Key Facts

Drug allergy is a specific immune-mediated adverse drug reaction. It is critically important because incorrect allergy labelling leads to suboptimal prescribing (broader-spectrum antibiotics, increased costs, resistance), while true allergy can be life-threatening.

Epidemiology

• ~10% of UK population labelled as 'penicillin allergic' — but ~90% are NOT truly allergic on formal testing
• Anaphylaxis: ~1 in 5,000 anaesthetics; ~1 in 100,000 penicillin exposures
• Drug allergy accounts for ~10% of all adverse drug reactions
• Most common causative drugs: penicillins, cephalosporins, NSAIDs, neuromuscular blocking agents

Classification (Gell and Coombs)

• Type I (IgE-mediated/immediate): minutes to hours; urticaria, angioedema, bronchospasm, anaphylaxis
• Type II (cytotoxic): hours to days; drug-induced haemolytic anaemia, thrombocytopenia
• Type III (immune complex): days to weeks; serum sickness, vasculitis
• Type IV (T-cell mediated/delayed): days to weeks; maculopapular rash, contact dermatitis, SJS/TEN, DRESS

Pathophysiology

• Type I: drug/metabolite acts as hapten → IgE production → mast cell/basophil degranulation on re-exposure → histamine, tryptase, prostaglandins → anaphylaxis
• Type IV: drug-specific T-cells → cytokine release, direct cytotoxicity → tissue damage
• Cross-reactivity: penicillin ↔ cephalosporin cross-reactivity ~2% (previously overestimated at 10%)
• Non-allergic hypersensitivity: NSAIDs → COX-1 inhibition → leukotriene overproduction → urticaria/angioedema (NOT immune-mediated)

Immediate Reactions (Type I — within 1 hour)

• Urticaria: wheals, pruritus
• Angioedema: swelling of lips, tongue, periorbital
• Bronchospasm: wheeze, dyspnoea
• Anaphylaxis: hypotension, tachycardia, stridor, collapse — life-threatening

Non-Immediate Reactions (Types II–IV — >1 hour to weeks)

• Maculopapular rash: most common drug eruption (7–14 days)
• SJS/TEN: mucosal erosions, epidermal detachment (1–3 weeks)
• DRESS: rash, fever, eosinophilia, organ involvement (2–8 weeks)
• Fixed drug eruption: recurrent lesion at same site
• Drug-induced haemolytic anaemia: penicillin, methyldopa
• Serum sickness: fever, rash, arthralgia, lymphadenopathy (7–14 days)

Red Flags

• Anaphylaxis: ABC approach, IM adrenaline 500 mcg immediately
• Angioedema with airway compromise (especially ACE inhibitor-related — does not respond to adrenaline)
• SJS/TEN: mucosal erosions, skin detachment
• DRESS: fever + rash + organ dysfunction
• Agranulocytosis: sore throat + fever — urgent FBC

Acute Assessment

• Mast cell tryptase: within 1–6 hours of suspected anaphylaxis; repeat at 24 hours (baseline)
  • Elevated tryptase confirms mast cell activation (anaphylaxis)
  • Normal tryptase does not exclude allergy
• Clinical observation: document timeline, morphology, associated features

Specialist Allergy Testing

• Skin prick test (SPT): for penicillin allergy — tests IgE-mediated sensitivity; performed ≥4 weeks after reaction
• Specific IgE (RAST): blood test for drug-specific IgE — useful if SPT not possible
• Intradermal testing: more sensitive than SPT; specialist use
• Drug provocation test (graded challenge): gold standard — supervised incremental drug administration in specialist allergy clinic
• Patch testing: for delayed (Type IV) reactions — applied for 48 hours

Bloods

• FBC: eosinophilia (DRESS, drug hypersensitivity), agranulocytosis
• LFTs, U&Es: organ involvement in DRESS
• Coomb's test: drug-induced haemolytic anaemia

Special Tests

• HLA typing: before starting high-risk drugs (abacavir → HLA-B5701; allopurinol → HLA-B5801)
• Basophil activation test: research/specialist use — measures CD63 expression

Anaphylaxis (Resuscitation Council UK Guidelines)

• IM adrenaline 1:1000 (500 mcg/0.5 mL): into anterolateral thigh — repeat every 5 minutes if no improvement
• High-flow oxygen: 15 L/min via non-rebreather mask
• IV fluids: 500 mL–1 L 0.9% saline bolus (crystalloid)
• Chlorphenamine 10 mg IV: antihistamine
• Hydrocortisone 200 mg IV: prevents biphasic reaction
• Nebulised salbutamol: if bronchospasm
• Mast cell tryptase: take at 1 hour and 24 hours
• Observation: minimum 6–12 hours (biphasic reaction risk ~5%)
• Discharge: with adrenaline auto-injector (EpiPen), allergy action plan, allergy clinic referral

Documentation

• Record allergy clearly: drug name, reaction type, date — in patient notes, drug chart, electronic record, GP letter
• NICE CG183: classify reaction as allergic vs non-allergic; specify whether immediate or non-immediate
• Patient information: allergy card/bracelet; action plan

Penicillin Allergy Delabelling

• ~90% of labelled patients are NOT truly allergic
• False label → broader-spectrum antibiotics → increased resistance, C. difficile, cost
• Delabelling pathway: detailed history → risk stratification → direct oral challenge or specialist testing
• Low-risk patients (remote non-severe reaction, >10 years ago): may be suitable for oral amoxicillin challenge
• High-risk patients (anaphylaxis, severe reaction): specialist allergy clinic assessment

Referral Criteria

• Allergy clinic: all suspected drug allergy — formal assessment, testing, delabelling
• Resuscitation/emergency: anaphylaxis
• Dermatology: severe cutaneous reactions (SJS/TEN, DRESS)
• Anaesthetics: perioperative anaphylaxis — specialist investigation

• Anaphylaxis: mortality ~1% with prompt treatment; biphasic reactions in ~5%
• SJS/TEN: mortality 5–30% depending on extent
• Drug avoidance: prevents recurrence — lifelong for true allergy
• Penicillin delabelling: ~90% of labelled patients can safely receive penicillins — improves antibiotic stewardship
• Incorrect allergy label: associated with worse outcomes (longer hospital stay, more resistant infections, higher costs)

Gell and Coombs Classification

Anaphylaxis Adrenaline Doses