AN OVERVIEW OF ASTHMA TREATMENT GUIDELINES FOR BETTER BREATHING

Pathophysiologic Changes Targeted in Bronchial Asthma Treatment

Bronchial asthma is a chronic inflammatory disease of the airways characterized by variable airflow obstruction, airway hyperresponsiveness, and airway remodeling. The treatment of asthma targets several key pathophysiologic changes:

1. Airway Inflammation:
   • Chronic inflammation is central to asthma pathogenesis and involves immune cells such as eosinophils, mast cells, T-helper type 2 (Th2) cells, and innate lymphoid cells (ILC2). These cells release cytokines like interleukin-4 (IL-4), IL-5, and IL-13, which contribute to airway inflammation.
   • Treatments aim to reduce this inflammation using inhaled corticosteroids (ICS) or biologics targeting specific cytokines.

2. Airway Hyperresponsiveness:
   • This refers to an exaggerated bronchoconstrictor response to stimuli. It results from increased smooth muscle contraction and structural changes in the airway.
   • β2-agonists (short-acting or long-acting) are used to relax airway smooth muscles.

3. Airway Remodeling:
   • Persistent inflammation can lead to structural changes such as collagen deposition, smooth muscle hypertrophy, and mucus gland hyperplasia.
   • While ICS can partially prevent remodeling, newer therapies like biologics may also play a role in mitigating these changes.

4. Mucus Hypersecretion:
   • Excessive mucus production contributes to airway obstruction.
   • Anticholinergic agents like long-acting muscarinic antagonists (LAMAs) help reduce mucus secretion.

5. Immune Dysregulation:
   • Type 2 inflammation driven by Th2 cells or ILC2s is targeted with biologics that inhibit IL-4, IL-5, or IL-13 pathways.
   • Non-Type 2 asthma involving neutrophilic inflammation may require alternative approaches like macrolides or small-molecule inhibitors.

Medication Categories for Bronchial Asthma

Asthma medications are broadly categorized into two groups: controller medications for long-term management and reliever medications for immediate symptom relief.

Controller Medications

1. Inhaled Corticosteroids (ICS):
   • First-line therapy for persistent asthma; reduces airway inflammation.
   • Examples: Budesonide, Fluticasone.

2. Long-Acting β2-Agonists (LABAs):
   • Used in combination with ICS for better control of symptoms.
   • Examples: Salmeterol, Formoterol.

3. Long-Acting Muscarinic Antagonists (LAMAs):
   • Add-on therapy for severe asthma; reduces bronchoconstriction and mucus secretion.
   • Example: Tiotropium.

4. Leukotriene Receptor Antagonists (LTRAs):
   • Oral medications that block leukotrienes involved in inflammation.
   • Example: Montelukast.

5. Biologics:
   • Target specific pathways in severe Type 2 asthma.
     • Anti-IgE: Omalizumab.
     • Anti-IL-5/IL-5R: Mepolizumab, Benralizumab.
     • Anti-IL-4/IL-13: Dupilumab.

6. Theophylline:
   • A less commonly used bronchodilator with anti-inflammatory effects.

7. Macrolides:
   • May be used in non-Type 2 asthma due to their anti-inflammatory properties.

Reliever Medications

1. Short-Acting β2-Agonists (SABAs):
   • Provide rapid relief of bronchospasm during acute exacerbations.
   • Example: Albuterol/Salbutamol.

2. Short-Term Systemic Corticosteroids:
   • Used during severe exacerbations to control acute inflammation quickly.
3. Combination Inhalers with ICS + LABA as Relievers (“SMART” Therapy):
   • Example: Budesonide/Formoterol combination inhaler used both as maintenance and reliever therapy.

Concepts of Step-Up & Step-Down Asthma Treatment

Step-Up Approach

The step-up approach involves increasing the intensity of treatment when asthma remains uncontrolled despite current therapy:

1. Start with low-dose ICS for mild persistent asthma.
2. Add LABA or increase ICS dose if symptoms persist at moderate levels.
3. For severe cases, add LAMA or consider biologics based on phenotype and biomarkers like blood eosinophil count or IgE levels.

Step-Down Approach

Once good control is achieved for at least three months, treatment can be gradually reduced while monitoring symptoms:

1. Reduce ICS dose first while maintaining LABA if applicable.
2. Discontinue add-on therapies cautiously under medical supervision if control persists at lower doses.

These strategies align with guidelines from organizations like GINA and ATS/ERS.

Recent vs Old Guidelines for Asthma Treatment

Older Guidelines

1. Focused heavily on symptom-based management without considering underlying phenotypes or biomarkers.
2. Relied primarily on stepwise escalation of ICS doses combined with LABAs without personalized approaches.
3. Limited options for patients with severe refractory asthma beyond systemic corticosteroids.

Recent Guidelines

1. Emphasize personalized medicine based on phenotypes (e.g., eosinophilic vs non-eosinophilic) and biomarkers like FeNO levels or blood eosinophil counts.
2. Incorporate biologics targeting Type 2 inflammatory pathways as add-on therapies for severe cases.
3. Recommend “SMART” therapy using single inhalers combining ICS + formoterol as both maintenance and reliever medication.
4. Stress early intervention to prevent disease progression and minimize reliance on systemic corticosteroids due to side effects.

Possible Future Therapies

Emerging therapies aim to address unmet needs in both Type 2 and non-Type 2 asthma:

1. Small-Molecule Drugs:
   • Target intracellular signaling pathways involved in inflammation (e.g., JAK inhibitors).

2. New Biologics:
   • Anti-alarmine therapies targeting TSLP, IL-33, or IL-25 are under investigation.
   • CRTH2 antagonists blocking prostaglandin D₂ pathways show promise in clinical trials.

3. Gene Therapy & RNA-Based Approaches:
   • Potentially modulate genetic predispositions contributing to severe asthma phenotypes.

4. Microbiome-Based Interventions:
   • Exploring gut-lung axis modulation through probiotics/prebiotics aimed at reducing systemic inflammation.