ARTICLE
Auteur(s) : Peter Simon
Friedmann1, Christopher Pickard1, Michael
Ardern-Jones1, Andreas J Bircher2
1Dermatopharmacology Unit, Division of Infection,
Inflammation and Immunity, University of Southampton School of
Medicine, Sir Henry Wellcome Laboratories, South Block, Southampton
General Hospital, Southampton SO16 6YD, United Kingdom
2Allergy Unit, Dermatology University Hospital Basel,
Petersgraben 4, CH-4031, Basel, Switzerland
accepté le 3 Novembre 2009
Drug rashes are a common problem occurring in patients across
the whole spectrum of medical specialties. They are a source of
confusion not only to the wider medical community but even among
dermatologists there is lack of clarity about how to describe,
classify and approach them. Common patterns of drug rash, apart
from the “classical” maculo-papular eruptions (MPE), include
urticarial wheals and urticaria-like rashes which it is important
to distinguish, because of differences in pathogenetic mechanisms,
therapeutic response and prognostic significance. The purpose of
this article is to try to offer some structure both from the point
of view of clinical classification and also of underlying
mechanisms.
The keys to successful diagnosis of cutaneous drug
hypersensitivities are firstly the recognition that the clinical
pattern of the skin rash fits with the known clinical patterns of
drug rashes (see below) and secondly a very careful and detailed
drug ingestion history [1, 2]. There is often confusion about the
significance of the time interval between exposure to a suspected
culprit drug and the time of onset of the adverse reaction. To
generate an immune response to a new “antigen” takes a minimum of
7 to 10 days [3]. So for a reaction to be truly
“allergic” i.e. immune-mediated, there must either be a previous
exposure to the causal drug (or possibly a related one which might
cross-react), or the initial exposure must be of sufficient
duration (7 days minimum) to initiate the immune response.
When a reaction develops at the first exposure to the drug, it is
highly unlikely to be a true allergic hypersensitivity and much
more likely to be a so-called pseudo-allergy or intolerance. These
reactions are due to direct drug-induced release of inflammatory
mediators such as histamine or leukotrienes, which can generate
clinical features including urticaria, asthma and even full-blown
anaphylaxis. The drug groups most likely to induce pseudo-allergic
intolerance reactions are the salicylate/non-steroidal
anti-inflammatories, the opiates, the radio contrast media and the
muscle relaxants used in anaesthesiology.
The generally accepted classification of immune mechanisms
involved in drug hypersensitivities is that devised by Gell and
Coombs [4], which describes four types of allergic mechanism.
Following the great advances in our understanding of the mechanisms
involved in T-cell mediated reactions, the classification has been
developed and extended by Pichler and colleagues (table 1) [5, 6].
- – Type 1, immediate hypersensitivities are mediated by
IgE antibodies bound to the surface of mast cells and basophils.
When the drug allergen interacts with the IgE, the mast
cells/basophils degranulate, releasing mediators and producing
urticaria, angioedema, asthma or anaphylaxis. The key to the
diagnosis of true urticaria is that the lesions, which consist of
raised itchy wheals, typically have the brightest erythema at the
outer edge of the lesion and rapidly become paler in the middle
(figure 1). The
individual lesions are of short duration, lasting 2-4 hours, but
the whole attack may last days with new lesions forming and
resolving continuously. Reactions mediated by Type I mechanisms can
begin within seconds or minutes of exposure to the relevant
drug.
- – Type 2 mechanisms involve the recognition of antigens
on the surface of cells – in the skin this is mainly manifested as
drug-related pemphigus – which will not be considered here.
- – Type 3 reactions involve small circulating immune
complexes sticking to the endothelium of cutaneous venules, fixing
complement and attracting neutrophils. This damages the endothelium
such that red cells extravasate into the tissues resulting in
haemorrhage/purpura – the clinical and microscopic picture of
vasculitis. Again, this is not a reaction pattern to be considered
here.
- – Type IV reactions are mediated by T lymphocytes and
called “delayed type” because they characteristically develop over
24-48 hours following challenge with the causative agent. Type IV
reactions have been further subclassified into types IVa-d [5, 6]
(table 1). There are many different
patterns of T cell-mediated reaction and corresponding skin rashes
(figures 2 and
3) and it is these that can cause the greatest
confusion.
Delayed type exanthemata
It must be remembered that, apart from drugs, there are several
other causes of exanthematous rashes (table
2). Therefore, the relevant clinician must undertake the
careful clinical assessment that should allow the differentiation
of the different diagnostic entities.
There is no unified terminology for naming these types of drug
eruption and terms used include maculo-papular eruption,
morbilliform eruption, “Ampicillin Rash”, acute generalized
exanthematous pustulosis (AGEP), toxic erythema and “toxicodermie”.
To us, the term drug-induced exanthema (DIE) is preferred, as it is
less determined by particular morphological characteristics. As
stated above, common patterns of drug rash include urticarial
wheals and urticaria-like rashes, which include many patterns of
drug-induced exanthemata as well as erythema multiforme (table 3). The key clinical features which allow
the rashes to be diagnosed include: firstly, the time course of
their evolution and the duration of individual lesions and
secondly, the details of distribution of colours within the lesions
(table 4).
From a “snap-shot” picture of some of the eruptions, with no
knowledge of the lesion history, it can be impossible to
distinguish between true urticarias (Type 1 mechanisms),
pseudoallergic urticarias and urticaria-like exanthemata (T
cell-mediated type IV reactions), although it should be possible to
separate these from erythema multiforme (also T cell-mediated). The
morphology and colour distribution of both true urticaria and most
DIE is of round or oval lesions with the strongest, brightest
erythema at the margins and a paler or slightly duskier erythema
more centrally. It is usually the time course of lesions that helps
distinguish: individual lesions of true urticarias last from
2 to 4 hours although the total attack of urticaria can
last for days. However, there is a continuous evolution of new
lesions forming while old ones resolve. It should be noted that
this time course relates specifically to allergic (IgE-mediated)
urticarias but there are many non-allergic urticarial reactions in
which lesions may last longer, even up to 24 hours. Lesions of
DIE usually last 7 to 10 days and the attack involves the
continuous accumulation of new lesions while the original ones
persist. Erythema multiforme generally comprises round/circular
lesions often with concentric rings of different colours.
Typically, the centres are dusky to mauve or even purple, this is
surrounded by a ring of pale erythema while the margins of the
lesions are of a brighter shade of erythema. However, even
experienced clinicians can be caught out by lesions which initially
look like a DIE but which then evolve into much more serious
blistering lesions accompanied by mucositis – Stevens-Johnson
syndrome and TEN [7].
Table 1 Mechanisms underlying T cell-mediated drug
eruptions. Table modified from Pichler et al. [5, 6]
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Type IVa
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Type IVb
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Type IVc
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Type IVd
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Immune mediators
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Th1/Tc1 cells IFN-γTNF-α
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Th2 cells IL-4/-13 IL-5
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CTL Perforin Granzyme B
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T cells CXCL8 GM-CSF
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Inflammation characterised by:
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T cells Macrophages
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Eosinophils
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T cells Keratinocyte apoptosis
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Neutrophils
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Clinical pattern:
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Contact dermatitis, Tuberculin reaction
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Maculopapular rash/Toxic Erythema with eosinophilia
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Contact dermatitis, Maculopapular rash/toxic Erythema, Bullous
eruptions (SJS.TEN)
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AGEP
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Table 2 Aetiological differential diagnosis of
exanthemata
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Aetiology
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Clinical examples
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Urticarias: Allergic, Physical and Idiopathic
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Drug-induced urticaria, cholinergic urticaria,
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Viral exanthemata:
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measles, rubella, infectious mononucleosis
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Bacterial exanthemata:
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Staphylococcal folliculitis
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Inflammatory exanthemata:
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miliaria, pityriasis rosea, psoriasis, lichen planus
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Autoimmune induced exanthemas:
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Systemic lupus erythematosus
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Drug-induced exanthemata (DIE)
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Maculo-papular eruption, erythema multiforme
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Table 3 Delayed type hypersensitivity reactions to
drugs
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Allergic contact dermatitis
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Local and systemic disseminated contact dermatitis
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Maculo-papular exanthemas
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Macular exanthema
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Maculo-papular exanthema
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Papular exanthema
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Special forms of exanthemas
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Fixed drug eruption Symmetrical drug-related intertriginous
flexural exanthema (SDRIFE, former Baboon syndrome) Acute
generalized exanthematous pustulosis (AGEP) Drug rash with
eosinophilia and systemic symptoms (DRESS)/ drug-hypersensitivity
syndrome (DHS)
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Serious cutaneous adverse drug reactions
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Cutaneous hypersensitivity vasculitis
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Erythema exsudativum multiforme major (EMA)
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Stevens-Johnson-Syndrome (SJS)
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Toxic epidermal necrolysis (TEN)
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Mucosal involvement, mucositis
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Internal organ manifestations
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Hepatitis
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Nephritis
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Vasculitis (systemic)
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Pneumonitis
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Blood cell dyscrasia (neutropenia, thrombopenia, anaemia)
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Eosinophilia
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Autoimmune disorders
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General symptoms
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Drug fever
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Table 4 Clinical features of Urticaria-like eruptions
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True urticarias
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Drug-induced exanthemata
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Erythema multiforme
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Time course of lesions
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Individual lesions last 2-4 hours; new lesions appear as older ones
resolve.
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Individual lesions accumulate over days with no resolution;
Generally do not blister; Mucosal involvement very unusual.
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Individual lesions accumulate over days with no resolution; May
blister; Mucosal involvement frequent.
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Lesion morphology and colour distribution
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Lesions typically circular raised wheals, may expand over hours.
Brightest erythema at margin, as lesion enlarges central area
becomes paler.
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Wide range of lesion size: from 1-2 mm pin-point
(morbilliform); 3-15 mm wheal-like but lasting days. Colour
distribution as for true urticaria, strong erythema at margins,
duller erythema centrally.
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Regularly circular lesions ranging from flat to significantly
raised, edematous & wheal-like; colour darkest in centre (maybe
dusky or blue), pale pink erythema at margin; frequently ring of
pallor between central dusky and peripheral bright erythema.
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Histological help
At the histological level, the key differences between true
urticarias and DIE is that in urticarias there is often little or
nothing to see, whereas the DIE are characterised by the presence
of a mononuclear infiltrate, with or without eosinophils. The
mononuclear cells are T cells typically with CD8+ cells in the
epidermis and CD4+ cells forming the superficial dermal infiltrate.
Diagnostic testing
There are a number of excellent publications concentrating on
diagnostic tests, so they are only given superficial consideration
here [8-11]. There are no universally reliable tests available for
proving suspected drug allergy in cutaneous adverse drug reactions
[12]. The two main approaches include skin tests which can readily
be done by clinicians, and blood tests, such as the lymphocyte
transformation test (LTT), which are usually not available except
in research settings. Skin tests include prick tests (only
appropriate for Type I urticarial reactions) and patch tests
(suitable for Type IV T cell-mediated reactions). Intradermal
challenges are sometimes used and the reactions are read either at
15 minutes when investigating Type I reactions or at 24-48h
when investigating T cell-mediated Type IV reactions. Skin tests
have been tried with many drugs in many different clinical
patterns. For some drugs such as the aromatic anti-convulsants
(carbamazepine, phenytoin) in Type IV reactions (especially
carbamazepine induced exanthema) and amoxicillin induced exanthema,
results of patch tests are rather reliable. However for many drugs,
there is low sensitivity and false negatives are often obtained.
There are many variables, including the water or lipid solubility
of the drug, its molecular weight (greater than 500 daltons
penetrate poorly) the possible requirement for the formation of
allergenic metabolites and the availability of pure forms of the
drug. Patch tests are generally a safe form of test and they can be
used in Type IV reactions. The proviso is that for the severe
reactions such as SJS/TEN, low concentrations (normally 1%) should
initially be used [8].
Conclusion
The purpose of this article is to provide some guidance on how to
approach the understanding and the diagnosis of a heterogeneous
group of drug-induced rashes that often cause both clinical and
mechanistic confusion. The aetiological as well as the
morphological differential diagnoses are crucial for the successful
identification of the eliciting drug. It is critically important to
understand that Type I allergy and chemical pseudo-allergy result
in urticarial lesions that run a time course of hours. New lesions
appear as older lesions fade, the whole attack may last days. Type
IV T cell-mediated allergic processes can resemble urticarias very
closely but the time over which they develop is completely
different and lesions tend to last for days, there is a steady
accumulation of new lesions over several days and, with more
serious reactions there may be systemic organ involvement.
Acknowledgements
Conflict of interest: none. Financial support: none.
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