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Asthma: Types, Diagnosis, and Management

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1. Overview and Classification

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2. Atopic (Allergic / Extrinsic) Asthma

Definition & Epidemiology

• The most common and most studied subtype
• Characterized by IgE-mediated sensitization to environmental allergens
• Found in nearly all school-aged children with asthma and ~50% of adult asthmatics

Pathophysiology

Structural/Remodeling Changes

• Epithelial fragility, mucosal edema and hyperemia
• Subepithelial reticular basement membrane thickening (collagen types III and IV)
• In chronic/severe disease: smooth muscle hyperplasia, mucus gland hypertrophy, subepithelial angiogenesis

Triggers

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3. Non-Atopic (Intrinsic) Asthma

Definition

• No demonstrable IgE-mediated sensitization to environmental allergens
• Also called "intrinsic" asthma (historically also "cryptogenic")
• Often adult-onset, can be more severe and persistent
• Both atopic and intrinsic asthma are classified as "Type-2-high" phenotypes — meaning eosinophilic inflammation driven by type-2 cytokines is still present, but without the IgE allergic mechanism

Key Differences from Atopic Asthma

Cluster analyses of large adult asthma cohorts have identified at least three subtypes that are not well described by the atopic/non-atopic binary. — Goldman-Cecil Medicine

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4. Additional Recognized Phenotypes / Endotypes

• Eosinophilic asthma (Type-2-high): responds well to ICS and anti-IL-5/anti-IL-4Rα biologics; can be atopic or non-atopic
• Neutrophilic asthma (Type-2-low): more severe, steroid-resistant; associated with obesity, smoking, occupational exposures
• Mixed eosinophilic/neutrophilic: most severe phenotype
• Exercise-induced bronchoconstriction
• Aspirin-exacerbated respiratory disease (AERD)
• Occupational asthma

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5. Diagnosis

Clinical Features

• Episodic wheeze, dyspnea, chest tightness, cough (especially nocturnal)
• Symptoms vary over time and in intensity
• Triggered by allergens, exercise, viral infections, irritants

Spirometry (Essential)

• FEV1/FVC <0.7 (or below lower limit of normal) = obstruction
• Bronchodilator reversibility: ≥12% AND ≥200 mL increase in FEV1 after SABA → strongly supports asthma
• If spirometry is normal between attacks, further testing is needed

Bronchoprovocation Testing

• PC20 (methacholine or histamine provocative concentration causing 20% fall in FEV1)
  • PC20 ≤0.125 mg/mL = severe hyperresponsiveness (score 3)
  • PC20 8–>0.5 mg/mL = mild hyperresponsiveness
• Exercise challenge or mannitol challenge can also be used

Peak Expiratory Flow (PEF)

• Serial PEF monitoring demonstrates variability >20% (diurnal or day-to-day)
• Useful for both diagnosis and monitoring control

Biomarkers Distinguishing Atopic from Non-Atopic / Endotyping

• 35–40 ppb in untreated patients = Type-2 (eosinophilic) inflammation

• 20–25 ppb despite moderate-to-high ICS = poor adherence or persistent Type-2 inflammation

• Easily suppressed by ICS, useful for adherence monitoring

Severity Classification (GINA-based)

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6. Management: International Protocol (GINA Stepwise Approach)

Goals of Therapy

1. Symptom frequency ≤2 times/week
2. Nighttime awakenings ≤2 times/month
3. Reliever use ≤2 times/week (except before exercise)
4. No more than 1 exacerbation/year
5. Optimized lung function
6. Normal daily activities
7. Minimal treatment side effects

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Non-Pharmacological Measures (All Types)

• Allergen mitigation (atopic): dust-mite impermeable covers as part of comprehensive strategy; pet removal if clearly symptomatic; pest control for cockroach-sensitized patients
• Remove or reduce occupational triggers
• Avoid secondhand smoke and cannabis combustion products
• Vaccination: annual influenza, pneumococcal (all adults regardless of age), COVID-19, RSV vaccines
• Allergen immunotherapy (subcutaneous): suitable only in mild-to-moderate controlled atopic asthma; variable evidence; risk of anaphylaxis
• Sublingual immunotherapy: evidence base not yet substantial for asthma

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Pharmacological Agents

Reliever Medications (Rescue / Bronchodilators)

Frequent SABA use (without ICS) is associated with increased asthma mortality. — Harrison's 22E

Controller Medications

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GINA Stepwise Treatment

STEP 1 — Intermittent Asthma
 • PRN low-dose ICS-formoterol (preferred) OR
 • PRN SABA alone (if truly infrequent, low risk)

STEP 2 — Mild Persistent
 • Low-dose ICS (daily)  +  PRN SABA
 • Alternative: LTRA daily  +  PRN SABA

STEP 3 — Moderate Persistent
 • Low-dose ICS + LABA  +  PRN SABA or ICS-formoterol (MART)
 • Alternative: Medium-dose ICS  +  PRN SABA

STEP 4 — Severe (Step-up)
 • Medium/high-dose ICS + LABA  +  PRN ICS-formoterol (MART)
 • Consider adding LAMA (tiotropium)
 • Add LTRA or theophylline
 • Consider specialist referral

STEP 5 — Severe Uncontrolled
 • High-dose ICS + LABA
 • Add LAMA
 • Biologics based on phenotype:
    – Elevated IgE + atopic     → Omalizumab (anti-IgE)
    – Eosinophilia (≥300/µL)   → Mepolizumab or Reslizumab (anti-IL-5)
    – Type-2 inflammation       → Dupilumab (anti-IL-4Rα)
    – Regardless of phenotype   → Tezepelumab (anti-TSLP)
 • Consider oral corticosteroids (lowest effective dose)

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Specific Considerations by Asthma Type

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Management of Acute Exacerbations

1. Oxygen to maintain SpO2 94–98%
2. Repeated SABA (albuterol) via MDI+spacer or nebulizer q20 min × 3 in first hour
3. Ipratropium added in moderate-severe exacerbations
4. Systemic corticosteroids — oral prednisolone 40–50 mg/day × 5–7 days (IV methylprednisolone if unable to take orally)
5. Magnesium sulfate IV (2 g over 20 min) — severe exacerbations not responding to initial therapy
6. Heliox, IV bronchodilators, or ICU intubation for life-threatening cases

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Assessment of Asthma Control (Goals Achieved)

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• Harrison's Principles of Internal Medicine, 22E — Chapter 298: Asthma
• Goldman-Cecil Medicine, International Edition — Chapter 75: Asthma
• Murray & Nadel's Textbook of Respiratory Medicine — Chapter 35
• Goodman & Gilman's Pharmacological Basis of Therapeutics — Asthma and COPD Therapeutics