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.