Bronchial Asthma - Practice of Medicine

Definition

• Harrison's Principles of Internal Medicine, 22E, Ch. 298
• Goldman-Cecil Medicine, Ch. 75

Epidemiology

• Affects approximately 262 million people globally (Harrison's) / 340 million (Cecil)
• 7.9% of the US population is asthmatic; ~4.3% worldwide prevalence
• More prevalent in children (8.4%) than adults (7.7%); boys > girls in childhood, then women > men after puberty (female:male ratio ~1.8:1 in adults)
• Prevalence increased >50% in the latter half of the 20th century, linked to industrialization and reduced farming/animal contact (the "hygiene hypothesis")
• In the United States, asthma is more prevalent and causes greater morbidity in Black patients and the Puerto Rican population
• Global mortality declined from 0.44/100,000 in 1993 to 0.19/100,000 in 2006 - largely attributed to increased use of inhaled corticosteroids
• Annual economic cost in the US: estimated at $82 billion (2013 data)

Asthma Development Pathway

Pathobiology

Genetics

Endotypes / Pathologic Subtypes

Cellular Mechanisms

1. IgE production by B cells, facilitated by Th2 cytokines (IL-4, IL-13)
2. Mast cell sensitization - on re-exposure, cross-linking of IgE on mast cells triggers degranulation, releasing histamine, prostaglandins, leukotrienes, and tryptase
3. Eosinophil recruitment driven by IL-5
4. Airway remodeling - subepithelial fibrosis, smooth muscle hypertrophy, goblet cell hyperplasia, and vascular changes over time

Structural Changes (Airway Remodeling)

• Subepithelial fibrosis (thickened reticular basement membrane)
• Smooth muscle hypertrophy and hyperplasia
• Goblet cell hyperplasia with mucus hypersecretion
• Vascular proliferation
• These changes contribute to the partially irreversible component of obstruction seen in long-standing disease

Triggers

• Allergens: dust mites, cockroach, cat/dog dander, mold, seasonal pollens
• Respiratory infections: rhinovirus (most common), RSV, influenza, parainfluenza, Chlamydophila pneumoniae, Mycoplasma pneumoniae
• Exercise (especially in cold, dry air)
• NSAIDs/aspirin (in aspirin-exacerbated respiratory disease)
• Occupational exposures: isocyanates, flour, latex, animal dander
• Irritants: tobacco smoke, air pollutants, strong odors, fumes
• Hormonal changes: menses, pregnancy
• GERD and post-nasal drip
• Emotional stress and anxiety
• Beta-blockers (including ophthalmic drops)

Clinical Manifestations

• Episodic wheezing (expiratory > inspiratory)
• Shortness of breath (dyspnea)
• Chest tightness
• Cough (may be the only symptom in "cough-variant asthma")
• Mucus production

• Occur at night or early morning (circadian variation in airway tone)
• Are triggered by the above stimuli
• Resolve spontaneously or with bronchodilator therapy
• Are worse in cold air or with exercise

Differential Diagnosis

Diagnosis and Evaluation

Clinical Approach

• Compatible history of recurrent wheezing, breathlessness, chest tightness, or cough - especially when episodic and triggered
• Pulmonary function testing (spirometry) is the cornerstone of objective confirmation

Key Investigations

• Shows an obstructive pattern: reduced FEV1, reduced FEV1/FVC ratio (<0.70)
• Post-bronchodilator reversibility: ≥12% AND ≥200 mL increase in FEV1 confirms diagnosis
• Normal spirometry does not exclude asthma (can be normal between attacks)

• Inexpensive, portable; serial measurements show diurnal variability >20% suggesting asthma
• Used for home monitoring

• Methacholine, histamine, or exercise challenge
• Used when spirometry is normal but clinical suspicion is high
• A PC20 methacholine <8 mg/mL is considered positive for airway hyperresponsiveness

• Elevated in eosinophilic airway inflammation (>25 ppb in adults)
• Guides choice of ICS dose and predicts steroid response

• Skin prick test or specific IgE (RAST/ImmunoCAP) to identify allergen triggers
• Essential if biologic therapy (omalizumab) is being considered

• Complete blood count with differential (peripheral eosinophilia)
• Serum IgE
• Sputum induction (eosinophil count)
• HRCT chest (to exclude structural lung disease, bronchiectasis)
• Testing for aspirin sensitivity, ABPA (Aspergillus IgE, precipitins)

Classification of Severity (NAEPP/GINA)

Treatment

Goals of Therapy (Goldman-Cecil, Ch. 75)

1. Allow pursuit of normal daily activities without limitation from asthma
2. Allow uninterrupted sleep
3. Minimize need for rescue inhaler use
4. Prevent unscheduled medical visits
5. Maintain near-normal lung function

Stepwise Treatment (GINA/NAEPP Steps 1-5)

• Rescue: Short-acting β₂-agonist (SABA) as needed - salbutamol (albuterol), terbutaline
• Preferred (GINA 2023): Low-dose ICS-formoterol as-needed (AIR therapy)

• Controller: Low-dose ICS (e.g., fluticasone 100 mcg/day, beclomethasone 200 mcg/day)
• Alternative: Leukotriene receptor antagonist (LTRA) - montelukast
• Rescue: SABA or low-dose ICS-formoterol

• Controller: Low-to-medium dose ICS + LABA (e.g., fluticasone/salmeterol, budesonide/formoterol)
• Alternative: Medium-dose ICS alone, or low-dose ICS + LTRA

• Controller: Medium-to-high dose ICS/LABA
• Add-on: Tiotropium (LAMA), LTRA, zileuton
• Consider biologic therapy if poorly controlled

• High-dose ICS/LABA
• Biologics:
  • Omalizumab (anti-IgE) - for allergic asthma, IgE 30-700 IU/mL, positive allergen sensitivity
  • Mepolizumab, Reslizumab, Benralizumab (anti-IL-5/IL-5R) - for severe eosinophilic asthma
  • Dupilumab (anti-IL-4Rα) - for type 2 asthma (eosinophilic + atopic dermatitis)
  • Tezepelumab (anti-TSLP) - for severe uncontrolled asthma regardless of phenotype
• Oral corticosteroids as last resort (minimum effective dose)

Key Medications in Detail

• Mainstay of persistent asthma control
• Reduce airway inflammation, improve lung function, decrease exacerbation frequency
• Reduction in asthma mortality attributed to widespread ICS use
• Side effects: thrush, dysphonia; at high doses - osteoporosis, cataract, growth suppression in children
• Do NOT alter the long-term natural history of asthma

• First-line rescue: salbutamol, terbutaline
• Onset within minutes; bronchodilation via smooth muscle relaxation (cAMP pathway)
• Overuse (>2 canister/month) is a risk factor for asthma death - mandates controller escalation

• Salmeterol, formoterol - never used as monotherapy in asthma; always combined with ICS
• Formoterol: fast onset, can also serve as reliever

• Montelukast (LTRA): oral, once daily; effective add-on or mild asthma alternative to ICS; preferred in exercise-induced asthma and aspirin-exacerbated disease
• Zileuton (5-lipoxygenase inhibitor): oral; increases liver transaminases in 3% of patients

• Targets Fc portion of IgE; prevents mast cell/basophil sensitization
• Reduces exacerbations by 25-50% in eligible allergic asthmatics
• Dosed subcutaneously every 2-4 weeks based on weight and IgE level

• Stabilizes mast cells; mild efficacy; primarily used in pediatrics via nebulization

• Narrow therapeutic window; now rarely used as add-on in step 3-4; requires serum level monitoring

Acute Asthma Attack - Management

Assessment of Severity

• Mild/Moderate: PEFR >50% predicted, O2 sat >92%, speaks in phrases
• Severe: PEFR 33-50%, O2 sat 90-92%, speaks in words, tachycardia >110, RR >25
• Life-threatening: PEFR <33%, silent chest, cyanosis, bradycardia, exhaustion, altered consciousness

Management Steps

1. Oxygen: target SpO2 93-95% (94-98% in children)
2. Inhaled SABA: repeated doses every 20 minutes for the first hour (salbutamol 2.5-5 mg via nebulizer or 4-8 puffs via MDI+spacer)
3. Ipratropium bromide: add to SABA nebulization in moderate-severe attacks (0.5 mg q20 min x 3 doses)
4. Systemic corticosteroids: oral prednisolone 40-60 mg or IV methylprednisolone; begin as early as possible; continue 5-7 days
5. IV magnesium sulfate: 2g IV over 20 minutes - for severe/life-threatening attacks or those not responding to above
6. Heliox (helium-oxygen mixture): can reduce work of breathing; adjunct use
7. IV aminophylline/theophylline: rarely used now; high toxicity
8. ICU / Intubation: for respiratory failure, fatigue, rising PaCO2

Patients at Risk of Death from Asthma

• Previous near-fatal attack (ICU/intubation)
• Two or more hospitalizations or >3 ED visits in past year
• Over-reliance on SABA (>1 canister/month)
• Lack of ICS use
• Psychosocial problems, poor adherence
• Comorbidities: cardiovascular disease, COPD, psychiatric illness
• Low FEV1, poor perception of symptoms

Special Considerations

Aspirin-Exacerbated Respiratory Disease (AERD)

• Samter's triad: asthma + nasal polyposis + aspirin/NSAID sensitivity
• Significant leukotriene overproduction - leukotriene modifiers are particularly effective
• Aspirin desensitization can be performed under supervision

Exercise-Induced Bronchoconstriction (EIB)

• Occurs 5-10 minutes after cessation of vigorous exercise
• Pre-treatment with SABA (10-15 minutes before) or montelukast is effective
• Warm-up and cool-down periods help blunt the response

Occupational Asthma

• Work-related sensitizer (isocyanates, flour, latex) or irritant (high-level exposure)
• Removal from exposure is the primary treatment; steroid therapy alone is insufficient
• Diagnosis: serial PEFR at/away from work, specific bronchoprovocation challenge

Asthma-COPD Overlap (ACO)

• Patients with features of both diseases: usually older smokers with partially reversible obstruction
• Require ICS-containing regimens; LABAs and LAMAs often needed
• High SABA-alone use increases risk

Asthma in Pregnancy

• Can worsen, improve, or remain unchanged during pregnancy
• Uncontrolled asthma carries greater risk to fetus than the risks of treatment
• ICS (budesonide preferred), SABAs, and montelukast are safe; systemic steroids when needed
• Close monitoring of PEFR and fetal wellbeing essential

Elderly Patients

• Diagnosis often delayed due to attribution of dyspnea to aging or cardiac disease
• Fixed airflow obstruction more common
• Inhaler technique issues more prevalent; risk of drug interactions (beta-blockers)

Severe / Refractory Asthma

• Defined as asthma requiring high-dose ICS/LABA to remain controlled, or uncontrolled despite Step 4-5 therapy
• Must first exclude poor adherence, inhaler technique errors, and comorbidities (GERD, rhinosinusitis, obesity, OSA, VCD)
• Phenotyping (FeNO, blood eosinophils, IgE, serology) guides biologic choice
• Bronchial thermoplasty: bronchoscopic procedure reducing airway smooth muscle mass; option for select refractory patients

Prognosis and Monitoring

• Many patients, especially children with mild-intermittent asthma, may enter remission in adulthood
• Patients with severe asthma, fixed obstruction, or smoking have worse long-term outcomes
• Regular monitoring tools: spirometry, FeNO, Asthma Control Test (ACT), Asthma Control Questionnaire (ACQ), symptom diary, PEFR charts
• A written Asthma Action Plan (green/yellow/red zones) given to every patient reduces exacerbations and emergency visits

• Harrison's Principles of Internal Medicine, 22nd Edition (2025), Chapter 298 - Asthma (Elliot Israel)
• Goldman-Cecil Medicine, International Edition, Chapter 75 - Asthma (Jeffrey M. Drazen & Elisabeth H. Bel)
• Murray & Nadel's Textbook of Respiratory Medicine (supplementary)