asthma page 1

Overview

General disease characteristics
- increased tracheobronchial responsiveness to many stimuli
- physiological air passage narrowing
- paroxysmal dyspnea, coughing, wheezing, chest tightness
- episodic disease
  - acute exacerbations
  - symptom-free periods
  - long-term, severe obstruction: status asthmaticus
- mild form of the disease most prevalent:
  - induced by:
    - exposure to allergens
    - exposure to certain pollutants
    - exercise
    - following upper respiratory viral infections
- Short-term pharmacological relief
  - bronchodilators (promote airway smooth muscle relaxation ® increased airway caliber
  - theophylline (methylxanthine)
  - antimuscarinic drugs
- Long-term pharmacological management:
  - inhaled corticosteroids
  - inhibitors of mast cell degranulation buffering (e.g.,cromolyn)
  - leukotriene pathway inhibitors
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Prevalence/Etiology

Prevalence:
- Very common disorder: 4-5% affected in the United States
- Typically presents in early life: approximately 50% of cases developed before age 10; another 33% before age 40
- in childhood: 2:1 male/female ratio; sex ratio equalizes by age 30

Etiology:heterogenous disease;two broad types of asthma
- Allergic asthma:-- associated with
  - familial history of allergic diseases:
    - rhinitis
    - urticaria
    - eczema
  - positive wheal-and-flare reactions to intradermal injection of airborne antigen extracts
    - increased serum IgE levels or
    - positive response to provocation involving inhaled specific antigen
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- Idiosyncratic asthma:
  - no familial history
  - negative skin tests
  - normal serum IgE
  - asthmatic symptoms occur following:
    - upper respiratory illness (precipitates wheezing/dyspnea lasting up two months)
    - this patient population is not the same as those in which bronchospasm is superimposed on chronic bronchitis/bronchiectasis
- Many patients: fall into a mixed group with features of allergic asthma and idiosyncratic asthma

Asthma Pathogenesis

Common Denominator: nonspecific irritability of tracheobronchial tree
Increased airway reactivity:
- more severe symptoms
- greater intervention required to control patient's symptoms
- greater diurinal lung function.

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Factors that increase airway reactivity (normal/asthmatic):
- Respiratory tract viral infections-- longer duration effects (many weeks)
- Oxidant air pollutants: nitrogen dioxide/ozone-- short duration effects (a few days)
- Allergens
- Drug-induced bronchial narrowing

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Possible mechanism(s) for increased airway reactivity and asthma:
- Airway inflammation
- Bronchial lavage from asthmatics reveal increased numbers of:
  - Mast cells--Classic Model
    - reaginic (IgA) antibodies bound to airway mucosal mast cells
    - then: antigen re-exposure
      1. antigen-antibody interaction on mast cell surface
      2. mast cell granules released mediators
      3. synthesis and release of other mediators
      4. Agents Responsible for early reaction,immediate bronchoconstriction:
        
        histamine
        
        tryptase/other neutral proteases
        
        leukotrienes C₄and D₄.
        
        platelet-activating factor (PAF)
        
        prostaglandin D₂ (PGD₂)
  - Endothelial cells
  - Neutrophils
  - Eosinophils
    - important in infiltrative component
    - eosinophilic granular proteins (major basic proteins (MBP) /eosinophilic cationic protein (ECP): destroy airway epithelium cells --
      - destroyed cells are sloughed into bronchial lumen (Creola bodies)
      - in addition to barrier lost and secretory function loss -- damage enhances chemotactic cytokine production which leads to further inflammation
  - Lymphocytes
    - T_H1 cytokine interleukin 2 and interferon gamma which promotes growth/differentiation of B cells inactivation of macrophages, respectively.
    - cytokines produced by T_H2 lymphocytes-- GM-CSF
      - interleukin 4, interleukin 5 which promote attraction and activation of eosinophils; stimulation of IgE production by B lymphocytes.
    - interleukin 5 which promotes eosinophil proliferation, differentiation, activation -- also enhances basophil granule release
  - Mediators (histamine; bradykinin; leukotrienes C, D, E; platelet-activating factor; prostaglandins (E₂, F₂a , D₂) produce:
    - intense, immediate inflammatory reaction including:
      - bronchoconstriction
      - vascular congestion
      - edema
    - Leukotrienes:
      - prolonged airway smooth muscle contraction
      - mucosal edema
      - probably responsible for increased mucus production
      - impaired mucociliary transport
    - Elaborated chemotactic factors (eosinophil, neutrophil chemotactic factors of anaphylaxis and leukotriene B₄):
      - attract eosinophils, polymorphonuclear leukocytes, platelets to the reaction site
      - these cells (in addition to local macrophages and airway epithelial cells) provide additional mediator sources
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Asthmatic patients may show evidence of an active inflammatory process (even if asymptomatic):
- suggested by endobronchial biopsy
- edematous airways; infiltrated with eosinophils, neutrophils, lymphocytes
- thickening of epithelial basement membrane may be present
- the most common finding: generalized increase in cellularity associated with increased capillary density
- epithelial denudation may be observed

Bronchoconstriction in asthma may be due to the combination of:
- direct mediator effects
- activation by mediators of neuronal/humoral pathways
  - in asthmatics: exaggerated physiological bronchospastic reactions occur
Pharmacological approaches suggested by multiple pathogenic mechanisms--
- reduction of mast cell degranulation
  - sympathomimetic agents
  - calcium channel blockers
  - cromolyn/nedocromil
- reduction of cholinergic influence from vagal motor nerves
  - antimuscarinic agents
- direct relaxation of airway smooth muscle
  - sympathomimetic drugs
  - theophylline