What are the GINA (Global Initiative for Asthma) guidelines for managing asthma with inhaled corticosteroids (ICS) and other therapies?

GINA Guidelines for Asthma Management with Inhaled Corticosteroids and Other Therapies

Inhaled corticosteroids (ICS) remain the cornerstone of asthma therapy at all steps of persistent asthma, and the most recent GINA strategy (2021-2024) now recommends that all adults and adolescents with asthma receive ICS-containing medication and should never be treated with short-acting beta-agonist (SABA) alone. 1, 2

Core Treatment Philosophy

GINA's current approach focuses on two primary domains 3, 4:

• Current asthma control: Day-to-day symptom management and functional limitations
• Future risk reduction: Prevention of exacerbations, decline in lung function, and medication side effects

The Two-Track Treatment Approach (2021-2024 Updates)

The most recent GINA strategy divides treatment into two distinct tracks for adults and adolescents 1, 2:

Track 1 (Preferred Track)

• Reliever medication: As-needed low-dose ICS-formoterol at ALL steps 1, 2
• Steps 1-2 (Mild asthma): As-needed ICS-formoterol only, no daily controller 2
• Steps 3-5: Daily maintenance ICS-formoterol PLUS as-needed ICS-formoterol (MART strategy) 2
• Rationale: Large trials demonstrate as-needed ICS-formoterol reduces severe exacerbations by ≥60% compared with SABA alone in mild asthma 2

Track 2 (Alternative Track)

• Reliever medication: As-needed SABA across all steps 1, 2
• Step 2: Regular low-dose ICS plus as-needed SABA 2
• Steps 3-5: Regular ICS-LABA combination plus as-needed SABA 2

Stepwise Treatment Algorithm

Step 1 (Intermittent Asthma)

• Preferred: As-needed low-dose ICS-formoterol 3
• Alternative: As-needed ICS plus SABA (separate inhalers) 3
• Never acceptable: SABA alone 1, 2

Step 2 (Mild Persistent Asthma)

• Preferred: As-needed low-dose ICS-formoterol OR daily low-dose ICS 3, 2
• Alternative: Leukotriene receptor antagonists (LTRAs) as second-line option 3
• Evidence: ICS monotherapy achieves asthma control in approximately 65-71% of steroid-naive patients with mild to moderate asthma after 4-8 weeks 5

Step 3 (Moderate Persistent Asthma)

• Preferred (Track 1): Low-dose ICS-formoterol daily PLUS as-needed ICS-formoterol (up to 8-10 puffs/day total) 3
• Alternative (Track 2): Medium-dose ICS OR low-dose ICS plus LABA 3, 6
• Key change from older guidelines: Combination ICS-LABA is now equally preferred with increasing ICS dose, balancing efficacy against LABA safety concerns 3

Step 4 (Moderate-Severe Persistent Asthma)

• Preferred (Track 1): Medium-dose ICS-formoterol daily PLUS as-needed ICS-formoterol 3
• Alternative (Track 2): Medium to high-dose ICS-LABA 6
• Additional option: Add leukotriene modifier if response incomplete 3

Step 5 (Severe Persistent Asthma)

• Preferred: High-dose ICS-LABA 6, 2
• Add-on therapies 3, 2:
  • Long-acting muscarinic antagonist (LAMA) 3, 2
  • Anti-IgE therapy (omalizumab) for patients ≥12 years with allergic asthma (elevated IgE, positive skin test/RAST) 3
  • Azithromycin for select patients 2
  • Other biologic therapies for severe asthma 2

Step 6 (Most Severe Asthma)

• Treatment: High-dose ICS-LABA plus oral corticosteroids 3, 4
• Add-on biologics: Consider omalizumab or other biologics 3

Critical Safety Considerations

LABA Safety

• Black-box warning removed but caution remains: LABAs should NEVER be used as monotherapy for asthma 3, 7
• Always combine with ICS: The FDA previously issued a black-box warning against LABA monotherapy due to increased asthma-related deaths 3
• Recent evidence: Large trials show ICS-LABA combinations do not significantly increase risk of serious asthma-related events compared with ICS alone 7

Formoterol vs. Salmeterol for SMART

• Use formoterol only: Formoterol has rapid onset of action suitable for reliever therapy 3
• Never use salmeterol: Salmeterol has delayed onset and should not be used for SMART strategy 3
• Evidence base: SMART studies were almost exclusively performed with budesonide/formoterol 3

ICS Dose-Response Relationship

• Greatest benefit at low-medium doses: For fluticasone, greatest clinical benefit occurs at 200 μg/day with minimal additional improvement at 500-1000 μg/day 3
• Systemic effects increase with dose: Risk of reduced growth in children and decreased bone mineral density in adults increases with higher ICS doses 3
• One-third may be corticosteroid-insensitive: Up to 33% of patients may not respond adequately even to high-dose ICS 3

Monitoring and Adjustment

Indicators of Poor Control

• SABA use >2 days/week (excluding exercise-induced bronchospasm prevention) indicates inadequate control and need to step up treatment 3
• Increasing SABA use: Generally indicates need for anti-inflammatory therapy intensification 3

Step-Down Therapy

• Essential principle: It is equally important to step down medication in well-controlled asthma as to step up in uncontrolled asthma 3
• Timing: Consider reducing treatment once asthma control is established 4

Special Populations

Children 5-11 Years

• Step 3-4 options: Low to medium-dose ICS-formoterol (up to 8 puffs/day) 3
• SMART not recommended by GINA: For children 5-11 years, GINA does not recommend SMART strategy 3
• New treatment options: Recent guidelines add additional options at Steps 3-4 2

Children 0-4 Years

• Treatment recommendations: Presented separately with age-appropriate considerations 3
• Device considerations: DPIs require sufficient inspiratory flow and may not be suitable 6

Additional Therapeutic Options

Leukotriene Modifiers

• Montelukast and zileuton: Provide anti-inflammatory and bronchodilatory effects 3
• Role: Alternative second-line treatment for mild persistent asthma; adjunctive therapy at higher steps 3
• Advantages: Easy to use, high compliance rates, good symptom control in many patients 3
• Preference: For patients ≥12 years, adding LABA to ICS is preferred over adding LTRA 3

Immunotherapy

• Subcutaneous allergen immunotherapy: Consider for patients with allergic asthma at Steps 2-4 when clear relationship exists between symptoms and allergen exposure 3
• Clinician preparedness: Must be prepared to treat anaphylaxis 3

Omalizumab (Anti-IgE)

• Indication: Patients ≥12 years with moderate to severe persistent asthma inadequately controlled with ICS, with positive skin test or RAST to perennial aeroallergen 3
• Mechanism: Blocks IgE-mediated allergic cascade by binding free IgE 3
• Efficacy: Reduces asthma exacerbations even in severe asthma 3
• Safety: Clinicians must be prepared to treat anaphylaxis 3

Essential Adjunctive Measures

At every step, the following are mandatory 3:

• Patient education and self-management support
• Written asthma action plan 1
• Environmental control (multifaceted approaches required; single interventions generally ineffective) 3
• Management of comorbid conditions 3
• Inhaler technique assessment and training 3
• Adherence monitoring 3

Common Pitfalls to Avoid

• Never prescribe SABA alone: Even for intermittent asthma, patients should receive ICS-containing medication 1, 2
• Don't ignore ICS/formoterol off-label status: In Steps 1-2, ICS/formoterol use is still off-label in EU and many countries 8
• Don't use salmeterol for SMART: Only formoterol has appropriate pharmacokinetics 3
• Don't overlook step-down: Failure to reduce therapy in well-controlled asthma exposes patients to unnecessary medication risks 3
• Don't forget spacers: Using spacers with MDIs improves delivery and reduces local side effects 6