Hypersensitivity

Explain the immunological basis and pathophysiological effects of hypersensitivity, including anaphylaxis.

Understand the pharmacology of the drugs used in the treatment of anaphylaxis.

Hypersensitivity reactions are exaggerated immune responses that cause host injury.

Classification of Hypersensitivity Reactions

The Gel and Coombs system classifies hypersensitivity reactions by the mechanism. It is commonly used but fails to classify more complex diseases.

Type I Hypersensitivity

• Antigen simulates a B lymphocyte to produce a specific IgE against it
• This IgE then binds to Fc receptors on mast cells, sensitising them to this exposure
• On re-exposure the antigen binds (cross-links) IgE on mast cells, causing degranulation:
  • Histamine, leukotrienes, and prostaglandins are released
  • This may cause local or systemic effects, depending on method of exposure:
    • A systemic reaction is called anaphylaxis, and manifests as a combination of:
      • Hypotension
      • Bronchospasm
      • Laryngeal oedema
      • Rashes
    • Local reactions depend on the route of exposure, and include
      • Asthma
        Inhaled.
      • Allergic rhinitis
        Nasopharyngeal mucosa.

• Non-immune anaphylaxis (also known as anaphylactoid) reactions are characterised by a immediate generalised reaction clinically indistinguishable from true anaphylaxis, but the immune nature is unknown, or not due to a type I hypersensitivity reaction

Management of Anaphylaxis

• Adrenaline is the drug of choice, as it treats cardiovascular collapse, bronchospasm, and decreases oedema formation.
  • In adults, 0.3-0.5mg IM Q5-15min
  • In children, 0.01mg/kg IM Q5-15min
• Glucagon may be used in β-blocked patients resistant to adrenaline.
  • In adults, 1-5mg IV over 5 minutes, followed by infusion at 5-15microg/min
  • In children, 20-30mcg/kg up to 1mg over 5 minutes
• Non-pharmacological management includes early intubation to protect against airway obstruction due to angioedema.
• Adjuncts include antihistamines and steroids. They are second line as they do not attenuate cardiovascular collapse, resolve airway obstruction, or have strong evidence behind their use. They include:
  • Diphenhydramine 25-50mg IV (Children: 1mg/kg up to 40mg) up to 200mg in 24/24
  • Salbutamol, for bronchodilation
  • Methylprednisolone 1-2mg/kg, ostensibly to protect against rebound anaphylaxis (though there is minimal evidence)

Type II Hypersensitivity

• Antibodies bind to cell surface antigen
• Antibody-Antigen complex activates complement
• Complement generates an inflammatory response
• Cell death occurs via:
  • Complement membrane attack complex
  • Phagocytosis

Clinical picture depends on affected organs. Examples include:

• Hyperacute allograft rejection
• Transfusion reactions and haemolytic disease of the newborn
• Goodpasture's syndrome
• Autoimmune cytopaenias
• Myasthenia Gravis

Type III Hypersensitivity

• Immune-complex reaction where Ab-Ag complexes are formed and deposited in tissues
• Subsequent complement activation causes inflammation and neutrophils activation, leading to tissue damage
• There are two subtypes of type III reactions:
  • Formation of complexes in circulation and subsequent deposition in tissues
    • e.g. Serum sickness
  • Formation of complexes in tissues
    Small amounts are typically removed by the reticuloendothelial system, but in this case there are too many, or they are too small, to be cleared effectively.
    • e.g. The Arthus reaction (a localised vasculitis, which may be necrotising)

Type IV Hypersensitivity

• Antigen is presented to T lymphocytes which proliferate and become sensitised
• T-cells then release cytokines, attracting macrophages and leading to local inflammation
• During prolonged exposure, macrophages may fuse to form giant cells and form a granuloma. Examples include:
• TB
• Granulomatous vasculitis

References

1. CICM July/September 2007
2. Kam P, Power I. Principles of Physiology for the Anaesthetist. 3rd Ed. Hodder Education. 2012.