Drug Hypersensitivity Reactions

Drug hypersensitivity reactions are adverse drug reactions that clinically resemble allergy, and are subdivided into immunologically mediated (allergic) and non-immunological forms. They account for about 6 to 10% of adverse drug reactions, and up to 10% of hospitalised patients experience a reaction. Most patients labelled penicillin-allergic (about 10% of the population) are not truly allergic (over 90% tolerate penicillin on evaluation).

Gell and Coombs classification

• Type I (immediate, IgE-mediated): minutes to 1 hour after exposure. Urticaria, angioedema, bronchospasm, anaphylaxis. Triggers: beta-lactams, neuromuscular blockers, NSAIDs (cross-reactive type), sulfonamides, opioids (pseudoallergy), contrast media, chlorhexidine.
• Type II (cytotoxic, IgG/IgM): haemolytic anaemia (penicillin, methyldopa, quinine), thrombocytopenia (heparin, quinine, vancomycin), neutropenia (clozapine, dipyrone).
• Type III (immune complex): serum sickness-like reactions (cefaclor, antithymocyte globulin, infliximab), drug-induced vasculitis (hydralazine, propylthiouracil).
• Type IVa to d (delayed, T-cell mediated): contact dermatitis (neomycin, topical antihistamines), maculopapular exanthem (aminopenicillins), AGEP, DRESS, SJS/TEN, fixed drug eruption, and drug-induced liver and kidney injury.

Non-allergic (pseudoallergic) reactions

• Direct mast cell activation (opioids, vancomycin infusion reaction ("red man syndrome"), neuromuscular blockers, fluoroquinolones, contrast media), NSAID-exacerbated respiratory disease and NSAID-induced urticaria (COX-1 inhibition), ACE inhibitor angioedema (bradykinin-mediated), and complement activation-related pseudoallergy (liposomal products).
• Risk factors: previous reaction, repeated courses, atopy (for IgE reactions to some drugs), HIV (sulfonamide reactions 30 to 60%), EBV infection (aminopenicillin rash), genetic (HLA-B57:01 abacavir, HLA-B58:01 allopurinol, HLA-B*15:02 carbamazepine), high-molecular-weight drugs, parenteral route, and asthma with NSAIDs.
• Clinical spectrum: urticaria and angioedema, anaphylaxis, bronchospasm, exanthems, fixed drug eruptions, erythema multiforme, severe cutaneous adverse reactions (SJS/TEN, DRESS, AGEP), serum sickness, drug fever, cytopenias, and organ-specific injury.

Timing is a major clue

• Immediate (within 1 hour): urticaria, flushing, pruritus, angioedema, wheeze, hypotension, abdominal cramps, vomiting, tachycardia (anaphylaxis).
• Accelerated (1 to 72 hours): urticaria, angioedema, bronchospasm.
• Delayed (more than 1 hour, usually days): maculopapular rash (most common, 5 to 14 days after first exposure), delayed urticaria, eosinophilia, serum sickness (7 to 14 days), DRESS (2 to 8 weeks), AGEP (within 48 hours, pustular rash), SJS/TEN (4 to 28 days, mucosal erosions, epidermal detachment, positive Nikolsky sign).

Common drug-pattern associations

• Penicillins and cephalosporins: urticaria, anaphylaxis, exanthems.
• Sulfonamide antibiotics: exanthem, SJS/TEN, DRESS.
• NSAIDs: urticaria, angioedema, anaphylaxis, aspirin-exacerbated respiratory disease (asthma, nasal polyps, rhinosinusitis).
• Fluoroquinolones, vancomycin, opioids, contrast: pseudoallergic.
• Perioperative anaphylaxis: neuromuscular blockers (rocuronium, succinylcholine), antibiotics (cefazolin), chlorhexidine, patent blue dye, latex, sugammadex.
• Biologics: infusion reactions (rituximab, infliximab), cytokine release.
• Chemotherapy: carboplatin and oxaliplatin (type I after repeated cycles), taxanes (infusion reactions).
• Red flags: hypotension, laryngeal oedema, wheeze, mucosal lesions, blistering, skin pain, facial swelling with fever, organ dysfunction, eosinophilia, and rapid progression.
• Differential diagnosis: infection-related rash, viral exanthem, urticaria from infection, mastocytosis, hereditary angioedema (no urticaria, family history), vasculitis, adult-onset Still disease, Kawasaki disease, and toxic shock syndrome.

Systematic drug allergy history is key: drug, dose, route, timing, symptoms, duration, treatment, previous exposures and tolerance, concomitant medications and infections.

Acute event

• Serum tryptase: baseline and 1 to 4 hours after onset (peak at 1 to 2 hours), with the formula 20% plus 2 ng/mL above baseline supporting mast cell activation. A baseline also detects mastocytosis.
• Anaphylaxis: urine histamine metabolites.
• CBC with eosinophils, CRP, liver and renal tests, urinalysis, skin biopsy for severe delayed reactions, and viral PCR.

Allergy work-up (4 to 6 weeks after recovery, by an allergist)

• Skin prick and intradermal tests: validated for penicillin (benzylpenicilloyl polylysine, minor determinant mixture or penicillin G, amoxicillin), neuromuscular blockers, perioperative drugs, platinum agents, and some cephalosporins. Negative predictive value of penicillin skin tests about 95-99%.
• Patch testing and delayed-reading intradermal tests: for non-severe delayed reactions, contact dermatitis, DRESS and AGEP (anticonvulsants, antibiotics). Not for SJS/TEN (except under specialist care).
• Specific IgE (ImmunoCAP) for penicillins, suxamethonium, chlorhexidine, latex: limited sensitivity.
• Basophil activation test, lymphocyte transformation test: specialist tools.
• Drug provocation (challenge) tests: the gold standard, graded oral challenge (10% of full dose, then 90% after 30 to 60 minutes, then observe 1 hour or more, extended challenge of 3 to 5 days for delayed reactions), performed in a monitored setting with resuscitation capability. Contraindicated in severe delayed reactions (SJS/TEN, DRESS, AGEP), organ involvement, and uncontrolled asthma or cardiovascular disease.
• Direct oral amoxicillin challenge without skin testing is safe for low-risk histories (remote, benign, non-urticarial rash, fewer than 5 years or more than 10 years ago).
• Pharmacogenetic screening (HLA-B57:01, B58:01, B15:02, A31:01).
• Risk assessment tools: PEN-FAST (penicillin allergy within 5 years: 2 points, anaphylaxis, angioedema or severe cutaneous reaction: 2 points, treatment required: 1 point), where scores below 3 indicate under 5% risk.

Acute management

• Stop the suspected drug.
• Anaphylaxis: adrenaline (epinephrine) 0.5 mg (0.5 mL of 1:1000) IM into the anterolateral thigh, repeat every 5 to 15 minutes if needed (children 0.01 mg/kg, maximum 0.5 mg), high-flow oxygen, IV fluid bolus 1 to 2 L isotonic crystalloid (20 mL/kg in children), lie flat with legs raised, nebulised salbutamol 5 mg for bronchospasm, adrenaline infusion (0.05 to 0.5 micrograms/kg/min) for refractory shock, and glucagon 1 to 5 mg IV over 5 minutes for patients on beta blockers. Antihistamines (cetirizine 10 mg, chlorphenamine 10 mg IV) and corticosteroids (hydrocortisone 200 mg IV, prednisolone 40 to 50 mg) are adjuncts only. Observe for 4 to 6 hours (up to 24 hours for severe, biphasic risk in 5 to 20%). Prescribe adrenaline autoinjectors (0.3 mg or 0.15 mg for children under 30 kg) with training.
• Urticaria and angioedema: non-sedating antihistamine (cetirizine 10 mg or fexofenadine 180 mg, up to 4 times licensed dose in chronic disease), short course prednisolone 0.5 mg/kg for 3 to 5 days if severe. ACE inhibitor angioedema: stop the ACE inhibitor, airway protection, avoid antihistamines as the main therapy (bradykinin), icatibant 30 mg SC may be used.
• Exanthems: stop drug if not essential, topical corticosteroids (betamethasone valerate 0.1% or mometasone 0.1%), antihistamines. Continue the drug in mild benign rash if essential and monitored. Aminopenicillin rash in EBV infection is not true allergy.
• Serum sickness-like reactions: prednisolone 0.5 to 1 mg/kg for 5 to 7 days, NSAIDs, antihistamines.
• Severe cutaneous adverse reactions: see DRESS, Stevens-Johnson syndrome and toxic epidermal necrolysis articles. Stop drug and give supportive care in a specialised unit.
• Infusion reactions (rituximab, infliximab, taxanes): stop the infusion, treat (hydrocortisone 100 mg, chlorphenamine 10 mg, paracetamol 1 g, adrenaline for severe), restart at half the rate after resolution. Premedication with paracetamol, antihistamine, steroid.
• Vancomycin infusion reaction: slow the infusion (over at least 1 to 2 hours), antihistamines. Not an allergy.
• Drug fever, cytopenias, hepatotoxicity: withdraw the drug and manage organ injury.

Long-term management

• Allergy label management: record the specific drug, reaction type and tolerated alternatives. Delabelling by testing improves outcomes (less use of broad-spectrum agents, MRSA, C. difficile, surgical site infection) and cost.
• Penicillin allergy: low-risk history: direct oral amoxicillin challenge (500 mg single dose or two-step 50 mg then 450 mg, observe 1 hour). Intermediate: skin tests then challenge. High-risk (anaphylaxis, severe cutaneous): avoid, referral to allergy. Cephalosporin cross-reactivity with penicillin is low (below 2%) when side chains differ, and cefazolin has a unique side chain (safe in most penicillin-allergic patients).
• Sulfonamide antibiotic allergy: non-antibiotic sulfonamides (furosemide, thiazides, celecoxib) do not cross-react. Graded challenge for non-severe history, and desensitisation in HIV for Pneumocystis prophylaxis (trimethoprim-sulfamethoxazole, 7 to 14 day protocols).
• NSAID hypersensitivity: cross-reactive types avoid all COX-1 inhibitors, use paracetamol (up to 500 mg), celecoxib 100 to 200 mg under supervision after challenge. Aspirin desensitisation for aspirin-exacerbated respiratory disease (reduces polyps and asthma), with 325 to 650 mg twice daily maintenance.
• Drug desensitisation (induction of temporary tolerance): for IgE-mediated reactions to essential drugs (penicillin in syphilis during pregnancy, chemotherapy such as carboplatin, monoclonal antibodies, antituberculosis drugs, aspirin in cardiovascular disease). Performed in a monitored setting using 12-step protocols over 4 to 6 hours, with continued drug dosing to maintain tolerance.
• Alternative drug selection: choose structurally unrelated agents. Contrast media: premedication is unproven for prevention of severe reactions, switch to a different agent with lower osmolality for previous reactors, and skin testing. Local anaesthetic allergy is rare (most reactions are vasovagal or epinephrine effects), and testing with preservative-free lidocaine confirms tolerance.
• Perioperative reaction: refer to specialist drug allergy clinic for testing of all agents given (neuromuscular blockers, antibiotics, chlorhexidine, latex, opioids, hypnotics), within 4 to 6 weeks.
• Mastocytosis: baseline tryptase above 20 ng/mL, venom or drug anaphylaxis with severe features. Lifelong adrenaline autoinjector, antihistamines, and specialist care.

Prevention

Pharmacogenetic screening (HLA-B57:01 before abacavir, B58:01 before allopurinol in at-risk populations, B15:02 and A31:01 before carbamazepine). Allergy alerts in the electronic record. Patient education and allergy wallet cards or medical identification.

Follow-up

Allergy clinic review for recurrent reactions or when drug-specific tests are indicated. Periodic review of labels, especially penicillin labels (loss of sensitisation in 80% after 10 years).