Gell-Coombs classification of hypersensitivity
The Gell and Coombs classification (1963) ↗ divides immunological hypersensitivity reactions into four types based on mechanism. Drug hypersensitivity reactions may involve one or more types; some severe reactions (e.g. DRESS syndrome) involve overlapping Type I and IV mechanisms.
| Type | Mechanism | Onset | Clinical examples | Implicated drugs |
|---|---|---|---|---|
| Type I | IgE-mediated (immediate) | Minutes to 1 h | Urticaria, angioedema, anaphylaxis | Penicillins, cephalosporins, neuromuscular blockers, latex |
| Type II | Cytotoxic (IgG/IgM antibody) | 5–12 days | Haemolytic anaemia, thrombocytopenia | Methyldopa, penicillin, quinine, heparin |
| Type III | Immune complex (IgG, complement) | 1–3 weeks | Serum sickness, vasculitis, drug fever | Penicillins, sulfonamides, allopurinol |
| Type IV | T-cell mediated (delayed) | 48 h to weeks | Contact dermatitis, SJS/TEN, DRESS, AGEP | Carbamazepine, allopurinol, TMP-SMX, lamotrigine |
Severe cutaneous adverse reactions (SCARs)
The spectrum of severe Type IV drug reactions includes four major entities — distinguished by skin involvement, systemic features, histology, and mortality:
SJS 1–5% mortality
Stevens-Johnson Syndrome
Skin: <10% BSA epidermal detachment
Features: Mucosal involvement (≥2 sites), fever, prodrome
Triggers: Aromatic antiepileptics, allopurinol, sulfonamides
TEN 25–35% mortality
Toxic Epidermal Necrolysis
Skin: >30% BSA detachment
Features: Confluent erythema, Nikolsky sign, mucosal
Triggers: Same as SJS; overlap at 10–30% = SJS/TEN overlap
DRESS ~10% mortality
Drug Reaction with Eosinophilia and Systemic Symptoms
Skin: Morbilliform rash; may be absent
Features: Fever, lymphadenopathy, eosinophilia, internal organ involvement (liver, kidney)
Triggers: Carbamazepine, phenytoin, allopurinol, dapsone, minocycline, vancomycin
AGEP <5% mortality
Acute Generalised Exanthematous Pustulosis
Skin: Sterile pustules on erythematous base
Features: Fever, neutrophilia, rapid onset
Triggers: Aminopenicillins, macrolides, calcium channel blockers, terbinafine
All SCARs require immediate drug withdrawal. SJS/TEN management is supportive (wound care in burn unit, fluid replacement, ophthalmology input for ocular involvement). DRESS requires prolonged systemic corticosteroids. Report all SCARs to FDA MedWatch ↗ and, for European patients, EudraVigilance ↗.
Pharmacogenomic screening for drug allergy risk
Several severe drug hypersensitivity reactions are strongly associated with specific HLA alleles, enabling pre-emptive genetic testing to prevent reactions. Pharmacogenomic screening is now mandated or recommended before starting several high-risk drugs:
| Drug | HLA allele | Reaction | Population at risk | Status |
|---|---|---|---|---|
| Abacavir | HLA-B*57:01 | Hypersensitivity syndrome | All ethnicities (~5–8% Caucasian) | FDA-mandated pre-treatment screen |
| Carbamazepine | HLA-B*15:02 | SJS/TEN | Han Chinese, Southeast Asian | FDA label warning; CPIC screen recommended |
| Carbamazepine | HLA-A*31:01 | DRESS, SJS, MPE | Japanese, European | CPIC screen recommended |
| Allopurinol | HLA-B*58:01 | SJS/TEN, DRESS | Han Chinese, Korean, Thai | CPIC screen recommended |
| Phenytoin | HLA-B*15:02 | SJS/TEN | Han Chinese, Southeast Asian | FDA label warning |
Full CPIC guidelines for HLA-drug pairs are available at cpicpgx.org/genes-drugs ↗. PharmGKB ↗ provides allele frequency data by population.
Frequently asked questions
What is the difference between a drug allergy and an adverse drug reaction?
An adverse drug reaction (ADR) is any unintended harmful response at a normal dose — this broad category includes side effects, toxicity, intolerance, and drug interactions. A drug allergy is an ADR mediated by an immunological mechanism. The Gell and Coombs classification ↗ divides hypersensitivity into four types: Type I (IgE, immediate — urticaria, anaphylaxis), Type II (cytotoxic), Type III (immune complex), Type IV (T-cell mediated, delayed — e.g. SJS/TEN). Only ~5–10% of reported penicillin allergies are true IgE-mediated; the rest are intolerance, pseudo-allergic, or mislabelled. See the FDA drug safety communications ↗ for specific alerts.
How is anaphylaxis to a drug treated?
Anaphylaxis requires immediate IM epinephrine 0.3–0.5 mg (anterolateral thigh preferred) — this is the only first-line treatment. Antihistamines and corticosteroids are adjuncts only and must never replace epinephrine. See the WAO Anaphylaxis Guidelines ↗ and UK Resuscitation Council guidance ↗. IV fluids (500–1000 mL normal saline) for distributive shock; nebulised salbutamol for bronchospasm. Biphasic reactions occur in 5–20% — observe ≥4–6 h in a monitored setting. Prescribe epinephrine auto-injectors on discharge with written action plan.
What is the penicillin allergy delabelling movement?
~10% of patients carry a penicillin allergy label, but >90% tolerate penicillin on formal testing. The label drives prescription of broader alternatives (vancomycin, fluoroquinolones, clindamycin), increasing antimicrobial resistance risk and Clostridioides difficile infection rates. AAAAI penicillin allergy delabelling resources ↗ and Blumenthal et al. JACI 2018 ↗ describe the structured approach: (1) allergy history risk stratification; (2) skin testing (penicilloyl-polylysine + minor determinant); (3) oral amoxicillin challenge if negative. Most low-risk patients can skip directly to oral challenge. See also the ASHP penicillin allergy resources ↗.
What is the cross-reactivity between penicillins and cephalosporins?
The widely quoted 10% cross-reactivity figure is outdated. Macy & Romano Allergy 2014 ↗ and subsequent studies show cross-reactivity is determined by R1 side chain similarity, not the beta-lactam ring. Cephalosporins with identical R1 side chains to the implicated penicillin carry higher risk (e.g. amoxicillin → cefadroxil, ampicillin → cefaclor). Cephalosporins with dissimilar R1 chains have <1–2% cross-reactivity. The Pichichero side chain similarity table ↗ and IDSA guidance ↗ support use of non-cross-reactive cephalosporins in most penicillin-allergic patients. For high-risk situations (prior anaphylaxis), formal allergy assessment is still recommended.
What drugs commonly cause Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)?
SJS/TEN are severe Type IV hypersensitivity reactions (keratinocyte apoptosis mediated by CD8+ T cells and NK cells via FasL, perforin/granzyme B, granulysin). Mortality: SJS ~1–5%, TEN ~25–35%. High-risk drugs: allopurinol (most common globally), carbamazepine, phenytoin, lamotrigine, TMP-SMX, nevirapine, oxicam NSAIDs. Pharmacogenomics: CPIC recommends HLA-B*15:02 screening ↗ before carbamazepine in patients of Han Chinese or other high-prevalence Asian ancestry. HLA-B*57:01 screening is mandated before abacavir ↗ (FDA-required). Report suspected cases to FDA MedWatch ↗.