Respiratory

Asthma-Pathogenesis

What is the pathogenesis behind asthma? 

  • Three corner stones of asthma pathogenesis are airflow obstruction, bronchial hyperresponsiveness, and an underlying inflammation.
  1. Airflow obstruction
  • Seondary be due to many causes
  • Bronchoconstriction
    • The dominant causative event behind clinical symptoms.
    • Secondary to IgE and non-IgE mediated pathways. 
      • IgE-mediated
        • Bronchial smooth muscle contraction after exposure to allergens or irritants. 
      • Non-IgE-mediated
        • ​Mediators are released from airway cells in response to aspirin and other NSAIDs that cause bronchoconstriction.
        • Stimuli like exercise, cold air, and irritants can also bronchoconstriction through a non-IgE-mediated pathway.
  • Airway edema
    • Edema, mucus hypersecretion and formation of mucus plugs are secondary to the persistent inflammation.
    • Persistent inflammation can also lead to irreversible structural changes to the airways (airway remodeling) that may not respond to traditional therapy.
  1. Airway hyperresponsiveness
  • Consists of an exaggerated response to stimuli.
  • It is a reversible phenomenon and is the principle behind the methacholine challenge, in which asthma patient show a dramatic decrease in FEV1.
  • Exact mechanism behind the hyperresponsiveness is not known
  • Inflammation, dysfunctional neuroregulation, and structural change are thought to be important.
  1. Inflammation
  • Plays a central role in the pathogenesis of asthma.
  • Consists of an ‘early-phase reaction’ and a ‘late-phase reaction.’

Early-phase reaction:

  1. An individual is exposed to allergens and produces IgE antibodies due to overexpression of Th2 T-cell response.
  • Th2 T-cell response is associated with helminthic responses as well as atopic diseases like asthma.
  • With a combination of genetics and environmental exposure,  susceptible individuals overexpress Th2 T-cells rather than Th1 T-cells.
  1. IgE antibodies produced by plasma cells bind to mast-cells.
  2. Exposure to the same allergen leads to cross-linking of IgE antibodies on the mast cell surface.
  • This leads to rapid degranulation and cytokine release. 
  • Histamine, prostaglandin D2, leukotrienes are released, leading to airway smooth muscle contraction. 

 

Late-phase reaction

  1. The mediators released during the early-phase reaction lead to recruitment of innate and adaptive inflammatory cells (e.g. neutrophils, monocytes, eosinophils, basophils, memory T-cells, etc.).
  2. These cells release more mediators that lead to smooth muscle contraction
    • Contraction occurs several hours after the exposure to the allergen.
    • The mediators shape other aspects of the inflammatory response.

 

What is wheezing and what do we hear in asthma patients? 

  • Wheezing is a continuous adventitious lung sound that lasts longer than 250 milliseconds heard during auscultation.
  • Produced by oscillation of opposing walls of an airway narrowed almost to the point of closure.
  • Most commonly heard in the expiratory phase of the respiratory cycle.
  • Most commonly is heard bilaterally
    • This is in contrast to a localized obstruction as a cause of wheezing that will be appreciated as radiating from a point of origin.
  • Timing, location, and location help differentiate the various types of wheezes
  • Wheezing in asthma is multitonal (or multiphonic) in contrast to wheezing in localized obstruction that are monotonal.
    • Many different sizes of airways oscillate and superimpose to produce a multiphonic sound
    • in a localized obstruction, an airway of one size will be obstructed to produce a more monotonal sound.
  • The absence of wheezing and breath sounds is a far more ominous finding in asthma than the presence of wheezing. 

References

  1. National Asthma Education and Prevention Program (NAEPP) Coordinating Committee (CC), National Heart, Lung, and Blood Institute (NHLBI). Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma - Summary Report 2007. http://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/summary-report-2007
  2. National Asthma Education and Prevention Program (NAEPP) Coordinating Committee (CC), National Heart, Lung, and Blood Institute (NHLBI). Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma : Section 2, Definition, Pathophysiology And Pathogenesis Of Asthma, And Natural History Of Asthma. http://www.nhlbi.nih.gov/files/docs/guidelines/03_sec2_def.pdf
  3. Liu, M. Pathogenesis of Asthma. In: Bochner BS, Hollingsworth H. UpToDate. Waltham, MA: UpToDate: 2015. http://www.uptodate.com/contents/pathogenesis-of-asthma

 

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