Etiology

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• Risk factors for asthma include:
  • Family history of asthma
  • Past history of allergies
  • Atopic dermatitis
  • Low socioeconomic status
• Allergic asthma (extrinsic asthma) vs Nonallergic asthma (intrinsic asthma)
  • Allergic asthma (extrinsic asthma)
    • Cardinal risk factor: atopy
    • Environmental allergens: pollen (seasonal), dust mites, domestic animals, mold spores
    • Allergic occupational asthma from exposure to allergens in the workplace (e.g., flour dust)
  • Nonallergic asthma (intrinsic asthma)
    • Viral respiratory tract infections (one of the most common stimuli, especially in children)
    • Cold air
    • Physical exertion (laughter, exercise-induced asthma)
    • Gastroesophageal reflux disease (GERD): often exists concurrently with asthma
    • Chronic sinusitis or rhinitis
    • Medication: aspirin/NSAIDS (aspirin-induced asthma), beta blockers
    • Stress
    • Irritant-induced occupational asthma (e.g., from exposure to solvents, ozone, tobacco or wood smoke, cleaning agents)

Tip

• Allergic asthma (extrinsic asthma): A type of asthma triggered by allergens (e.g., pollen, dust mites, mold spores, pet allergens). Typically onset in childhood.
• Nonallergic asthma (intrinsic asthma): A type of asthma that typically develops in patients > 40 years of age.

Pathophysiology

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Common underlying pathophysiology

Asthma is an inflammatory disease driven by T-helper type 2 cells (Th2-cell) that manifests in individuals with a genetic predisposition. It consists of the following three pathophysiologic processes:

1. Bronchial hyperresponsiveness
2. Bronchial inflammation
   • Symptoms are primarily caused by inflammation of the terminal bronchioles, which are lined with smooth muscle but lack the cartilage found in larger airways.
3. Endobronchial obstruction caused by:
   • Increased parasympathetic tone
     • Reversible bronchospasm
     • Increased mucus production
     • Mucosal edema and leukocyte infiltration into the mucosa with hyperplasia of goblet cells
   • Hypertrophy of smooth muscle cells

Type-specific pathophysiology

• Allergic asthma
  • IgE-mediated type 1 hypersensitivity to a specific allergen
  • Characterized by mast cell degranulation and release of histamine after a prior phase of sensitization
• Nonallergic asthma
  • Irritant asthma: irritant enters lung → ↑ release of neutrophils → submucosal edema → airway obstruction
  • Aspirin-induced asthma (NSAID-exacerbated respiratory disease) is characterized by the Samter triad:
    • Inhibition of COX-1 → ↓ PGE2 → ↑ leukotrienes and inflammation → submucosal edema → airway obstruction
    • Chronic rhinosinusitis with nasal polyposis
    • Asthma symptoms

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Clinical features

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Diagnostics

Spirometry

• Supportive findings: Expiratory airway limitation: i.e., ↓ FEV1 and ↓ FEV1/FVC ratio
• Bronchodilator Responsiveness Testing:
  • Used when the patient has abnormal baseline spirometry showing obstruction (FEV1/FVC ≤70%)
  • Tests if the obstruction is reversible (suggesting asthma) or fixed (suggesting conditions like COPD)
  • Not useful if current spirometry is normal, even if the patient has asthma symptoms
  • Quick test: perform spirometry → give bronchodilator → repeat spirometry
• Bronchial Challenge Testing:
  • Identify airway hyperresponsiveness and bronchoconstriction in response to direct, nonallergic stimuli (e.g., methacholine, histamine) or indirect stimuli (e.g., exercise, hyperventilation).
  • Used when patient has symptoms suggestive of asthma but normal baseline spirometry
  • Tests for airway hyperresponsiveness by attempting to provoke bronchospasm
  • Particularly useful for patients with intermittent symptoms who are asymptomatic during office visits
  • More time-intensive: involves giving increasing doses of the provocative agent and measuring response

Treatment

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Antileukotrienes

Leukotriene receptor antagonists (LTRAs)

• Montelukast, Zafirlukast
• Uses
  • Exercise-induced
  • Prevent leukotrienes from binding to their receptors (CysLT1)→ ↓ bronchoconstriction and inflammation
  • Asthma aspirin-induced asthma
  • Long-term maintenance treatment (particularly in children)

Leukotriene pathway modifiers

• Zileuton
• Inhibit 5-lipoxygenase → ↓ production of leukotrienes → ↓ bronchoconstriction and inflammation
• Uses
  • Exercise-induced asthma
  • Aspirin-induced asthma

Mnemonic

Antileukotrienes → Montelukast, zafirlukast, zileuton

Long-acting muscarinic antagonists (LAMA)

• Tiotropium bromide（噻托溴铵）
• Long-term maintenance treatment

Mast cell stabilizers (chromones)

• Cromolyn
• Inhibit mast cell degranulation and prevent release of preformed chemical mediators.
• Uses
  • Preventive treatment prior to exercise

Biologics

Anti-IgE antibodies

• Omalizumab 单抗记忆
• Binds to serum IgE → ↓ expression of high-affinity IgE receptors (FcεRI) on mast cells and basophils
• Uses
  • Select cases of severe asthma

IL-5 antibodies

• mepolizumab, reslizumab,benralizumab
• Block the effects of IL-5 on eosinophils → ↓ chemotaxis and ↓ cell differentiation, maturation, and activation
• Uses
  • Refractory severe eosinophilic asthma

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