ImmunologyTier 1Medical Sciences concept

Drug hypersensitivity reactions - mechanisms (SJS/TEN)

Core concept

Immediate (IgE, type I) - minutes to 1 h; urticaria, angioedema, bronchospasm, anaphylaxis
- Requires prior sensitisation; skin prick / intradermal testing and specific IgE are valid
Delayed (T-cell, type IV) - hours to weeks; the great majority of drug rashes
- Type IVa Th1/macrophage - contact dermatitis, tuberculin
- Type IVb Th2/eosinophil - DRESS, maculopapular exanthem
- Type IVc cytotoxic CD8 - SJS/TEN, fixed drug eruption
- Type IVd neutrophilic (IL-8) - AGEP
p-i concept (pharmacological interaction) - some drugs bind the TCR or MHC directly, non-covalently, without processing or covalent hapten formation
- -> explains reactions on FIRST exposure and the strong HLA associations
Non-immune ("pharmacological") reactions look identical but have no antibody
- Direct MRGPRX2 mast cell activation - vancomycin ("red man"), opioids, quinolones, neuromuscular blockers
- Complement anaphylatoxins - radiocontrast, liposomal drugs
- COX-1 inhibition -> leukotriene shunt - aspirin/NSAID exacerbated respiratory disease
- Bradykinin - ACE inhibitor angioedema (no urticaria, normal tryptase, may begin years into therapy)

Severe cutaneous adverse reactions (SCARs)

	SJS / TEN	DRESS / DiHS	AGEP
Onset from drug start	4-28 days	2-8 weeks (late)	1-3 days (fast)
Skin	Painful dusky macules, targetoid, blisters, POSITIVE Nikolsky; >=2 mucosal surfaces in >90%	Morbilliform becoming confluent, facial oedema, >50% BSA	Sterile non-follicular pustules on erythema, flexural
Systemic	Fever, ocular, mucosal, sepsis risk	Fever, lymphadenopathy, EOSINOPHILIA, atypical lymphocytes, hepatitis, nephritis, myocarditis, thyroiditis	Fever, neutrophilia
Mechanism	CD8 cytotoxic - granulysin, perforin, granzyme B, Fas-FasL -> keratinocyte apoptosis	Th2/eosinophil + HHV-6/EBV/CMV reactivation	Neutrophilic, IL-8/IL-36
Mortality	SJS ~5%, TEN 25-35%	~10%	<5%
Culprits	Aromatic anticonvulsants (carbamazepine, phenytoin, lamotrigine), allopurinol, sulfonamides, nevirapine, oxicam NSAIDs, checkpoint inhibitors	Anticonvulsants, allopurinol, sulfasalazine, vancomycin, minocycline, dapsone	Beta-lactams (aminopenicillins), macrolides, diltiazem, hydroxychloroquine, terbinafine

BSA detachment defines the spectrum: SJS <10%, SJS/TEN overlap 10-30%, TEN >30%
SCORTEN at 24 h predicts mortality (age >40, malignancy, HR >120, BSA >10%, urea, glucose, bicarbonate)
Risk factors for SJS/TEN: HIV (a major risk factor), age >70, active malignancy, autoimmune disease, chronic kidney disease
HLA associations - the pharmacogenomic screening list
- *HLA-B15:02 - carbamazepine SJS/TEN* (Han Chinese, Thai, Malay, Indian; screen before prescribing*)
- *HLA-B58:01 - allopurinol SJS/TEN and DRESS**
- *HLA-B57:01 - abacavir hypersensitivity* (mandatory pre-prescription screening*)
- HLA-A*31:01 - carbamazepine DRESS (European, Japanese)
DRESS relapses and flares weeks after drug withdrawal, and autoimmune sequelae (thyroiditis, T1DM) appear months later - warn and follow up

Testing

Skin prick and intradermal testing are only valid for IgE-mediated reactions - useless, and unsafe, in SJS/TEN
Patch testing and delayed intradermal reading may help in DRESS, AGEP and fixed drug eruption
Drug provocation (challenge) testing is the gold standard - used to
- exclude allergy when the history is unconvincing
- confirm or exclude when skin testing and specific IgE are negative (penicillin)
- assess drugs with no useful in-vitro or skin test (aspirin/NSAIDs)
- *Absolutely contraindicated after SJS/TEN, DRESS or any severe delayed reaction*
Tryptase rises in mast-cell-mediated (immediate) reactions; normal in bradykinin angioedema and in SCARs

Beta-lactam cross-reactivity - the practical numbers

~90-95% of "penicillin allergy" labels are wrong - delabelling is a stewardship priority
Cross-reactivity is driven by the R1 SIDE CHAIN, not the beta-lactam ring
Carbapenems ~1%; cephalosporins ~2% overall (higher for first-generation sharing an aminopenicillin side chain: cefalexin/cefaclor with amoxicillin/ampicillin)
Aztreonam has negligible cross-reactivity with penicillins - the exception is ceftazidime, which shares an identical side chain

Desensitisation

Induces temporary mast cell/IgE tolerance - it does not cure allergy
Indicated when no alternative exists or the alternative is clearly inferior (penicillin for syphilis in pregnancy, aspirin for ACS, chemotherapy, biologics)
Method: supervised setting, asthma well controlled and beta-blockers withheld, start below the reactive dose and double roughly every 15-30 minutes
*Tolerance is lost within ~48 h of stopping - the drug must be continued without interruption, and desensitisation repeated if it lapses*
*Contraindicated in SJS/TEN, DRESS, AGEP, drug-induced haemolysis or cytopenia, hepatitis, and acute interstitial nephritis* - these are not IgE-mediated and cannot be desensitised

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