Asthma: Anatomy, Physiology, Pathophysiology, and Clinical Presentation

Respiratory Disorders: Asthma

Learning Objectives

This section outlines the foundational concepts necessary to understand asthma from an anatomy and physiology perspective, including its pathophysiology, clinical presentation, and management.

• Th1 and Th2 Pathways: Describe the role of environmental exposure in the development of Th1 and Th2 immune pathways as they relate to asthma.

• Clinical Signs and Symptoms: Differentiate between clinical signs and symptoms of asthma and other respiratory diseases.

• Diagnosis: Provide a diagnosis using laboratory data, diagnostic tests, physical exam findings, and clinical presentation.

• Key Mediators: Identify key mediators of asthma and their role in pathophysiology.

• Abnormal Findings: Explain abnormal laboratory, diagnostic tests, and physical exam findings using knowledge of physiology and pathophysiology.

• Airway Obstruction: Describe the processes leading to airway obstruction in asthma.

• Acute Severe Asthma: Identify a patient experiencing an acute, severe asthma presentation based on signs and symptoms.

• Differentiation: Differentiate key pathophysiology mechanisms, signs, and symptoms between asthma and COPD.

Asthma Defined

Characteristics of Asthma

Asthma is a heterogeneous disease characterized by chronic inflammation and variable airflow obstruction.

• Acute/Chronic Airway Inflammation: Persistent inflammation of the bronchial mucosa.

• Bronchial Hyper-responsiveness: Airways are overly reactive to various stimuli.

• Intermittent Bronchospasm: Sudden constriction of bronchial smooth muscle.

• Mucus Hypersecretion: Excessive production of mucus by goblet cells.

• Airway Obstruction: Blockage of airflow due to inflammation, bronchospasm, and mucus.

• Airway Remodeling: Long-term structural changes in the airway wall.

Asthma Phenotypes

Types of Asthma

Asthma presents in several phenotypes, each with distinct pathophysiological mechanisms and clinical features.

• Allergic (High Type 2):

  • Eosinophilic airway inflammation.

  • Associated with atopy (eczema, rhinitis, food/drug allergy).

  • Common in childhood; may remit with age.

• Non-allergic (Low Type 2, Neutrophilic):

  • Variable inflammatory mediators.

  • Poor response to inhaled corticosteroids.

• Late-onset:

  • More common in adults (female > male).

  • Non-allergic, poor response to ICS, unlikely to remit.

• Exercise-induced:

  • Triggered by physical activity.

• Asthma with Obesity:

  • Limited eosinophil involvement.

Asthma Risk Factors

Host and Environmental Factors

Asthma risk is influenced by genetic predisposition and environmental exposures.

• Host Factors:

  • Genetic: Family history of asthma or allergies.

  • Atopy: Predisposition to allergic rhinitis, eczema (atopic dermatitis), and allergies.

• Environmental Factors:

  • Exposure to allergens, pollution, tobacco smoke, occupational irritants.

Protective and Risk Factors Table

Protective Factors	Risk Factors
Being younger sibling, natural birth, farm living, exposure to animals, higher socioeconomic status, certain microbiological exposures	Asthma history in family, formula feeding, urban living, lower socioeconomic status, use of antibiotics, certain microbiological exposures

Th1 vs Th2 Phenotype Influences

Factors Favoring Th1	Factors Favoring Th2
Older siblings, early daycare, rural environment, certain infections	Antibiotic use, western lifestyle, urban environment, diet, allergen sensitization

Th1: Promotes protective immunity. Th2: Associated with allergic diseases including asthma.

Pathophysiology of Asthma

Airway Narrowing and Obstruction

Asthma involves complex pathophysiological processes leading to airway narrowing and obstruction.

• Bronchospasm (Bronchoconstriction): Sudden contraction of bronchial smooth muscle.

• Airway Hyper-responsiveness: Increased sensitivity to stimuli.

• Bronchial Inflammation/Edema: Swelling and infiltration of inflammatory cells.

• Mucus Secretion: Goblet cell hyperplasia increases mucus production.

• Key Mediators:

  • IgE: Immunoglobulin E involved in allergic responses.

  • Mast Cells: Release histamine and leukotrienes, causing bronchoconstriction and hyper-responsiveness.

  • Eosinophils: Contribute to inflammation and tissue damage.

  • T Helper Cells (Th2 > Th1): Th2 cells drive allergic inflammation.

Normal vs Asthmatic Airway Table

Normal Airway	Asthmatic Airway
Open lumen, thin smooth muscle, minimal mucus	Narrowed lumen, thickened smooth muscle, increased mucus, goblet cell hyperplasia, collagen deposition

Type 2 vs Non-Type 2 Inflammation

High Type 2 Inflammation	Low/Non-Type 2 Inflammation
IL-4, IL-5, IL-13, eosinophils, mast cells, IgE	Neutrophils, Th1 cells, IL-17, TGF-β, poor ICS response

Inflammatory Cascade in Asthma

1. Allergen exposure

2. Mast cell release of histamine and leukotrienes

3. Th2 cell activation and cytokine release (IL-4, IL-5, GM-CSF)

4. Eosinophil production and migration

5. Adhesion to vascular endothelium

6. Migration into bronchial mucosa

7. Proinflammatory cytokine activation

8. Further leukotriene release

Airway Remodeling

Structural Changes in Asthma

Chronic asthma leads to irreversible structural changes in the airway, known as airway remodeling.

• Goblet Cell Enlargement and Proliferation: Increases mucus production.

• Thickened Basement Membrane: Due to collagen deposition.

• Increased Smooth Muscle Cells: Contributes to airway narrowing.

• Angiogenesis: Formation of new blood vessels.

• Non-reversible Component: Remodeling is not fully reversible with treatment.

Clinical Presentation of Asthma

General Features

• Chronic Inflammation: Periods of exacerbation and remission.

• Variable Severity: Signs and symptoms vary between attacks and individuals.

• Trigger Variability: Similar triggers can produce different severity in different people.

Respiratory Symptoms

• Dyspnea: Shortness of breath.

• Expiratory Wheeze: Most common symptom.

• Chest Tightness

• Cough

Symptom Characteristics

• Intensity varies over time.

• Multiple symptoms often present.

• Symptoms commonly worse at night or early morning.

• Triggers include emotions, exercise, allergens, cold air, and respiratory infections.

Signs and Diagnostic Tests

• Physical Exam: Expiratory wheezing (not always present).

• Pulmonary Function Tests:

  • Forced Expiratory Volume (FEV1): Measures volume of air exhaled in one second.

  • FEV1/FVC Ratio: Used to indicate airflow limitation. Normal values:

    • Adults: > 0.75–0.80

    • Children: > 0.90

Variability and Reversibility

• Variability: Lung function changes hour-to-hour, day-to-day, or seasonally.

• Reversibility:

  • Improved lung function after bronchodilator (albuterol): $\text{FEV}_1 > 12\% \text{ and } 200\text{ml over baseline}$

  • Improved after exercise: $\text{FEV}_1 > 10\% \text{ and } 200\text{ml}$

  • Provocation test (methacholine/histamine/hypertonic saline): $\text{FEV}_1 > 15-20\%$

Acute Severe Asthma

Clinical Features

• Rapid Progression: Sudden worsening of symptoms.

• Symptoms:

  • Severe dyspnea

  • Distress, unable to complete full sentences

• Signs:

  • Tachycardia (increased heart rate)

  • Tachypnea (increased respiratory rate)

  • Hyperinflated chest (air trapping)

  • Use of accessory breathing muscles

  • FEV1 < 40% predicted

  • Low oxygen saturation (O2), cyanosis (lips, nailbeds)

Asthma Medications

Pharmacological Management

• β2 Agonists:

  • Bronchodilation

  • Short-acting (albuterol, levalbuterol)

  • Long-acting (salmeterol, formoterol)

• Anticholinergics:

  • Reverse cholinergic-induced bronchoconstriction

  • Short-acting (ipratropium)

  • Long-acting (tiotropium)

• Inhaled/Systemic Corticosteroids:

  • Reduce inflammation

• Leukotriene Receptor Antagonists:

  • Montelukast

• Cromolyn Sodium:

  • Mast cell stabilizer

• Biologics:

  • Omalizumab (IgE antibody)

  • Reslizumab, mepolizumab, benralizumab (IL5 antibody)

  • Dupilumab (IL4 antibody)

  • Tezepelumab (TSLP antibody, downregulates multiple inflammatory mediators)

Summary Table: Asthma Medications

Class	Examples	Mechanism
β2 Agonists	Albuterol, Salmeterol	Bronchodilation
Anticholinergics	Ipratropium, Tiotropium	Reverse bronchoconstriction
Corticosteroids	Fluticasone, Prednisone	Reduce inflammation
Leukotriene Antagonists	Montelukast	Block leukotriene-mediated inflammation
Cromolyn Sodium	Cromolyn	Mast cell stabilization
Biologics	Omalizumab, Mepolizumab	Target specific immune mediators

Key Equations

• FEV1/FVC Ratio: $\text{FEV}_1/\text{FVC}$

• Reversibility Criteria: $\text{FEV}_1 > 12\% \text{ and } 200\text{ml \ increase}$

Additional info:

• Asthma is a chronic inflammatory disorder of the airways involving many cells and cellular elements. It is characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and underlying inflammation.

• Long-term airway remodeling can lead to fixed airflow limitation, which is less responsive to standard asthma therapies.