Syndrome de Lyell
Approche diagnostique
Veronique del Marmol
Alexandre Chamoun
Service de Dermatologie Hôpital Erasme
Serge Jennes
Hôpital Militaire se
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Rash benign
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Benign versus severe
Pustulose exanthematique
Aigue et généralisée
AGEP DRESS
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Benign versus severe ?
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Versus severe rash
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Drug induced Rash
• The skin is one of the most common targets for adverse drug
reactions
• To determine the cause of the eruption, a logical approach based on
clinical characteristics, chronologic factors and a literature search is
required
• Exanthematous eruptions and urticaria are the two most common
forms of cutaneous drug reactions
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Viral versus Drug induced exantheme
• Viral infection is the most important differential diagnosis.
• Drugs were responsible for 25% of the exanthems (more commonly
in adults) of which antibiotics and NSAIDs were most frequently
implicated.
• It is useful in differentiating exanthematic drug eruptions from viral
exanthems to remember that viral rashes tend to start on the face
and acral sites with subsequent progression to involve the trunk,
and are more often accompanied by fever, sore throat,
gastrointestinal symptoms, conjunctivitis, cough and insomnia .
• Pruritus is typically associated with drug causes in adults.
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Viral exanthemes
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Clinical characteristics
• Type of primary lesion (e.g. urticaria, erythematous papule, pustule,
purpuric papule, vesicle or bulla)
• Distribution and number of lesions
• Mucous membrane involvement, facial edema
• Associated signs and symptoms: fever, pruritus, lymph node enlargement,
visceral involvement
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Chronological factors
• Document all drugs to which the patient has been exposed and the dates
of administration
• Date of eruption
• Time interval between drug introduction (or reintroduction) and skin
eruption
• Response to removal of the suspected agent
• Consider excipients (e.g. soybean oil)
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Benign drug eruption
• The latency from drug initiation to onset of rash ranges from 5 to 21
days, but typically occurs at 7–10 days.
• A drug‐induced exanthem may be accompanied by pruritus.
• The clinical features are variable; lesions may be scarlatiniform,
rubelliform or morbilliform, or may consist of a profuse eruption of
small pink papules showing no close resemblance to any infective
exanthem . There is a broad spectrum of phenotypes encountered
in cutaneous adverse reactions and many can mimic other
inflammatory rashes.
• Rarely, drug hypersensitivity dermatoses can be life threatening and
involve internal organs; however, most eruptions are mild, affect the
skin only and are self‐limiting on drug withdrawal. These disorders
can be considered as the benign cutaneous adverse reactionsse
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Alerting Clinical features
Clinical features that can alert the clinician to the possibility of a more
severe drug-induced eruption include
• edema of the face or a marked peripheral blood hypereosinophilia
(suggestive of DRESS [DIHS])
• mucous membrane lesions or painful or dusky skin, which may
announce TEN or SJS
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Severe drug reaction
Drug reactions including
• acute generalized exanthematous pustulosis (AGEP),
• Stevens–Johnson syndrome (SJS),
• toxic epidermal necrolysis (TEN) and
• drug reaction with eosinophilia and systemic symptoms (DRESS)
Are severe cutaneous adverse reactions to drugs acknowledged to be
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Immunologically Mediated Drug Reactions
• IgE-dependent drug reactions (formerly type I, Gell–Coombs
classification): urticaria, angioedema and anaphylaxis.
• Cytotoxic drug-induced reactions (antibody against a fixed antigen;
formerly type II): petechiae secondary to drug-induced
thrombocytopenia.
• Immune complex-dependent drug reactions (formerly type III):
vasculitis, serum sickness and certain types of urticaria.
• Possible delayed-type, cell-mediated drug reactions (formerly type
IV; sometimes not well defined) exanthematous, fixed and lichenoid
drug eruptions, as well as Stevens–Johnson syndrome (SJS) and TEN.se
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Forms of type 4 hypersensitivity reaction:
mechanisms and clinical correlations
Adapted from Pichler , 2007
Rook textbook of dermatology , 9th edition, 2016
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Drug reaction
• Immunologically Mediated Drug Reactions
• Non-immunologic Mechanisms
• Overdose
• Pharmacological effects
• Cumulative toxicity
• Delayed toxicity
• Drug-drug interctaction
• Alteration in metabolism
• Exacerbation of disease
• Idiosyncratic with Possible Immunologic Mediation
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Idiosyncratic with Possible Immunologic
Mediation
Idiosyncratic drug eruptions represent reactions that are
unpredictable and cannot be explained on the basis of the
pharmacologic properties of the drug.
• Reactive metabolites of drugs can bind covalently to proteins, and
the altered protein, considered as foreign, then induces an immune
response.
• However, the way in which a drug is metabolized into a reactive
species (or fails to be metabolized) differs in nature and amount
depending upon the patient’s specific metabolic pathways. These
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Idiosyncratic with Possible Immunologic
Mediation
• Examples would be the increased incidences of the procainamide-
induced systemic lupus syndrome and sulfonamide-induced TEN in
slow acetylators as opposed to rapid acetylators.
• In addition, certain HLA alleles increase the risk of adverse drug
reactions, e.g. the association of HLA-B*5701 with hypersensitivity
reactions to abacavir and HLA–B*1502 with SJS/TEN in Han Chinese.
The pathophysiology of drug-induced skin reactions such as
exanthematous drug eruptions, DRESS (DIHS), acute generalized
exanthematous pustulosis (AGEP) and TEN, as well as the increased
susceptibility of HIV-infected patients, may be partially explained by
an interplay between immune mechanisms and genetic
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HLA and drug reactions
The association of drug‐induced adverse reactions with particular HLA
alleles is increasingly well recognized
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Erythema Multiform vs SJS-TEN
It has now become clear that Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN) are variants within a continuous
spectrum of adverse drug reactions,
Whereas erythema multiforme (EM) is a distinct disorder with
different clinical signs and precipitating factors, e.g. herpes simplex
virus (HSV) infections. Therefore, EM will be discussed separately from
SJS and TEN.
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Erythema Multiform-
The characteristic elementary skin
lesion of EM is the typical target
lesion.
• The latter measures
Erythema Multiform- Minor and Major
• Erythema multiforme minor: typical and/or occasionally atypical
papular target lesions with little or no mucosal involvement and no
systemic symptoms
• Erythema multiforme major: typical and/or occasionally atypical
papular target lesions with severe mucosal involvement and systemic
features
• A preceding HSV infection is the most common precipitating factor;
occasionally, there are other preceding infections or, rarely, drug
exposure
• Diagnosis of erythema multiforme requires clinicopathologic
correlation and is not based solely on histologic findings
• Erythema multiforme does not carry the risk of progressing to toxic
epidermal necrolysisse
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Erythema multiform-Infection
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Erythema multiform –
drugs and others
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Erythema Multiform- SJS-TEN
Differentiation of SJS from erythema
multiforme major (EMM) is difficult:
• In both EMM and SJS, there is
mucous membrane involvement
and cutaneous blistering with
epidermal detachment of less than
10% body surface area (BSA).
• However, in EMM the lesions
consist of typical targets or raised
atypical targets, predo
