#Hypersensitivity and anaphylaxis

#Classify hypersensitivity reactions

#Type I - Allergic (immediate)

Onset within minutes if already sensitised

Physiology

1. Initial sensitisation

   • detection of an antigen triggers lymphocytes to secrete IgE, which are taken up by basophils (in plasma) or mast cells (in tissue)

2. Subsequent exposures

   • the antigen binds to membrane-bound IgE on basophils and mast cells, forming cross-links
   • these cells degranulate, releasing various vasodilatory, inflammatory and chemotactic mediators:
     • histamine
     • tryptase
     • leukotrienes
     • prostaglandins
     • SRSA (slow releasing substance of anaphylaxis)
     • eosinophilic chemotactic factor (ECFA)
     • neutrophilic chemotactic factor (NCF)

3. Effects

   • vasodilation with increased vascular permeability / capillary leak
     • → hypotension, oedema (e.g. laryngeal)
   • eosinophil/neutrophil infiltration → contributing to immune response
   • bronchospasm
   • urticarial rash

4. Regulatory role of eosinophils

   • eosinophils play a complex role in anaphylaxis, both contributing to and regulating inflammation
   • they inhibit some inflammatory mediators (e.g. SRSA) and destroy antibody-antigen complexes, which may limit the severity of inflammation

Examples

• anaphylaxis
• asthma
• allergy
• atopy

#Type II - Cytotoxic (membrane-bound Ag-Ab complex)

Onset within hours to days.

Physiology

• IgM or IgG binds to antigens on cell membrane
• the cell-bound antigen-antibody complex triggers an immune response:
  • antibody opsonises the cell, leading to phagocytosis of the cell
  • complement is activated via the classical pathway → cell lysis
  • neutrophils bind the Ag-Ab complex → degranulate, releasing inflammatory mediators
  • NK cells bind the Ag-Ab complex → induce apoptosis (antibody dependent cellular cytotoxicity)
  • macrophages activated → phagocytosis and cytokine release

Examples

• acute or delayed haemolytic transfusion reaction
• autoimmune haemolytic anaemia
• haemolytic disease of the newborn (Rh)
• myasthenia gravis

#Type III - Immune complex mediated (soluble Ag-Ab complex)

Onset within hours to weeks, typically 3-4 days.

Physiology

• antigen-antibody complexes form either in tissue, causing local effects, or in blood where they deposit in vessel walls causing systemic effects
• activates complement via classical pathway and recruits granulocytes and macrophages as seen in type II hypersensitivity

Examples

• SLE - ANA and nuclear antigens bind in serum and lodge in blood vessels → vasculitis
• IgA nephropathy - complexes lodge in glomeruli → glomerulonephritis

#Type IV - Delayed (cell-mediated)

Onset in 2 to 3 days

Physiology

• an antigen presenting cell presents an antigen to a Th1 cell → T-cell proliferation
• repeat presentation causes T-cell activation and cytokine release
  • → activates macrophages
  • → may cause granuloma formation with fibrosis and calcification
• it is a delayed response due to the time required for T-cell replication and activation

Examples

• TB
• sarcoidosis
• granulomatosis with polyangiitis (GPA)
• poison ivy / contact dermatitis
• SJS/TENS

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#Anaphylaxis

Anaphylaxis is an acute, severe abnormal immune response affecting multiple systems with at least one of skin, respiratory or cardiovascular symptoms.

Anaphylaxis is a type 1 hypersensitivity reaction.

#Describe the drug treatment of anaphylaxis

#Supportive

O2

• to treat hypoxia as a result of bronchospasm, airway obstruction, or haemodynamic compromise
• avoid hyperoxic hypoventilation

IV fluids

• vasodilation causes distributive shock
• IV fluid supports blood volume

#Immediate management

Adrenaline

• onset: <2min
• route: IM 500mcg initial dose, IV infusion, nebulised
• mechanism of action
  • α1 agonism
    • Gq-coupled receptor
    • → activates PLC → ↑IP3/DAG → ↑ intracellular Ca
    • → vasoconstriction
      • → decreases oedema (e.g. airway)
      • → supports blood pressure
  • β agonism
    • Gs-coupled receptor
    • → activates adenylate cyclise → ↑cAMP → activates PKA → several downstream effects
      • β1 effect
        • ↑ Ca → inotropy to support haemodynamics
      • β2 effect
        • acts on mast cells to inhibit release of histamine and SRSA
        • inhibits MLCK and indirectly activates MLCP → bronchodilation

Salbutamol (β2 agonist)

• inhaled/nebulised salbutamol may be used as an adjunct for additional β2 effect

#Auxiliary management

Second generation antihistamine (anti-H1)

• antagonist at H1 receptors e.g. cetirizine
• does not relieve shock or airway obstruction

Corticosteroids

• e.g. hydrocortisone IV or prednisolone PO
• onset ~1h (hydrocortisone) or 1-2h (prednisolone)
• not part of routine management and should not replace adrenaline
• mechanism of action
  • binds to cytoplasmic glucocorticoid receptors
  • these undergo conformational change and are actively transported into the nucleus
  • there they bind to transcription factors, regulating RNA synthesis
    • ↓ synthesis of proinflammatory cytokines and inflammatory mediators (e.g. prostaglandins, platelet activating factor, leukotrienes, COX-2)
    • inhibits function of virtually all immune cell lineages
    • ↑ number and activation of adrenergic receptors
• effects
  • ↓ vascular permeability → ↓ oedema, secretions
  • ↓ inflammatory response → ↓ vasodilation/bronchoconstriction
  • supports haemodynamics via adrenergic effects