What are the causes, hallmark symptoms, diagnostic tests, and typical pulmonary function test (PFT) presentation for asthma, and how is it managed?

Asthma: Pathology, Causes, Diagnostic Tests, and PFT Presentation

Pathophysiology

Asthma is fundamentally a chronic inflammatory disorder of the airways characterized by three interconnected pathophysiologic processes: inflammation, bronchial hyperresponsiveness, and airway remodeling that together produce the variable and reversible airflow obstruction defining the disease. 1, 2

The inflammatory cascade involves multiple cellular players working in concert 2:

• Mast cells, eosinophils, T lymphocytes, macrophages, and epithelial cells drive the inflammatory response, with neutrophils playing a particularly important role in sudden-onset fatal exacerbations, occupational asthma, and in patients who smoke 2, 3

• Activated CD4 T-lymphocytes recruit leukocytes from the bloodstream to the airway and direct the release of inflammatory mediators from eosinophils, mast cells, and lymphocytes 3

• Th2 helper T-lymphocytes produce IL-4, IL-5, and IL-13, where IL-4 and IL-13 signal the switch from IgM to IgE antibodies, and IL-5 activates eosinophil recruitment 3

Three Mechanisms of Airflow Limitation

The pathophysiology produces airflow obstruction through three distinct mechanisms 2:

1. Bronchoconstriction: Bronchial smooth muscle contracts rapidly in response to allergens, irritants, and other stimuli, representing the most immediately reversible component 2

2. Airway edema and mucus plugging: Persistent inflammation causes edema, mucus hypersecretion, and formation of inspissated mucus plugs that further limit airflow, being less immediately reversible than bronchoconstriction alone 2

3. Airway remodeling: Persistent inflammation leads to permanent structural changes including sub-basement membrane fibrosis, smooth muscle hypertrophy, epithelial cell injury and shedding, angiogenesis, and mucus gland hyperplasia, explaining why airflow limitation may become incompletely reversible despite aggressive treatment 2, 3

Causes and Risk Factors

The development of asthma requires both genetic susceptibility and environmental triggers, with 80% of children with two asthmatic parents developing asthma. 1, 2

Genetic Factors

• Strong genetic component with gene-environment interactions being critical during immune system development 1, 2

Environmental Exposures

• In utero exposures such as maternal smoking increase childhood asthma risk in a dose-dependent pattern 1, 2
• Allergens including pollens, dust, feathered or furry animals trigger symptoms in allergic asthma 4
• Irritants such as environmental tobacco smoke, chemicals, and cold air provoke airway obstruction 4, 3
• Viral upper respiratory infections commonly trigger exacerbations 3, 5

Medication Triggers

• Aspirin and NSAIDs can worsen symptoms in susceptible patients 4
• Beta-blockers should be avoided as they can precipitate bronchospasm 4

Occupational Exposures

• Workplace exposures can cause new-onset occupational asthma through IgE-mediated mechanisms (after latency period with high-molecular-weight agents) or irritant-induced mechanisms (with or without latency) 1

Hallmark Clinical Features

The hallmark symptoms are episodic dyspnea, wheezing, chest tightness, and cough, associated with variable airflow limitation and airway hyperresponsiveness. 4, 5

Key Clinical Characteristics

• Paroxysmal or persistent symptoms that vary over time 4
• Symptom triggers including exercise, allergens, viral infections, and cold air 4
• Personal or family history of atopic conditions (eczema, allergic rhinitis) 4, 1
• Physical examination may show hyperinflation with or without wheeze in chronic asthma 4, 2

Clinical Phenotypes

• Allergic asthma: Associated with atopic conditions and worsens with allergen exposure 1
• Cough variant asthma: Nonproductive cough as predominant or sole symptom without wheeze, responding to standard asthma treatment 1, 6
• Occupational asthma: New-onset asthma from workplace exposures 1

Diagnostic Tests

Asthma diagnosis requires a compatible clinical history AND objectively confirmed variable expiratory airflow limitation on lung function testing—objective testing is mandatory before starting long-term therapy. 4, 1

Gold Standard: Spirometry with Bronchodilator Testing

The 2024 GINA guidelines recommend five methods to objectively confirm excessive variability in lung function 4:

1. Positive bronchodilator responsiveness test: FEV1 increase ≥15% AND ≥200 mL, or PEF increase ≥20% AND ≥60 L/min after inhaled short-acting β2-agonist (salbutamol 400 μg by MDI + spacer or 2.5 mg by nebulizer) 4

2. Excessive PEF variability: ≥20% amplitude variability (highest-lowest/highest × 100) with minimum change ≥60 L/min over twice-daily measurements for 2 weeks 4

3. Improvement after ICS trial: Increase in lung function following 4 weeks of inhaled corticosteroid treatment 4

4. Positive bronchial challenge test: Decreased FEV1 with methacholine or histamine challenge demonstrates airway hyperresponsiveness, though failure to demonstrate hyperresponsiveness in an untreated person should prompt reconsideration of the diagnosis 4, 7

5. Excessive variation between visits: Variable lung function measurements over time 4

Exercise Challenge Testing

• Six-minute exercise test (e.g., running) with PEF or FEV1 measurements at rest, immediately post-exercise, and every 10 minutes for 30 minutes, looking for ≥20% decrease in PEF (≥60 L/min) or ≥15% decrease in FEV1 (≥200 mL) 4

Special Diagnostic Considerations

For patients already on ICS-containing medications who may not meet standard criteria, the GINA report recommends repeating objective lung function measures and trialing a step-down of ICS treatment 4

Additional Testing

• Chest x-ray should be performed in all patients to exclude alternative diagnoses 4
• Allergy testing may be useful in allergic asthma phenotypes 1

Pulmonary Function Test Presentation

The characteristic PFT pattern in asthma is obstructive spirometry with reversible airflow limitation and evidence of bronchial hyperresponsiveness. 4

Spirometry Findings

Obstructive pattern 4, 8:

• Decreased FEV1 (forced expiratory volume in 1 second)
• Decreased PEF (peak expiratory flow)
• Reduced FEV1/FVC ratio indicating airflow obstruction
• May be normal if measured between episodes of bronchospasm—repeatedly normal spirometry in the presence of symptoms should prompt reconsideration of the diagnosis 4

Reversibility Testing

Positive bronchodilator response demonstrates the hallmark reversibility 4:

• FEV1 increase ≥15% AND ≥200 mL from baseline
• PEF increase ≥20% AND ≥60 L/min from baseline
• Measured 10-15 minutes after short-acting β2-agonist administration

Variability Patterns

PEF variability calculation (amplitude % best method) 4:

• Formula: (highest PEF - lowest PEF) / highest PEF × 100
• ≥20% variability with minimum change ≥60 L/min over 2 weeks is highly suggestive of asthma
• Example: If highest PEF = 400 L/min and lowest = 300 L/min, then variability = (400-300)/400 × 100 = 25%

Bronchial Challenge Testing

Methacholine or histamine challenge demonstrates airway hyperresponsiveness 4, 7:

• Shows exaggerated bronchoconstrictor response to stimuli
• Positive test supports diagnosis but can occur in COPD
• Negative test in untreated patient should prompt diagnostic reconsideration

Air Trapping

Hyperinflation may be evident on examination or testing 2:

• Results from small airway obstruction, inflammation, and mucus plugging
• Incomplete expiration leads to breath stacking and auto-PEEP, particularly during acute exacerbations

Important Caveats

Many patients with asthma demonstrate variability below 20%, making marked variability a reasonably specific but insensitive diagnostic test—smaller changes do not necessarily exclude the diagnosis 4

Lung function tests may show changes suggesting alternative diagnoses such as COPD (reduced diffusing capacity, pressure-dependent airway collapse on flow-volume curves), but these changes are not diagnostic and do not exclude asthma, which may coexist with other conditions 4

Failure to respond to asthma treatment should prompt a search for an alternative or additional diagnosis 4