Asthma

Question 1

Th2 Pathophysiology

Answer 1

• Sensitization to common aeroallergens (selective expansion of Th2 cells that create type 2 cytokines –> inflammatory cascade)
• Mast cells bind FcepsilonRI of IgE –> mast cell degranulation (histamine, proteases, proteoglycans) + mast cells make leukotrienes/prostanoids –> all contribute to smooth muscle contraction AND mast cells recruit Th2 cells, eosinophils, inflammatory cells into airway
• Leads to epithelial damage and lumen narrowing

Question 2

Which 6 cytokines are involved in asthma sensitization?

Answer 2

• IL-3, IL-4, IL-5, IL-9, IL-13 and GM-CSF (granulocyte macrophage colony-stimulating factor)

Question 3

Early v Late Allergic Response

Answer 3

• 1- Early Allergic Response
  
  • 10 min after exposure; peaks at 30 min; resolves in 1-3 hrs
  • Involves IgE activation of mast cells
• 2- Late Allergic Response
  
  • Several hrs after exposure; last days
  • Involves influx of eosinophils and T cells

Question 4

How to dx asthma?

Answer 4

• CLINICAL Dx - is airflow obstruction eliminated w/ bronchodilator use?
• FVC - maybe slightly decreased; same or slight improvement w/ bronchodilator
• FEV1 and FEV1/FVC - both dec and improve sig w/ bronchodilator
• Diffusion Capacity (DLCO) - unchanged by asthma; no change w/ bronchodilator

**Eventually may have remodeling –> fixed obstruction –> no longer reversible

Question 5

Asthma Predictive Index

Answer 5

(dx in kids < 3 yo)

• 3+ episodes of wheezing / yr PLUS
• 1 major criteria (eczema, parental asthma)
  OR 2 minor criteria (allergic rhinitis, wheezing unrelated to colds, high blood eosinophil count)
• If pos… they are at sig higher risk of developing asthma symptoms later in life

Question 6

Histology of Asthma

Answer 6

• Inflammation, edema and smooth muscle hypertrophy in airway
• Inc # goblet cells, thicker BM, eosinophils present

Question 7

Symptoms

Answer 7

• Chest tightness, wheezing (may worsen w/ exercise), dyspnea, nocturnal wakening w/ SOB
• Can be cont or intermittent; may only follow exposure
• Exacerbations - (acute worsening of symptoms beyond baseline) can be due to allergen exposure, viral infection or med non-compliance or unknown; common cause of mortality

Question 8

5 Descriptive Classifications

Answer 8

1- Exercise-Induced Bronchospasm - symptomatic unless CV exercise (Pre-treat b/f exercise)

2- Occupational Asthma -triggered by work-related exposure (Avoidance)

3- Mild Intermittent Asthma -Intermittent symptoms; often specific trigger (Symptom management; relief meds; tx prn)

4- Mild to Moderate Persistent Asthma - Cont symptom often worse w/ exercise; can be Type 2 High or Low (daily med use)

5- Severe Persistent Asthma -cont symptoms despite steroid or other med use; Type 2 High or Low usually w/ confounding factors (Daily med use + additional tx)

Question 9

Phenotype Groups (2 historic systems + current system)

Answer 9

• Historic Grouping
  
  • Extrinsic (external trigger) v. Intrinsic
  • Eosinophilic (eosinophils in sputum seemed to respond better to steroids) v. Non-eosinophilic
• Current Grouping - Type 2 High v. Type 2 Low
  
  • High - elevated levels of cytokines and cells seen in Type 2 inflammation
    
    • IL-4, IL-5, IL-13, GM-CSF
    • Th2 CD4+ cells –> B cell isotype switching to IgE
    • Mast cell differentiation and eosinophils
  • Low - do not have these features and are less likely to respond to steroids

Question 10

General Overview of Tx

Answer 10

Controllers (control disease)

- 1- Corticosteroids (local - inhaled) 
- 2- Leukotriene Pathway Modifiers
- 3- Biological Agents (antibodies against specific parts of inflammatory path) **requires that you know the phenotype/biomarkers** 

Relievers (quickly alleviate symptoms)

- 1- Bronchodilators
    - Beta agonists, Theophylline (RARELY USED), Anti-cholinergics
- 2- Systemic Corticosteroids ( in exacerbation) 

Strategy = start w/ high dose corticosteroid; then add additional controller (leuk, LAMA, oral steroid); if still uncontrolled use bio therapy

Question 11

Corticosteroids (mechanism + side effects + examples)

Answer 11

• Reduce inflammation; bind GR in cell cytoplasm then translocation to nucleus
• Transactivation - inc transcription of anti-inflammatory proteins
• Trans-repression - block NF-kB and AP-1 in nucleus to prevent transcription of pro-inflammatory genes
• Side Effects - HPA axis suppression, bone resorption, cataracts, skin thinning, purpura, dysphonia, candidiasis, growth retardation, hyperlipidemia, HTN, hypogonadism
  
  • Minimize by giving topical/just lungs via inhaler

Inhaled - beclomethasone, fluticasone, budesonide, mometasone, ciclesonide, flunisolide

Systemic - prednisone (oral), triamcinolone (IM), methylprednisolone (IV)

Question 12

Leukotriene Pathway Inhibitors (2 types)

Answer 12

• Leukotrienes come from AA (uses the 5-LOX enzyme) and induce bronchospasm
• CysLT1 Receptor Antagonists - Montelukast, zafirlukast
• 5-LOX Inhibitors - Zileuton
• Less effective than corticosteroids but used in addition; good compliance b/c oral pill

Question 13

Beta Agonists (mechanism and side effects)

Answer 13

• Airway bronchodilation
• May also inhibit mast cell release, less leaks/edema, enhance mucociliary clearance (all help acute process)
• Side effects - agitation, tremor, insomnia, arrhythmia, tachy, inc hyperglycemia in diabetic, hypokalemia (comp for intake of K+ into muscles)

Short-Acting (3-6 hrs)-albuterol, levalbuterol, terbutaline, metaproterenol, isoproterenol, epi (shortest)

Long-Acting

• Salmeterol, formoterol (12 hr)
• Indecaterol, vilanterol (24 hr)

**Often use combo; should not use long-acting on own

Question 14

Anti-Cholinergics (mechanism and examples)

Answer 14

• Generally, compete w/ Ach at M3 receptors of bronchial smooth muscle –> relaxation and bronchodilation (lower baseline vagal tone)
• Atropine
• Ipratropium - quart amine; poorly absorbed so can give via inhaler
• LAMA (longer-acting) - have high affinity for all muscarinic receptors but dissociate more slowly from M3 (ex - trotropium)

Question 15

Biomarkers to Look For

Answer 15

IgE in blood

Eosinophil count in blood

Exhaled NO (prod in inflammation)

Question 16

How to Manage Asthma Exacerbation in ED

Answer 16

• give systemic steroids + SABA (broncho agonist) + SAMA (muscarinia antagonist) ;
• supplement w/ oxygen and if severe Mg++ IV (bronchodilatory properties)
• Once controlled, taper off high steroids over 5-10 days or weeks