I Introduction:
Drug hypersensitivity reactions (DHR) are immune or inflammatory
reactions elicited by a small molecule and occasionally proteins etc..
DHR can be sub-classified as a specific immune reaction against the drug
acting as antigen with drug-specific stimulations of antibodies or
T-cells (drug allergy ), as off-target p harmacological
activity of drugs with i mmune receptors (human leukocyte
antigens, HLA or T cell receptor for antigen, TCR) leading to T-cell
mediated immune stimulations (p-i-concept ) and as pseudo-allergic
reactions where the drug therapy results in activation of inflammatory
cells or mediators without the involvement of the specific immune system
(“pseudo-allergy ”) (1 ).
The clinical picture of DHR is very heterogeneous as different cell
types (T-cells, mast cells (MC), basophils, eosinophils, neutrophils,
etc) and inflammations are involved (2,3,4). This report focusses on
IgE-mediated adverse reactions to small molecules, normally
<1000 D. They represent an uncommon, but potentially dangerous
complication of drug therapy. Symptoms appear rapidly after drug
exposure and include generalized urticaria, angioedema, bronchospasm and
anaphylaxis with respiratory and/or gastrointestinal symptoms, cardiac
arrest and even death. Indeed, drug elicited anaphylaxis is considered
to be particularly dangerous with a high rate of deadly outcomes (5).
The underlying mechanism of IgE-mediated drug allergy is based on the
hapten concept. It was developed more than 80 years ago by K Landsteiner
and others, stating that small molecules like drugs or other chemicals
are too small to function as antigen for the immune system (6). Only if
the drug acts as a “hapten” and binds to a protein and thus forms a
larger drug-protein adduct, it functions as antigen to which immune
reactions, including IgE, may develop. This hapten-protein (or
hapten-carrier) concept relies on the ability of the drug (or
metabolite) to bind via covalent bonds stably to a
protein. The immunity may persist for years after stopping therapy.
Importantly, the potentially severe symptoms mentioned above do not
happen during the sensitization and only may become apparent through a
new exposure/re-challenge.
This hapten-carrier concept was validated in an endless number of
experiments. It was used to investigate immunity in animal models of
autoimmunity, cancer immunology, allergy, and specific immunity to small
molecules, etc.. It also served as an explanation for IgE-mediated drug
allergy in the clinic: For example, allergy and clinical manifestations
after beta-lactam therapy were explained by the hapten-carrier concept
(7).
Since only haptens were considered as potential elicitors of drug
allergy, drugs in development were assessed for their ability to
covalently bind to proteins (8, 9). To reduce the risk for DHR only the
development of drugs not capable of forming covalent bonds with
proteins was pursued. Nevertheless, drug-induced allergy and in
particular IgE-mediated anaphylaxis remained a substantial clinical
problem. Anaphylaxis to beta-lactams, to proton-pump inhibitors (PPI),
to neuromuscular blocking drugs (NMBA), to disinfectants like
chlorhexidine, to radiocontrast media (RCM) and many more still occurs
(2, 7, 10-11). Additionally, other ways of mast cell stimulation and
degranulation by drugs were recently described, such as reactions
triggered by mast cell-specific G protein-coupled receptors (MCGPR)
(12).
A critical evaluation of patients with IgE-mediated allergy/anaphylaxis
to drugs reveals some inconsistencies in the prevailing concepts, in
particular regarding the symptoms during re-challenges: many of the
drugs causing anaphylaxis are per se not haptens, but inert chemicals,
not able to form covalent bonds; some might have acquired hapten
characteristics by metabolism (e.g. sulfamethoxazole, 13). Most
importantly, some of the reactions occur very fast before covalent
binding or metabolism can occur. Of note as well, the immediate reaction
in skin tests or a positive in-vitro basophil activation test (BAT) to
an inert drug can not be explained by the hapten-concept. The involved
drugs are not “haptens” - leaving open how cross-linking of specific
IgE, MC degranulation, and symptoms of IgE-mediated reactions are
elicited by the drug (1).
This paper addresses some of these inconsistencies comparing clinical
observations to accepted features of IgE-mediated reactions. Such
observations comprise the rapidity of the appearance of symptoms, in-
vitro and in-vivo diagnosis of drug allergy, experience with
desensitizations, pharmaceutical features of drugs and speed of covalent
vs non-covalent drug binding to proteins. The result is a new
interpretation of IgE mediated drug allergy : It extends the hapten
concept and postulates: i) When IgE is induced, the antigen
simultaneously induce an MC-unresponsiveness. ii) Some non-covalent
bindings of drugs to proteins are affine enough to allow IgE
cross-linking by the formed complexes; iii) the formation of covalent
hapten-protein adducts in vivo is slow and may allow
MC-unresponsiveness both during sensitization and even during
re-exposure: No symptoms occur.
The new concept is radical as covalent hapten-protein adducts are
considered to be “good” (controlled) antigens, which, although they
induce an unwished immunity, do simultaneously induce
MC-unresponsiveness; In contrast, non-covalent drug-protein complexes
are taking the role of “fake antigens” responsible for harmful
effects. The consequences of this new interpretation are potentially
wide-reaching both for IgE-mediated drug allergy but also for IgE
reactions and symptoms in general.