Bronchial Asthma

Definition

Etiology and Pathogenesis

Classification

• Most common type; classic example of type I IgE-mediated hypersensitivity
• Usually begins in childhood; positive family history of atopy/asthma common
• Often preceded by allergic rhinitis, urticaria, or eczema
• Triggers: allergens in dust, pollen, animal dander, food, infections
• Skin test with offending antigen produces immediate wheal-and-flare

• No evidence of allergen sensitization; skin tests usually negative
• Less common family history
• Triggered by viral respiratory infections (rhinovirus, parainfluenza), inhaled pollutants (sulfur dioxide, ozone), cold air, stress, exercise
• Virus-induced mucosal inflammation lowers the threshold of subepithelial vagal receptors

Triggering Factors (Precipitants)

Immunopathogenesis

• IL-4 and IL-13: stimulate B cells to produce IgE
• IL-5: recruits and activates eosinophils
• IL-13: increases mucus production

• Bronchoconstriction triggered by histamine, prostaglandin D₂, leukotrienes C₄, D₄, E₄
• Increased mucus production, vasodilation, increased vascular permeability

• Inflammatory mediators stimulate epithelial cells to release chemokines (including eotaxin) → recruitment of Th2 cells, eosinophils, neutrophils, basophils
• Eosinophils release major basic protein and eosinophil cationic protein → further epithelial damage and bronchoconstriction

Comparison of a healthy airway and an airway in asthma, along with the immunological cascade — Robbins Basic Pathology

Airway Remodeling

• Hypertrophy and hyperplasia of bronchial smooth muscle
• Subepithelial fibrosis and basement membrane thickening
• Mucus gland hyperplasia and hypersecretion (goblet cell metaplasia)
• Angiogenesis
• Deposition of sub-epithelial collagen (may begin years before symptoms)

Genetic Factors

• Asthma shows familial clustering but genetics are complex
• GWAS studies have identified variants in genes such as the IL-4 receptor and others clearly linked to asthma pathogenesis
• Genetic predisposition to atopy (type I hypersensitivity) is key
• The hygiene hypothesis proposes that lack of microbial exposure in early childhood results in later immunological hyperreactivity — Robbins Basic Pathology

Morphology (Pathological Changes)

• Lungs over-distended with patchy atelectasis
• Airway lumens contain thick mucus plugs (composed of mucus, serum proteins, inflammatory cells, cellular debris)

• Goblet cell metaplasia of airway epithelium; increased mucus
• Charcot-Leyden crystals (from eosinophil-derived galectin-10) in mucus
• Thickened basement membrane (subepithelial fibrosis)
• Marked inflammatory infiltrate: eosinophils, macrophages, lymphocytes, neutrophils
• Hypertrophy and hyperplasia of bronchial smooth muscle
• Hypertrophy of submucosal glands

Clinical Features

Symptoms

• Episodic dyspnea (breathlessness), classically worse at night and early morning
• Wheezing (expiratory > inspiratory)
• Chest tightness
• Cough (may be the only symptom — "cough-variant asthma")
• Symptoms have wide-spread and variable airflow obstruction, characteristically reversible between episodes

Signs During an Attack

• Tachypnea, tachycardia
• Use of accessory muscles of respiration
• Prolonged expiration; expiratory polyphonic wheeze
• Hyperinflated (barrel) chest
• Pulsus paradoxus (>10 mmHg drop in systolic BP during inspiration) in severe attacks
• Cyanosis in severe/life-threatening attacks

Features of Severe/Life-Threatening Attack

• Silent chest (no wheeze despite severe obstruction — ominous sign)
• Inability to speak in sentences
• Altered consciousness
• SpO₂ < 92%; PaCO₂ rising (indicates fatigue and impending respiratory failure)
• Respiratory muscle fatigue with ventilatory failure

Investigations

• Spirometry: reduced FEV₁, reduced FEV₁/FVC ratio (obstructive pattern), with ≥12% (and ≥200 mL) reversibility after bronchodilator
• Peak Expiratory Flow Rate (PEFR): reduced; diurnal variation >20% is diagnostic
• Bronchoprovocation testing (methacholine/PC20): used when spirometry is normal

• Eosinophilia (peripheral blood)
• Elevated total and allergen-specific IgE

• Elevated (>35–40 ppb) indicates type 2 airway inflammation; useful to guide ICS therapy

• CXR: hyperinflation, peribronchial thickening; useful to exclude pneumothorax, infection
• CT chest: bronchiectasis, air trapping in refractory cases

Management

Goals of Therapy (GINA)

1. Symptoms ≤2 times/week
2. Nocturnal awakenings ≤2 times/month
3. Reliever use ≤2 times/week (except pre-exercise)
4. No more than 1 exacerbation/year
5. Optimization of lung function and maintenance of normal daily activities
6. Minimal or no treatment side effects

A. Non-Pharmacological Management

• Allergen/trigger avoidance: remove pets, pest control, dust mite covers, avoid tobacco smoke and cannabis combustion products
• Occupational asthmatics: removal from offending environment may achieve resolution
• Patient education: inhaler technique, PEFR monitoring, action plans
• Treat comorbidities: rhinosinusitis, GERD, obesity, OSA — all worsen asthma control

B. Pharmacological Management — Stepwise (GINA/NAEPP)

• Reliever medications: rapid-onset bronchodilators for acute symptoms
• Controller medications: anti-inflammatory agents for long-term control

GINA Step Therapy (Ages 12+)

Key Drug Classes

• Examples: budesonide, beclomethasone, fluticasone
• Reduce airway inflammation, prevent remodeling
• Side effects at high doses: thrush (reduced by spacer + gargling), hoarseness, bruising, osteoporosis, cataracts, growth suppression in children

• Albuterol (salbutamol) 2.5–5 mg via nebulizer q20 min × 3 doses in acute attack; or 4–8 puffs via MDI q20 min
• Levalbuterol: active R-isomer, half the dose equivalent
• Mechanism: relax airway smooth muscle via β₂-receptor activation → rapid bronchodilation

• Examples: formoterol, salmeterol
• Must always be combined with ICS — never used as monotherapy in asthma
• Formoterol has rapid onset, used as both controller and reliever

• Short-acting: Ipratropium bromide 0.5 mg q20 min × 3 doses — added to SABA in severe acute asthma; not first-line
• Long-acting: LAMA (tiotropium) as add-on at Step 5

• Montelukast (CysLT1 antagonist): oral, once daily; preferred in children (avoids ICS growth concerns); effective in exercise-induced bronchoconstriction and aspirin-exacerbated respiratory disease
• Zileuton (5-lipoxygenase inhibitor): raises LFTs in 3%; inhibits CYP1A2
• Zafirlukast: oral, twice daily
• Safety note: montelukast carries a black-box warning for neuropsychiatric events (suicidal ideation)

• Oral: prednisone 40–60 mg/day with taper over 1–2 weeks for acute exacerbations; lowest possible dose for refractory disease
• IV: methylprednisolone in hospitalized patients; transitioned to oral once stable
• IM: triamcinolone acetonide for poorly adherent patients
• Chronic OCS side effects: diabetes, osteoporosis, cataracts, hypertension, truncal obesity, peptic ulcers, immunosuppression

• Anti-IgE: omalizumab — for allergic asthma with elevated IgE
• Anti-IL-5: mepolizumab, reslizumab, benralizumab — reduce eosinophils; for eosinophilic asthma
• Anti-IL-4Rα: dupilumab — blocks IL-4 and IL-13 signaling
• Anti-TSLP: tezepelumab — blocks upstream innate immune trigger

• Cromolyn sodium: mast cell stabilizer; nebulized, 4×/day; used in children, exercise prophylaxis
• Azithromycin: adjunctive in severe non-eosinophilic asthma; reduces exacerbations

C. Management of Acute Severe Asthma / Status Asthmaticus

1. High-flow oxygen to maintain SpO₂ 94–98%
2. SABA (albuterol): 2.5–5 mg nebulized q20 min × 3, or continuous nebulization 10–15 mg/hr
3. Ipratropium bromide 0.5 mg q20 min × 3 (added to SABA)
4. Systemic corticosteroids: IV methylprednisolone or oral prednisolone 40–60 mg immediately
5. IV magnesium sulfate (2 g over 20 min): bronchodilator effect in severe/refractory cases
6. Consider IV salbutamol or IV aminophylline if failing initial therapy
7. NIV/intubation and mechanical ventilation for impending respiratory failure

D. Step-Down Therapy

Key Comorbidities Worsening Control

• Allergic rhinitis ("united airway disease") — treating upper airway inflammation improves asthma
• GERD — acid reflux triggers bronchoconstriction
• Obesity — associated with a difficult-to-control phenotype
• OSA — worsens asthma outcomes; CPAP improves quality of life and reduces exacerbations
• Anxiety/depression — contribute to nonadherence