Key Facts

Hypersensitivity reactions represent immune-mediated tissue damage. The Gell and Coombs classification (1963) remains the standard framework for understanding these reactions.

Epidemiology

• Allergic disease (Type I) affects approximately 30% of the UK population
• Anaphylaxis incidence is rising — approximately 20 deaths per year in the UK
• Hospital admissions for anaphylaxis have increased 7-fold over the past 20 years
• Autoimmune diseases (Types II, III, IV) affect approximately 5-8% of the population

Aetiology

Each type has a distinct immunological mechanism:

• Type I: Allergen cross-links IgE on mast cells/basophils → degranulation → histamine, leukotrienes, prostaglandins
• Type II: IgG/IgM antibodies bind cell surface antigens → complement activation, ADCC, opsonisation → cell destruction
• Type III: Antigen-antibody complexes deposit in tissues → complement activation → neutrophil recruitment → tissue damage
• Type IV: Sensitised T cells encounter antigen → cytokine release → macrophage activation → tissue damage (48-72h delayed)

Pathophysiology

Type I: Two-phase response

1. Sensitisation: First exposure → IgE production → IgE binds FcεRI on mast cells
2. Re-exposure: Allergen cross-links surface IgE → mast cell degranulation
3. Early phase (minutes): Histamine, tryptase, prostaglandins → vasodilation, bronchospasm
4. Late phase (4-8 hours): Leukotrienes, cytokines → prolonged inflammation, eosinophil recruitment

Type I Reactions

• Mild: Urticaria, rhinitis, conjunctivitis
• Moderate: Angioedema, bronchospasm, GI symptoms
• Severe (anaphylaxis): Airway compromise, cardiovascular collapse, shock
• Common triggers: Foods (nuts, shellfish), drugs (penicillin, NSAIDs), insect stings, latex

Type II Reactions

• Haemolytic anaemia (warm: IgG — extravascular; cold: IgM — intravascular)
• Haemolytic disease of the newborn (anti-RhD antibodies)
• Goodpasture's syndrome (anti-GBM antibodies → pulmonary haemorrhage, glomerulonephritis)
• Myasthenia gravis (anti-AChR antibodies), Graves' disease (TSH receptor stimulating antibodies)

Type III Reactions

• SLE (anti-dsDNA immune complexes → nephritis, arthritis, serositis)
• Post-streptococcal GN (immune complex deposition in glomeruli)
• Serum sickness (fever, rash, arthralgia 7-14 days after foreign protein exposure)

Type IV Reactions

• Contact dermatitis (nickel, latex)
• Tuberculin (Mantoux) test
• Granulomatous disease (TB, sarcoidosis)
• Transplant rejection (acute cellular)

Red Flags

• Stridor, wheeze, or respiratory distress → anaphylaxis
• Hypotension with urticaria/angioedema → anaphylaxis
• Rapid-onset symptoms after allergen exposure → treat immediately

Bedside

• A-E assessment: Airway, breathing, circulation in suspected anaphylaxis
• Peak flow: Bronchospasm assessment

Bloods

• Mast cell tryptase: Serial samples at presentation, 1-2 hours, and >24 hours (baseline)
• Specific IgE (RAST): To identified allergens
• C3, C4: Low in Type II and III (complement consumption)
• Autoantibodies: Coombs test (Type II), ANA, anti-dsDNA (Type III)
• Eosinophil count: Elevated in atopic conditions

Imaging

• As clinically indicated (CXR if respiratory symptoms, renal imaging if nephritis)

Special Tests

• Skin prick testing: Type I hypersensitivity — must be done in specialist setting with resuscitation facilities
• Patch testing: Type IV (contact dermatitis) — reading at 48 and 96 hours
• Component-resolved diagnostics: Specific IgE to allergen components for risk stratification
• Drug provocation testing: Specialist setting for drug allergy clarification
• Direct and indirect Coombs test: Autoimmune haemolytic anaemia

Non-pharmacological

• Allergen avoidance: Education, food labelling awareness
• Allergy action plan: Written plan for patients at risk of anaphylaxis
• Medical alert identification: Bracelet/necklace

Pharmacological

Anaphylaxis (NICE CG134 / Resuscitation Council UK):

1. Remove trigger, call for help
2. IM adrenaline 0.5mg (1:1000) into anterolateral thigh — repeat every 5 minutes if needed
3. High-flow oxygen
4. IV fluid bolus (500-1000mL crystalloid)
5. Chlorphenamine 10mg IM/slow IV and hydrocortisone 200mg IM/slow IV
6. If bronchospasm: Nebulised salbutamol 5mg
7. Observe for minimum 6-12 hours (biphasic reaction risk)

Adrenaline auto-injector doses:

• Child <6 years: 150mcg (EpiPen Jr)
• Child 6-12 years: 300mcg
• Adult/child >12 years: 300-500mcg

Chronic allergic conditions:

• Antihistamines (cetirizine 10mg OD, fexofenadine 180mg OD)
• Intranasal corticosteroids (allergic rhinitis)
• Allergen immunotherapy (specialist-led desensitisation)

Referral Criteria

• All confirmed anaphylaxis → allergy clinic within 6 weeks
• Suspected drug allergy → specialist allergy testing
• Consideration of allergen immunotherapy (venom, aeroallergens)
• Recurrent angioedema without urticaria → exclude HAE

• Anaphylaxis: Fatal in 1-2% of hospitalised cases; most deaths occur within 30 minutes
• Risk of biphasic reaction: ~5-20% — typically within 4-12 hours
• Food allergy: Many children outgrow milk and egg allergy (~80% by school age); peanut/tree nut allergy tends to persist
• Autoimmune haemolytic anaemia: Variable — depends on underlying cause
• SLE: 10-year survival >90% with modern treatment; renal involvement is main prognostic determinant

Gell and Coombs Classification Summary

Adrenaline Doses for Anaphylaxis