III Conclusion:
DHRs are interesting diseases on one hand, as the eliciting cause (drug) is well defined with exact data on dose, duration of exposure, availability, kinetic, metabolism, and serum concentrations in humans. On the other hand, DHR is clinically difficult. It occurs only rarely and unexpectedly, and many reactions may represent an exception and not the rule. As iatrogenic diseases, they are hard to reproduce for ethical reasons. Additionally, some DHRs are a result of a series of weak non-covalent and reversible reactions, but not a very strong, quasi irreversible, covalent reaction. Moreover, and maybe partly because of this, for most DHRs we do not have animal models.
The methodological approach taken in this paper is unusual: The novel conclusions and alternative explanation of IgE-mediated drug reactions are based on well known facts and neglected inconsistencies. By combining clinical observation and history, skin and in-vitro tests, pharmacological features of drugs and their protein-binding ability as well as immunological concepts of IgE response, the old dogma that only covalent drug-protein complexes can induce IgE, remains. But theeffector phase, which is elicited by IgE and MC, cannot be reduced to antigens formed by covalent bonds. When considering the different kinetic of forming non covalent drug-protein complexes or covalent hapten-protein adducts, the speed of clinical reactivity, particularly of anaphylaxis, and insights from drug-desensitizations, a new concept of IgE-mediated drug-reactions emerges: It’s three main concepts are summarized in figure 3:
1) Inducing IgE goes along with silencing MC-reactivity to the same antigen. This is a natural and normal process in IgE-mediated reactions, both for drugs, but also for normal protein allergens. It combines non-reactivity of IgE-coated mast cells to small concentrations of drug/allergen while permitting reactivity to high local levels.
2) At re-exposure, anaphylaxis causing drugs form fake antigens fast and in high quantity. They are dangerous as they can react and cross-link preformed drug-specific IgE and cause MC degranulation with urticaria/anaphylaxis.
3) If at re-exposure only covalent hapten-protein complexes react with drug-specific IgE, the reaction may remain asymptomatic, as the slow generation of such stable antigens may re-establish MC-unresponsiveness.
The beauty of this concept is its simplicity. The involved components are drug concentrations, type of bonds (covalent or non-covalent), and affinity of drug-protein bindings: together they result in a slow or fast formation and +/- high amount of drug-protein complexes, which then determine MC-unresponsiveness with silent immunity vs. MC-reactivity with allergy.
It should be emphasized that part of the concepts proposed here apply to allergy in general. The IgE antibody is evolutionarily very old (30) and cannot and should not be seen from an allergy perspective alone. IgE may represent a normal, potentially beneficial immune response tolocal antigen accumulations . Anaphylaxis to drugs is a rare event, which only appears when various exceptional conditions occur together: some rely on the drug, others are due to the individual (e.g. prior exposure to IgE-inducing antigens, drug metabolism).
The possible consequences of this new interpretation of IgE-mediated drug allergy would be far-reaching for the clinical practice, risk estimation and prevention of drug allergy, and our concept of IgE-mediated allergy in general. It is hoped that these ideas promote discussions to further shed light on the topic, and consequently prompt new research confirming or disapproving the theories discussed.