What is the optimal steroid regimen for asthma‑COPD overlap syndrome, including inhaled corticosteroid dosing based on exacerbation frequency, acute oral steroid burst, side‑effect precautions, and adjunct therapies?

Steroid Management in Asthma-COPD Overlap Syndrome (ACOS)

For patients with ACOS, initiate inhaled corticosteroid/long-acting β-agonist (ICS/LABA) combination therapy as first-line maintenance treatment, with dosing intensity guided by exacerbation frequency and blood eosinophil count ≥300 cells/μL predicting superior response. 1

Maintenance Inhaled Corticosteroid Regimen

Initial ICS/LABA Selection Based on Exacerbation History

• For patients with ≥2 exacerbations per year: Start combination ICS/LABA therapy immediately, as this represents GOLD category C or D disease requiring dual therapy 2
• For patients with <2 exacerbations per year but persistent symptoms: ICS/LABA combination is still preferred over monotherapy in ACOS due to the underlying eosinophilic inflammation 3
• Blood eosinophil count ≥300 cells/μL identifies patients who will experience significantly reduced exacerbations with ICS treatment (incidence rate ratio 0.52, P=0.03) 1

Recommended ICS Dosing Strategy

• Moderate-to-high dose ICS is required in ACOS, unlike pure COPD 4, 5
• Fluticasone/salmeterol or budesonide/formoterol are the most studied combinations, with strong evidence for exacerbation reduction 2
• The combination of ICS/LABA leads to clinically meaningful improvements in lung function, symptoms, and reduced rescue medication use compared to LABA alone 2
• ICS/LABA combination reduces exacerbation rates more effectively than ICS monotherapy (Grade 1B recommendation) 2

Triple Therapy Consideration

• For severe ACOS with persistent exacerbations despite ICS/LABA: Add long-acting muscarinic antagonist (LAMA) to create triple therapy 2, 4, 5
• Triple therapy (ICS/LABA/LAMA) is appropriate for GOLD category D patients with severe disease and recurrent exacerbations 2
• Several fixed-dose triple combination inhalers are now available for convenient administration 4

Acute Exacerbation Management: Oral Corticosteroid Burst

Standard Oral Steroid Regimen

Prednisone 30-40 mg orally once daily for 5 days is the evidence-based standard for ACOS exacerbations 6, 7

• This 5-day course is as effective as 10-14 day courses while minimizing adverse effects 6, 7
• Never extend oral corticosteroid treatment beyond 5-7 days for a single exacerbation, as longer courses increase adverse effects without additional benefit 6, 7
• Oral administration is strongly preferred over IV unless the patient is vomiting or severely ill 6, 7

Exacerbation Response Predictors

• Patients with ACOS show greater corticosteroid reversibility than pure COPD 8, 3
• Eosinophilic inflammation (elevated blood eosinophils, elevated ECP in BAL) predicts better response to systemic corticosteroids 8
• Thicker reticular basement membrane (asthma feature) correlates with corticosteroid responsiveness 8

Post-Exacerbation Strategy

• After completing the 5-day oral prednisone course, immediately optimize or initiate ICS/LABA combination therapy to maintain improved lung function and reduce relapse risk 7
• Systemic corticosteroids prevent hospitalization for subsequent exacerbations only within the first 30 days following the initial event 7
• Beyond 30 days, systemic corticosteroids should never be given for preventing exacerbations (Grade 1A recommendation) 2, 6, 7

Side-Effect Precautions and Monitoring

Short-Term Oral Corticosteroid Risks (5-7 day course)

• Hyperglycemia (odds ratio 2.79), especially in diabetics—monitor blood glucose closely 6, 7
• Weight gain, fluid retention, insomnia, and mood changes are common 6, 7
• Increased risk of gastrointestinal bleeding, particularly in patients with prior GI bleeding or taking anticoagulants 6, 7

Long-Term ICS Risks

• Increased pneumonia risk with ICS use in COPD-predominant ACOS (4% increased risk compared to LABA alone) 2
• Oropharyngeal candidiasis (OR 2.65) and hoarseness 2
• Upper respiratory tract infections 2
• Long-term studies show no major effect on fractures or bone mineral density over 3 years 2

Critical Pitfall to Avoid

Never use oral prednisone for long-term maintenance therapy in ACOS—it has no role in chronic management and the risks (infection, osteoporosis, adrenal suppression) far outweigh any benefits 7

Adjunct Therapies for Refractory ACOS

For COPD-Predominant ACOS with Persistent Exacerbations

• Long-term macrolide therapy (azithromycin) for patients with ≥1 moderate-to-severe exacerbation in the previous year despite optimal inhaler therapy (Grade 2A recommendation) 2, 5
• Roflumilast (phosphodiesterase-4 inhibitor) for severe COPD phenotype with chronic bronchitis 5
• N-acetylcysteine as mucolytic therapy 5

For Asthma-Predominant ACOS with Type-2 Inflammation

• Omalizumab (anti-IgE) for patients with elevated IgE and demonstrated immediate hypersensitivity to inhaled allergens 2, 5
• Leukotriene receptor antagonists (montelukast) or 5-lipoxygenase inhibitors (zileuton) for atopic ACOS patients 5
• Biologic therapies targeting IL-5, IL-13, IL-33, or TSLP for patients with elevated blood eosinophils (≥300 cells/μL) and persistent exacerbations 4, 5

Bronchodilator Optimization

• Theophylline is an alternative adjunctive therapy with ICS, though not preferred due to need for serum monitoring and side effects 2
• Short-acting β-agonists (albuterol) remain the most effective therapy for rapid symptom relief, used as needed 2

Algorithmic Approach to ACOS Steroid Management

1. Confirm ACOS diagnosis: Previous asthma diagnosis in a patient with COPD is the most reliable criterion; blood eosinophils ≥300 cells/μL support the diagnosis 1, 3

2. Initiate maintenance therapy: Start ICS/LABA combination (not ICS monotherapy) at moderate-to-high dose 2, 4

3. Assess exacerbation frequency:

   • If ≥2 exacerbations/year → Continue ICS/LABA, consider adding LAMA for triple therapy 2
   • If <2 exacerbations/year → Continue ICS/LABA, monitor response 2

4. For acute exacerbations: Prednisone 30-40 mg daily × 5 days, then stop (no taper needed) 6, 7

5. Post-exacerbation: Optimize ICS/LABA dose, ensure proper inhaler technique, provide written action plan 7

6. If persistent exacerbations despite triple therapy: Check blood eosinophils—if ≥300 cells/μL, consider biologic therapy; if neutrophilic phenotype, consider macrolide 4, 5, 1