Asthma Flashcards
Th2 Pathophysiology
- 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
Which 6 cytokines are involved in asthma sensitization?
- IL-3, IL-4, IL-5, IL-9, IL-13 and GM-CSF (granulocyte macrophage colony-stimulating factor)
Early v Late Allergic Response
- 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
How to dx asthma?
- 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
Asthma Predictive Index
(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
Histology of Asthma
- Inflammation, edema and smooth muscle hypertrophy in airway
- Inc # goblet cells, thicker BM, eosinophils present
Symptoms
- 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
5 Descriptive Classifications
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)
Phenotype Groups (2 historic systems + current system)
- 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
- High - elevated levels of cytokines and cells seen in Type 2 inflammation
General Overview of Tx
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
Corticosteroids (mechanism + side effects + examples)
- 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)
Leukotriene Pathway Inhibitors (2 types)
- 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
Beta Agonists (mechanism and side effects)
- 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
Anti-Cholinergics (mechanism and examples)
- 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)
Biomarkers to Look For
IgE in blood
Eosinophil count in blood
Exhaled NO (prod in inflammation)
