Term
| What is the difference between extrinsic and intrinsic asthma? |
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Definition
Both involve "bronchial hyper-responsiveness," or bronchoconstriciton in response to nonspecific stimuli such as exercise, cold air and cigarette smoke.
1) Extrinsic asthma is exaggerated smooth muscle contraction caused by an inflammatory response to a particular inhaled allergen.
2) Intrinsic asthma occurs in non-allergic patients |
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Term
| What is the basic immunological response that causes chronic inflammation in asthma? |
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Definition
1) Dendritic cells take up allergen, process it and present it on MHC class II molecules to T cells in regional lymph nodes.
2) TCR activation leads to differentiation into TH2 lymphocytes that secrete IL-R and activate B cells.
2) B cells undergo heavy chain class switching to produce and secrete IgE antibodies.
4) IgE-dependent mast cell activation/degranulation produces early allergic response (EAR) within 10 minutes, lasting for 1-3h.
5) Inflammatory cells recruited by mast cell secretions produce IL-4, IL-5, IL-13 and TNF-a, which produce a late allergic response several hours later. |
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Term
| What is the pathophysiological basis of the early and late allergic responses seen in asthma? |
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Definition
Together, these responses lead to bronchial smooth muscle contraction, increased vascular permeability (airway edema) and increased mucous production
1) EAR
- IgE-dependent mast cell activation/degranulation produces early allergic response (EAR) within 10 minutes, lasting for 1-3h.
- Mast cells release histamine, proteases, leukotrienes and prostanoids, all of which produce inflammation and recruit other inflammatory cells.
2) LAR
- Inflammatory cells recruited by mast cell secretions produce IL-4, IL-5, IL-13 and TNF-a, which produce a late allergic response several hours later. |
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Term
| What are the 3 major pathophysiological features of asthma? |
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Definition
1) Airway smooth muscle contraction
2) Increased vascular permeability (airway edema)
3) Increased mucous production |
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Term
| What are the cardinal clinical symptoms of asthma? |
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Definition
Waxing and Waning symptoms
**severity and frequency are critical for diagnosis/treatment**
1) Wheezing
2) Coughing
3) Chest tightness
4) Shortness of breath
On PE, see prolonged expiratory phase |
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Term
| What are the 4 clinical classifications of asthma? |
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Definition
1) Intermittent
2) Mild persistent
3) Moderate persistent
4) Severe persistent |
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Term
| How can a methacholine challenge test assist in classifying asthma? |
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Definition
| Provocation test that is useful in staging asthma in patients with normal lung function (e.g. no changes in FVC, FEV1 or FEV 25-75) where methacholine (ACh analogue) is added and resulting smooth muscle contraction is measured. |
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Term
| What 3 factors is an asthma management strategy based on? |
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Definition
Use bronchodilators (rapid symptom relief) and/or anti-inflammatory drugs (decrease underlying lung inflammation for long-term control).
1) Frequency of attacks
2) Severity of attacks
3) Previous response to treatments. |
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Term
| Why are bronchodilators used to treat asthma and how do they work? |
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Definition
1) Beta 2 adrenoreceptor agonists relax bronchial smooth muscle and treat bronchospasm in short term (Albuterol)
2) Salmeterol (partial agonist) and Formeterol (full agonist) also stimulate B2, but last up to 12 h (good when combined with inhaled corticosteroids).
3) Ipratropium is an anti-cholinergic that can be used as an adjunct therapy: it prevents muscarininc M3-receptor-dependent smooth muscle contraction (cGMP mediated).
4) Cromones like Cromoglycate and Nedocromil sodium inhibit IgE-mediated mast cell degranulation
5) Methylxanthines are rarely used, because beta agonists are better. |
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Term
| Why might you add Cromoglycate or Nedocromil to your Formoterol treatment of asthma? |
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Definition
| These are Cromone drugs that inhibit IgE-dependent mast cell degranulation and therefore prevent the late allergic response and chronic airway inflammation. |
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Term
| Why might you add Ipratropium bromide to your Formoterol treatment of asthma? |
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Definition
Especially useful in ACUTE SEVERE asthma
It will inhibit M3 ACh receptors in bronchial smooth muscle, thereby preventing cGMP-mediated contraction. |
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Term
| Why are Corticosteroid drugs used to treat asthma? |
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Definition
Glucocorticoids suppress acute and chronic inflammation by
1) Reducing pro-inflammatory cytokine production in Th2 cells, mast cells and eosinophils
2) Reducing mast cell and eosinophil influx and maturation
3) Promoting inflammatory cell apoptosis |
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Term
| Why might you treat asthma with Zafirlukast or Zileutin? |
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Definition
These are Leukotriene modifiers.
Remember, cysteinyl leukotrienes (LT) like LTC4 and LTD4 are produced from AA following oxidation by 5-lipoxygenase and bind cysLT1 receptors, producing features of asthma
1) Zafirlukast and Montelukast block the cysLT1 receptor
2) Zileuton inhibitors LT production by inhibiting 5-lipoxygenase |
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Term
| What is Omalizumab and how is it used to treat asthma? What patients benefit from it most? |
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Definition
Only for moderate/severe asthma.
- Monoclonal IgE antibody that binds free serum IgE and leads to decreased mast cell activation.
- it also down-regualtes IgE receptors on mast cell surfaces and decreases eosinophils in the airways |
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Term
| Describe how the early and late allergic inflammatory responses occur in asthma. |
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Definition
Remember, asthma is bronchial constriction, increased permeability of vasculature (edema) and mucous production.
Early Response
1) DCs uptake and process allergens and then present them on MHC-II molecules to T cells in regional lymph nodes.
2) T cells differentiate into Th2 type cells and activate B cells by releasing Il-4
3) B cells undergo class-switching and make IgE, which binds and activates Mast cells, causing them to release inflammatory molecules like histamines, PGE and LCT.
Late Response
4) Mast cell activation recruits T cells and eosinophils that release IL-4, IL-5, IL-13 an TNF-a, leading to a secondary inflammatory response, |
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