Drug allergies and mechanisms - mechanisms

Framework

Gell and Coombs classification - the framework for immune-mediated drug reactions
Distinguishes true immunological hypersensitivity from non-immune adverse drug reactions (intolerance, toxicity, idiosyncratic, pseudo-allergic) - the majority of reported "allergies" are not immune-mediated at all

Reported drug allergy in ~10% of the population; true confirmed IgE-mediated allergy in <10% of those labelled
Over-labelling (esp. penicillin) drives inferior antibiotic choice, worse infection outcomes, and antimicrobial resistance

Type	Mechanism	Timing	Examples
I - Immediate (IgE)	Mast cell/basophil degranulation via pre-formed IgE	Minutes-1h	Anaphylaxis, urticaria, angioedema (penicillin, NMBAs)
II - Cytotoxic	IgG/IgM against drug-hapten on cell surface + complement	Days	Drug-induced haemolytic anaemia, thrombocytopenia (penicillin, methyldopa)
III - Immune complex	Antigen-antibody complexes deposit in tissue	1-3 weeks	Serum sickness, drug-induced vasculitis, some drug fever
IV - Delayed (T-cell)	T-cell mediated, subtypes IVa-d	Days-weeks	Contact dermatitis, SJS/TEN, DRESS, AGEP (see below)

Type IV subtypes - relevant to severe cutaneous adverse reactions (SCARs)

Pseudo-allergic/direct mast cell activation (MRGPRX2 receptor) - opioids, vancomycin ("red man syndrome"), radiocontrast - clinically resembles Type I but not IgE-mediated
Pharmacological side effect - ACEi cough, NSAID GI upset
Intolerance - metallic taste, nausea
Idiosyncratic/genetic - G6PD-related haemolysis, *HLA-B57:01 with abacavir hypersensitivity, HLA-B15:02 with carbamazepine-induced SJS/TEN in Southeast Asian populations*

Timing relative to dose, nature of the reaction, treatment required, and outcome - determines risk category and whether testing is needed
Distinguish immediate (Type I pattern - urticaria, angioedema, wheeze, hypotension within 1h) from delayed (rash days into a course) from a SCAR pattern (mucosal involvement, skin pain, blistering, fever, organ involvement, eosinophilia)

Skin prick/intradermal testing - for suspected Type I (validated for penicillin, limited for other drugs)
Serum tryptase - raised during/soon after a suspected anaphylactic reaction (peaks ~1-2h, returns to baseline by 24h)
Patch testing - for delayed/contact-type reactions
Graded/direct oral drug challenge - gold standard to confirm tolerance in low-risk histories
HLA typing before high-risk drugs in at-risk populations (abacavir, carbamazepine)

By mechanism

Type I - avoid the drug, treat acute reaction as anaphylaxis if severe (adrenaline IM first-line); desensitisation possible if drug essential and no alternative
SCARs (SJS/TEN, DRESS, AGEP) - stop the culprit drug immediately, supportive care +/- burns-unit level care for TEN, avoid re-exposure to the drug and structurally related agents lifelong
Type II/III - stop the drug, treat the immune-mediated cytopenia/vasculitis as needed

Most reported penicillin "allergy" is not IgE-mediated and delabelling improves antibiotic choice - see companion note on drug allergy assessment/delabelling
Document the specific reaction phenotype in the record, not just "allergic" - enables future risk stratification

Atopy - risk factor for Type I reactions, not for T-cell mediated SCARs
Viral infection (esp. EBV, HIV) - increases risk of maculopapular drug eruptions (e.g. amoxicillin rash with EBV)
Specific HLA alleles - abacavir (HLA-B57:01), carbamazepine/allopurinol (HLA-B15:02, HLA-B*58:01) SJS/TEN risk

IgE-mediated allergy can wane over years (~80% of penicillin allergy resolves by 10 years) - supports re-assessment rather than a permanent label
SCAR reactions carry lifelong avoidance recommendations for the culprit and cross-reactive drugs - do not wane
Accurate mechanism-based labelling materially changes lifetime antibiotic and drug choices

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