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Bronchial Asthma - A Comprehensive Overview

Definition

Unlike COPD, cystic fibrosis, and bronchiectasis, asthma is usually not a progressive disease. However, if untreated, it may cause airway remodeling, resulting in increased severity and death.

• Symptom to Diagnosis: An Evidence-Based Guide, 4th Ed.

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Pathophysiology

1. Bronchoconstriction - contraction of bronchial smooth muscle
2. Airway wall inflammation - edema of the bronchial wall, driven by eosinophils, macrophages, T lymphocytes, and mast cells
3. Mucus hypersecretion - increased mucus production narrowing the lumen

• Airway hyperresponsiveness (exaggerated bronchoconstrictor response to stimuli)
• Airflow limitation (worst during expiration)
• Recurrent respiratory symptoms
• Disease chronicity and potential airway remodeling

Mediators of Inflammation

• Cysteinyl leukotrienes (LTC4, LTD4, LTE4) - cause airway smooth muscle constriction, eosinophil migration, and edema
• LTB4 - attracts neutrophils and eosinophils via chemotaxis
• IgE-mediated mast cell degranulation releases histamine, prostaglandins, and leukotrienes on allergen exposure
• Lippincott Illustrated Reviews: Pharmacology

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Triggers

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Clinical Features

• Recurrent episodes of dyspnea, chest tightness, cough, and wheezing
• Symptoms typically reversible (spontaneously or with treatment)
• Stereotypical triggers help in diagnosis
• Rapid response to beta-agonist inhalers
• Airway function fluctuates widely - PEF varies > 20% over the course of the day, lowest in the morning
• Absence of wheezing does not exclude asthma

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Classification by Severity

• Symptom to Diagnosis: An Evidence-Based Guide, 4th Ed.

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Diagnosis

Spirometry (Most Useful Test)

• Demonstrates obstructive pattern: reduced FEV1/FVC ratio
• Reversibility: ≥ 12% improvement AND ≥ 200 mL increase in FEV1 after bronchodilator = positive
• Severity also assessed by post-bronchodilator FEV1 (% predicted)

Other Tests

• Fishman's Pulmonary Diseases and Disorders; Murray & Nadel's Textbook of Respiratory Medicine

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Treatment

Goals of Therapy (GINA Guidelines)

• Decrease intensity and frequency of symptoms
• Prevent future exacerbations
• Minimize limitations in physical activity
• Minimize adverse effects

Step-by-Step Treatment (GINA - Patients ≥ 12 years)

• Lippincott Illustrated Reviews: Pharmacology

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Drug Classes

1. Inhaled Corticosteroids (ICS) - Foundation of Therapy

• Examples: budesonide, fluticasone, beclomethasone
• Mechanism: Inhibit phospholipase A2 → reduce arachidonic acid release → anti-inflammatory
• Decrease eosinophils, macrophages, T lymphocytes; reverse mucosal edema; reduce capillary permeability; inhibit leukotriene release
• After months of regular use: reduce airway hyperresponsiveness
• Adverse effects: oropharyngeal candidiasis, hoarseness (use spacer + rinse mouth)
• Systemic ICS (oral/IV methylprednisolone, prednisone): for severe exacerbations; no taper needed for short burst

2. Short-Acting β2 Agonists (SABAs)

• Examples: albuterol (salbutamol), levalbuterol
• Onset: 5-15 minutes; duration: 3-6 hours
• Direct relaxation of airway smooth muscle
• No anti-inflammatory effect; should not be used as monotherapy in persistent asthma
• Used as needed for quick relief; can prevent exercise-induced bronchospasm
• Adverse effects: tachycardia, hyperglycemia, hypokalemia, hypomagnesemia, skeletal muscle tremors

3. Long-Acting β2 Agonists (LABAs)

• Examples: salmeterol, formoterol
• Duration: ≥ 12 hours
• Formoterol also has rapid onset (used for both control and quick relief)
• LABA monotherapy is contraindicated in asthma - must combine with ICS
• ICS/formoterol combination (e.g., budesonide/formoterol) = preferred controller AND reliever

4. Anticholinergics

• Ipratropium (short-acting): Not for routine acute bronchospasm (slower onset than SABAs); useful add-on in ED; useful if SABA not tolerated or asthma-COPD overlap
• Tiotropium (long-acting): Add-on for severe asthma with history of exacerbations

5. Leukotriene Receptor Antagonists (LTRAs)

• Examples: montelukast, zafirlukast
• Block CysLT1 receptors → prevent smooth muscle constriction, edema, eosinophil migration
• Alternative controller option; useful in aspirin-exacerbated asthma and allergic rhinitis comorbidity

6. 5-Lipoxygenase Inhibitor

• Zileuton: Inhibits 5-lipoxygenase → blocks leukotriene synthesis

7. Theophylline

• Methylxanthine bronchodilator; now rarely used
• Narrow therapeutic window, serious adverse effects (seizures, fatal arrhythmias at toxicity), numerous drug interactions (CYP1A2/OAA substrate)
• Requires serum concentration monitoring

8. Monoclonal Antibodies (Biologics) - For Severe Persistent Asthma

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Management of Exacerbations

• Mild exacerbation: FEV1 or PEF ≥ 70% predicted
• Moderate exacerbation: FEV1 or PEF 40-69%
• Severe/life-threatening: FEV1 or PEF < 40%; accessory muscle use, paradoxical breathing, altered consciousness

1. Inhaled SABA (albuterol) - first-line, repeated doses
2. Ipratropium added to SABA - additional benefit in ED
3. Systemic corticosteroids (IV methylprednisolone or oral prednisone) - reduce inflammation
4. Supplemental oxygen to maintain SpO2 ≥ 95%
5. IV magnesium sulfate - for severe exacerbations not responding to initial therapy
6. Heliox, IV aminophylline - rarely used
7. Intubation/mechanical ventilation - last resort

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ATS Impairment Classification (for Disability Rating)

• Murray & Nadel's Textbook of Respiratory Medicine

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Recent Evidence (PubMed, 2025)

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Key Clinical Pearls

• Asthma should be in the differential diagnosis of any patient with intermittent respiratory symptoms
• The absence of wheezing does not exclude asthma
• PEF values are lowest in the morning and vary > 20% daily in asthmatics
• LABA monotherapy is contraindicated in asthma - always combine with ICS
• After ICS use: rinse mouth to prevent oropharyngeal candidiasis
• Corticosteroid short "burst" for exacerbations does not require a taper
• Downregulation of β2 receptors occurs with long-term SABA/LABA use (tolerance via GRK-mediated phosphorylation and β-arrestin internalization)

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Bronchial Asthma

1. Definition

Unlike COPD, cystic fibrosis, and bronchiectasis, asthma is usually not progressive. However, if untreated, it may cause irreversible airway remodeling, increasing severity, exacerbations, and death.

• Textbook of Family Medicine, 9e; Lippincott Illustrated Reviews: Pharmacology

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2. Epidemiology & Risk Factors

• Most common chronic disease of childhood; affects >300 million people worldwide
• Causes >15 million disability-adjusted life-years (DALYs) annually
• Prevalence is increasing globally
• Strongest risk factors: household smoker exposure, family history of asthma or atopy (atopic dermatitis, allergic rhinitis)
• High-disparity condition - hospitalization rates 3.3x higher in Black vs. White patients in the US
• The hygiene hypothesis: reduced microbial exposure in early childhood increases risk of allergic/autoimmune disease
• Textbook of Family Medicine, 9e

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3. Types of Asthma

• Robbins & Cotran Pathologic Basis of Disease; Textbook of Family Medicine, 9e

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4. Pathogenesis

Immune Mechanism (Atopic Asthma)

• Antigen (allergen) is processed by dendritic cells and presented to T cells
• T cells differentiate into Th2 cells, secreting:
  • IL-4 → stimulates B cells to produce IgE
  • IL-5 → activates and recruits eosinophils
  • IL-13 → stimulates mucus secretion from submucosal glands; promotes IgE production
• IgE binds to Fc receptors on mast cells and basophils

• Re-exposure to allergen → cross-linking of IgE on mast cells
• Mast cells release preformed mediators (histamine, tryptase) and synthesize new mediators
• Results: bronchoconstriction (via vagal reflexes), increased vascular permeability, mucus production
• Leukotrienes C4, D4, E4 → prolonged smooth muscle constriction, edema, ↑ mucus
• Acetylcholine (parasympathetic) → smooth muscle constriction via muscarinic receptors
• Galectin-10 (GAL10) from eosinophils → forms Charcot-Leyden crystals → induces inflammation + mucus

• Recruitment of leukocytes: eosinophils, neutrophils, basophils, T cells, monocytes
• Eosinophils release major basic protein (MBP) and eosinophil cationic protein (ECP) → epithelial damage
• Th2 cells sustain the cycle via continued IL-5 production
• Group 2 innate lymphoid cells (ILC2s) - activated by damaged epithelial cell cytokines; amplify Th2-type responses without antigen receptors

Airway Changes in Asthma (Airway Remodeling)

• Thickening of the airway wall
• Sub-basement membrane fibrosis (type I and III collagen deposition)
• Goblet cell proliferation → mucus accumulation
• Hypertrophy of submucosal glands
• Smooth muscle hypertrophy and hyperplasia
• Increased vascularity (angiogenesis)

Genetics

• Susceptibility locus on chromosome 5q near IL-3, IL-4, IL-5, IL-9, IL-13 gene cluster
• IL-13 gene polymorphisms - strongest association with asthma/allergic disease
• IL-4 receptor gene variants - associated with atopy, elevated total IgE, and asthma
• HLA class II alleles linked to IgE production against specific allergens
• IL-33 / ST2 variants - induce Th2 cytokine production
• TSLP (thymic stromal lymphopoietin) gene variants - epithelial cytokine initiating allergic reactions
• Robbins & Cotran Pathologic Basis of Disease

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5. Airflow Obstruction Mechanism

1. Bronchoconstriction - bronchial smooth muscle contraction
2. Mucosal edema and inflammation - eosinophils, macrophages, lymphocytes, neutrophils
3. Mucus hypersecretion - goblet cell proliferation + submucosal gland hypertrophy

• Lippincott Illustrated Reviews: Pharmacology

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6. Pathological Findings (Morphology)

Gross

• Lungs overinflated, small areas of atelectasis
• Thick, tenacious mucus plugs occluding bronchi and bronchioles

Microscopic (Sputum/BAL)

• Curschmann spirals - extrusion of mucus plugs from subepithelial gland ducts/bronchioles
• Charcot-Leyden crystals - composed of eosinophil-derived galectin-10
• Eosinophilia (peripheral blood and sputum)
• Thickened basement membrane
• Smooth muscle hypertrophy/hyperplasia
• Sub-basement membrane fibrosis
• Robbins & Cotran Pathologic Basis of Disease

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7. Triggers

• At night - decreased mucociliary clearance, airway cooling, low endogenous catecholamines
• With exercise - airway cooling and drying

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8. Clinical Features

• Recurrent episodic dyspnea, chest tightness, cough, wheezing
• Symptoms often worse at night or early morning
• Rapid response to beta-agonist inhalers
• Stereotypical triggers identify individual pattern

Physical Examination Findings

The absence of wheezing does NOT exclude asthma.

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9. Classification by Severity

• Textbook of Family Medicine, 9e; Symptom to Diagnosis, 4th Ed.

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10. Diagnosis

Spirometry (Most Useful Test)

• Obstructive pattern: reduced FEV1/FVC ratio (< 70%)
• Reversibility: ≥ 12% AND ≥ 200 mL increase in FEV1 post-bronchodilator = confirms diagnosis
• PEF varies > 20% over the course of the day in asthmatics; lowest in morning

Other Investigations

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11. Treatment

Goals of Therapy (GINA Guidelines)

1. Decrease intensity and frequency of asthma symptoms
2. Prevent future exacerbations
3. Maintain normal lung function (PEF/spirometry)
4. Maintain normal levels of physical activity
5. Minimize adverse effects of medications

GINA Step-Based Treatment (≥12 years)

• Lippincott Illustrated Reviews: Pharmacology (GINA guidelines)

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12. Pharmacotherapy

Leukotriene Pathway (Drug Targets)

A. Inhaled Corticosteroids (ICS) - Foundation of Therapy

• Examples: budesonide, fluticasone, beclomethasone, mometasone
• Mechanism: Inhibit phospholipase A2 → ↓ arachidonic acid → anti-inflammatory; decrease eosinophils, macrophages, T lymphocytes; reverse mucosal edema; inhibit leukotriene release
• After months of regular use: reduce airway hyperresponsiveness
• Adverse effects: Oropharyngeal candidiasis, hoarseness (local immune suppression)
  • Prevention: use spacer + rinse mouth ("swish-and-spit") after each dose
• Systemic (IV methylprednisolone / oral prednisone): for severe exacerbations; short burst does not require a taper

B. Short-Acting β₂ Agonists (SABAs)

• Examples: albuterol (salbutamol), levalbuterol
• Onset: 5-15 minutes; duration: 3-6 hours
• Direct relaxation of airway smooth muscle via ↑ cAMP
• No anti-inflammatory effect - must NOT be used as monotherapy in persistent asthma
• Use: as-needed quick relief; prevention of exercise-induced bronchospasm
• Adverse effects: tachycardia, hyperglycemia, hypokalemia, hypomagnesemia, skeletal muscle tremors

C. Long-Acting β₂ Agonists (LABAs)

• Examples: salmeterol (slow onset), formoterol (rapid onset + long duration)
• Duration: ≥ 12 hours
• LABA monotherapy is CONTRAINDICATED in asthma - always combine with ICS
• ICS/formoterol (e.g., budesonide/formoterol) = preferred controller AND reliever
• Downregulation of β₂ receptors occurs with chronic use (GRK phosphorylation → β-arrestin internalization)

D. Anticholinergics

• Ipratropium (SAMA): Block vagally mediated smooth muscle contraction; slower onset than SABAs; add-on in acute severe exacerbations in ED; useful in COPD-asthma overlap
• Tiotropium (LAMA): Add-on for severe asthma with frequent exacerbations
• Adverse effects: xerostomia (dry mouth), bitter taste

E. Leukotriene Modifiers

• LTRAs - Montelukast, Zafirlukast: Block CysLT₁ receptors → prevent smooth muscle constriction, edema, eosinophil migration
• Zileuton: 5-Lipoxygenase inhibitor → blocks leukotriene synthesis
• Particularly useful in aspirin-sensitive asthma and when allergic rhinitis is a comorbidity

F. Theophylline

• Methylxanthine bronchodilator; rarely used now
• Replaced by β₂ agonists and ICS due to narrow therapeutic window
• Toxicity: seizures, potentially fatal arrhythmias
• CYP1A2/OAA substrate - numerous drug interactions
• Requires serum concentration monitoring when used chronically

G. Monoclonal Antibodies (Biologics) - Severe Persistent Asthma

• Indicated for add-on therapy in severe persistent asthma poorly controlled on conventional therapy
• Adverse effects: anaphylaxis (rare), arthralgias, fever, rash, ↑ infection risk, new malignancies reported

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13. Management of Acute Exacerbations

Severity Assessment

Acute Management (ED/Hospital)

1. Inhaled SABA (albuterol via nebulizer) - repeated doses, first-line
2. Ipratropium added to SABA - additional bronchodilation in ED
3. Systemic corticosteroids (IV methylprednisolone or oral prednisone) - anti-inflammatory, reduce recovery time
4. Supplemental oxygen - target SpO₂ ≥ 95%
5. IV magnesium sulfate - for severe exacerbations not responding to initial therapy
6. Heliox (helium-oxygen mixture) - reduces work of breathing in severe obstruction
7. NIV (BiPAP) / Mechanical ventilation - last resort for respiratory failure

Danger Signs (Impending Respiratory Failure)

• Rising PaCO₂ (normalization of CO₂ in severe asthma = impending failure - these patients are normally hypocapnic)
• Decreasing SpO₂ despite O₂ therapy
• Exhaustion, altered mental status
• Silent chest

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14. Special Considerations

Asthma in Pregnancy

• Affects ~4% of pregnant women
• One-third will have exacerbations during pregnancy
• Moderate-to-severe asthma increases risk of preterm labor, low birth weight, perinatal death, preeclampsia
• FEV1 and PEF remain unchanged in normal pregnancy; residual volume decreases
• Management: Same as non-pregnant patients; risks of uncontrolled asthma outweigh medication risks

Aspirin-Sensitive Asthma (Samter's Triad)

• Asthma + nasal polyps + aspirin/NSAID hypersensitivity
• Mechanism: COX inhibition → ↓ PGE₂ → ↑ leukotrienes (LTB4, C4, D4, E4)
• Treatment: leukotriene modifiers particularly effective; desensitization possible

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15. Key Clinical Pearls

• Asthma should be considered in any patient with intermittent respiratory symptoms
• The absence of wheezing does NOT exclude asthma
• PEF values are lowest in the morning and vary >20% daily in uncontrolled asthma
• LABA monotherapy is contraindicated in asthma - always pair with ICS
• Rinse mouth after ICS to prevent oropharyngeal candidiasis
• Short corticosteroid bursts for exacerbations do NOT require a taper
• Up to 50% of childhood asthma remits in adolescence, but may return in adulthood
• A rising PaCO₂ in an acute attack = ominous sign - patient is fatiguing

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