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Asthma

3 main characteristics

  • Airflow limitation
  • Airway hyper-responsiveness – see ‘bronchial provocation test’
  • Bronchial inflammation – with T lymphocytes, mast cells, eosinophils
    • Associated with plasma exudation, oedema, smooth muscle hypertrophy, matrix deposition, mucus plugging

Etiology

Atopy and allergy

Bronchial Provocation Test

  • Demonstrates airway hyper-responsiveness (AHR)
  • Ask pt to inhale gradually increasing amounts of histamine/methacholine
  • This induces transient airflow limitation
  • Asthmatics have a low PD20 FEV1
    • This means that a low provocation dose (PD) of methacholine is needed to reduce their FEV1 by 20%
  • Atopy – group of disorders (asthma + hayfever) which
    • Runs in families
    • Have wheeling skin reactions to common allergens
    • Have circulating IgE
  • ↑serum IgE is linked to airway hyper-responsiveness

Genetics

  • IL-4 gene cluster on chromosome 5q31-33
    • Control production of IL-3,4,5,9,13 and GM-CSF
  • ADAM33 – associated with airway hyper-responsiveness and tissue remodelling
  • PHF11 – IgE synthesis

Environmental

  • Maternal smoking + early childhood exposure to allergens – influences IgE production
  • Hygiene hypothesis
  • Components of bacteria (LPS), viruses, fungi
    • Stimulate TLRs to direct immune/inflam response away from allergic (Th2) and towards protective (Th1 + Treg) pathway
    • Therefore, early exposure to bacteria can reduce risk of developing asthma

Precipitating factors

Occupational exposure

  • Low molecular weight (non IgE-related) – bond to epithelial cells to activate them
    • Isocyanates, wood dust, drugs, bleaches, dyes
  • High molecular weight (IgE-related) – involve specific IgE antibodies
    • Allergens from animals, antibiotics, latex

Non-specific factors

  • Cold air
  • Exercise – wheezing due to release of histamine, PG and LTs from mast cells
  • Atmospheric pollutants
  • Diet + Emotion

Drugs

  • NSAIDs – especially aspirin
    • Blockade of COX pathway – leads to ↓PGE2
    • More metabolism via LOX pathway – leads to ↑ LTs
  • Beta blockers (BB) – e.g. propanolol cause bronchoconstriction
    • Cardio-selective BB are safe to use – atenolol, bisoprolol

Pathogenesis

  • Predominantly Th2 response in mild disease – inflammatory
  • Shifts towards Th1 response in severe, chronic disease – causes tissue damage, mucus metaplasia, aberrant epithelial repair

Inflammation

  • Mast cells – release histamine, PGD2, LTs
  • Eosinophils – attracted to the airways by IL3,5 + GM-CSF
    • Activated eosinophils release LTC4 that are toxic to epithelial cells
    • Corticosteroids decrease the number and activation of eosinophils
  • Lymphocytes – airways show a predominance of Th2 pattern
    • Exposure to the antigen makes CD4+ cells differentiate into Th2 – which secretes IL-4 + 5
      • IL-4 – causes B cells to become plasma cells and secrete IgE
      • IL-5 – activates eosinophils and mast cells (chemotaxis)
    • In severe disease Th1 cells are more predominant

Remodelling – characteristic feature of asthma

  • Deposition of matrix proteins, swelling, cellular infiltration – expands the submucosa beneath the epithelium
  • Causes airway narrowing
  • Epithelial damage → ↑NO synthetase → ↑NO – feature of epithelial activation
  • Thickened epithelial basement membrane – due to deposition of collagen + matrix proteins (laminin)
  • Smooth muscle hyperplasia and sustained contraction

Clinical features

  • Wheezing + episodic dyspnoea
  • Chest tightness
  • Symptoms are worse at night/early morning
  • Cough

Diagnosis

  • PEFR – measurements on waking, before taking a bronchodilator, after a bronchodilator
    • Demonstrates diurnal variation of asthma
  • Spirometry – asthma diagnosed by demonstrating 15% improvement in FEV1 after inhaling a bronchodilator
  • Exercise tests – run for 6 mins on a treadmill at 160bpm
  • Cold air challenge
  • Histamine/methacholine bronchial provocation test – see box
  • Trial of corticosteroids
    • Prednisolone 30mg/day x 2 weeks – measure lung function before and after treatment
    • If FEV1 increased by >15% then discontinue and give inhaled beclomethasone 40mcg bid
  • Exhaled NO – measure of airway inflammation
  • CXR – hyperinflated lungs in chronic disease
  • Skin prick tests

Complications

  • Pneumonia
  • Pneumothorax
  • Respiratory failure
  • Growth delay in children
  • Depression/anxiety

Differential diagnosis

  • Cystic fibrosis
  • Congenital heart disease
  • Bronchiolitis
  • Foreign body aspiration
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