind to proteins to cross-link [see chap- tivity by the ubiquitous presence of mast cells ter of Torres et al., pp 190–203]. However, it is to armed with high-affinity Fc-IgE receptors (Fc- be noted that in ca. 50% of patients with imme- IgE-RI), to which allergen/drug-specific IgE is diate reactions, no prior contact with the drug bound. Very small amounts of a drug are appar- can be elucidated [see con tribution of Chris- ently sufficient to interact and stimulate these re- tiansen, pp 233–241] and that 80% of the pa- ceptor-bound IgE molecules, as occasionally even tients with lethal anaphylaxis had no prior con- skin tests with drugs can elicit systemic reactions tact with the drug [10] .

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