Asthma

Definition

1. Airway inflammation - driven primarily by eosinophils, mast cells, T-lymphocytes, and their mediators
2. Airway hyperresponsiveness (AHR) - exaggerated bronchoconstriction to stimuli such as methacholine, exercise, cold air
3. Variable airflow obstruction - mostly reversible, either spontaneously or with treatment

Epidemiology

• Affects approximately 300 million people worldwide
• Prevalence is rising, particularly in westernized nations and urban populations
• Affects all ages; often begins in childhood
• About 4% of pregnant women have asthma; one-third experience exacerbations during pregnancy
• Significant morbidity: increased preterm labor, low birth weight, and perinatal death in poorly controlled disease

Pathophysiology

Inflammation

• Eosinophils and lymphocytes (especially Th2 cells)
• Mast cells - releasing histamine, prostaglandins, leukotrienes
• Neutrophils - prominent in severe/fatal asthma

Oxidative Stress

• Leukocyte activation induces NADPH oxidase, generating superoxide (O₂⁻) and H₂O₂, which correlate negatively with FEV₁
• Exhaled NO is elevated in asthma (marker of airway inflammation, mainly from iNOS induction)
• ROS decrease beta-adrenergic function, sensitize smooth muscle to acetylcholine, and stimulate mucin secretion
• Peroxynitrite formation leads to protein nitration and further dysregulation of inflammation

Structural/Pathologic Changes ("Airway Remodeling")

• Epithelial desquamation - sloughing of cohesive clusters forms "Creola bodies" in sputum
• Goblet cell metaplasia - markedly increased, especially in small airways
• Thickened reticular basement membrane (lamina reticularis) - approximately 20% thicker than normal; characteristic of asthma (unlike COPD)
• Subepithelial fibrosis and extracellular matrix deposition
• Smooth muscle hypertrophy/hyperplasia - more pronounced in large airways; some patients show generalized increases, others restricted to larger airways
• Mucus plugging - classically in large airways in fatal asthma; rubbery, tenacious plugs; CT imaging reveals high prevalence of distal airway plugs persisting for months

Classification / Severity

By Control (GINA-based framework)

By Severity (Stepwise)

• Intermittent: symptoms <2 days/week, PEFR ≥80%
• Mild persistent: symptoms >2 days/week but not daily, PEFR ≥80%
• Moderate persistent: daily symptoms, some nighttime awakening, PEFR 60-80%
• Severe persistent: continuous symptoms, frequent nighttime awakening, PEFR <60%

Diagnosis

Clinical Features

• Wheezing (expiratory, high-pitched)
• Dyspnea - especially expiratory difficulty
• Cough - often worse at night or early morning
• Chest tightness
• Symptoms triggered by allergens, exercise, cold air, infections, NSAIDs, beta-blockers, irritants

Pulmonary Function Tests

• Spirometry: obstructive pattern - reduced FEV₁/FVC ratio
• Reversibility: ≥12% and 200 mL improvement in FEV₁ post-bronchodilator is diagnostic
• Bronchoprovocation (methacholine challenge): PC₂₀ ≤8 mg/mL is positive; used when spirometry is normal but asthma is suspected
• Peak expiratory flow rate (PEFR): useful for monitoring; does not change in pregnancy

ATS Impairment Rating (Post-Bronchodilator FEV₁)

Triggers

• Allergens: house dust mites, animal dander, cockroach, mold, pollen
• Infections: viral URTIs (especially rhinovirus)
• Exercise (exercise-induced bronchoconstriction)
• Occupational exposures: isocyanates, grain dust, latex, animal proteins (IgE-mediated), reactive chemicals
• Drugs: NSAIDs/aspirin, beta-blockers (including topical eye drops)
• Environmental: cold air, tobacco smoke, air pollution
• Comorbidities: GERD, rhinosinusitis, obesity, OSA

Phenotypes / Endotypes

• Allergic (atopic) asthma: most common; early onset; associated with atopy (elevated IgE, eosinophilia); Th2-driven; responds well to ICS
• Non-allergic asthma: adult onset; often neutrophilic; less ICS-responsive
• Exercise-induced bronchoconstriction
• Aspirin-exacerbated respiratory disease (AERD)
• Occupational asthma: sensitizer-induced (IgE-mediated, e.g., HMW agents like proteins) or irritant-induced
• Severe/refractory asthma: requires step 4-5 treatment; biologics often needed
• Obesity-associated asthma: non-eosinophilic; difficult to control

Management

Stepwise Approach (GINA / NAEPP)

• Omalizumab (anti-IgE): allergic asthma
• Mepolizumab, benralizumab, reslizumab (anti-IL-5): eosinophilic asthma
• Dupilumab (anti-IL-4Rα): type 2 inflammation
• Tezepelumab (anti-TSLP): broadest indication including non-type 2

Note (2025 GINA update): Current GINA guidelines favor ICS-formoterol as preferred reliever (over SABA alone) to reduce exacerbation risk. This "anti-inflammatory reliever" approach has shifted Step 1-2 management significantly.

Key Drug Classes

Acute Exacerbation Management

1. SABA (salbutamol) nebulization - repeat every 20 min in first hour
2. Systemic corticosteroids - oral prednisolone (40-50 mg/day) or IV methylprednisolone for severe episodes
3. Ipratropium bromide (anticholinergic) - added to SABA in moderate-severe exacerbations
4. Oxygen - target SpO₂ 93-95%
5. IV magnesium sulfate - for severe exacerbations not responding to above
6. Heliox (helium-oxygen mixture) - may reduce work of breathing in severe cases
7. NIV / intubation - for impending respiratory failure

Asthma in Pregnancy

• The best parameter for monitoring is FEV₁ (PEFR and FVC remain unchanged in pregnancy; residual volume decreases)
• Poorly controlled asthma increases risk of preterm labor, LBW, perinatal death, and preeclampsia
• ICS are safe in pregnancy - the risk of uncontrolled asthma far exceeds medication risk
• Moderate-severe asthma is more likely to exacerbate during pregnancy

Comorbidities

• Allergic rhinitis / sinusitis - "one airway" concept; treat together
• GERD - a common trigger; treat with PPI
• Obesity - worsens asthma control; non-eosinophilic phenotype
• OSA - more prevalent in asthma; worsens outcomes; CPAP improves quality of life and reduces exacerbations; apnea-hypopnea index directly correlates with severe exacerbation frequency
• Anxiety and depression - more common in asthma; impair sleep and adherence

Monitoring

• Asthma Control Test (ACT) and similar questionnaires assess symptom burden
• FeNO (fractional exhaled nitric oxide) - elevated in eosinophilic/allergic asthma; guides ICS dosing
• Blood eosinophil count - guides biologic selection
• Spirometry - periodic monitoring of FEV₁ and FEV₁/FVC
• Peak flow diary - home monitoring, identifies triggers

Recent Evidence (2024-2025)

• A 2025 Lancet Respiratory Medicine meta-analysis (ORACLE2, PMID 40215991) identified key inflammatory and clinical risk factors for asthma attacks across 22 RCTs, reinforcing eosinophil count and type-2 inflammation markers as central to exacerbation risk
• Machine learning-based prediction of pediatric asthma exacerbations shows promise (PMID 39537241)
• Aerobic exercise-based pulmonary rehabilitation improves quality of life in pediatric asthma (PMID 39276534)