What is the best add-on therapy for a patient with severe asthma, no type 2 (T2) inflammation biomarkers, and worsening symptoms when tapering prednisone (corticosteroid), currently on fluticasone (corticosteroid)/umeclidinium (anticholinergic)/vilanterol (long-acting beta2-adrenergic agonist)?

Azithromycin is the Best Add-on Therapy for Severe Asthma Without Type 2 Inflammation

For a patient with severe asthma without type 2 inflammation biomarkers who experiences worsening symptoms when tapering prednisone, azithromycin is the most appropriate add-on therapy.

Understanding the Patient's Asthma Phenotype

This 42-year-old woman presents with several key characteristics that guide treatment selection:

• Severe asthma with multiple severe exacerbations
• Dependence on oral corticosteroids (prednisone 20 mg daily for 3 months)
• Already on triple therapy (fluticasone/umeclidinium/vilanterol)
• No biomarkers of type 2 (T2) inflammation
• Symptoms worsen with each attempt to taper prednisone

Treatment Options Analysis

Why Azithromycin is the Best Choice

For non-T2 severe asthma that is steroid-dependent, azithromycin offers the best evidence-based approach. While not explicitly mentioned in the older guidelines provided, current clinical practice recognizes azithromycin's role in non-T2 asthma phenotypes. The absence of T2 inflammation biomarkers is critical in this decision, as it indicates that biologics targeting T2 pathways would be ineffective.

Why Other Options Are Less Appropriate

1. Tiotropium:

   • Already has an anticholinergic component (umeclidinium) in her current triple therapy
   • Adding another anticholinergic agent would be redundant and unlikely to provide additional benefit 1, 2
   • Studies show tiotropium is beneficial as add-on to ICS or ICS/LABA, but this patient is already on triple therapy 3, 4, 5

2. Dupilumab:

   • Specifically targets type 2 inflammation pathways 6
   • FDA approved for "moderate-to-severe asthma characterized by an eosinophilic phenotype" 6
   • Not appropriate for patients without T2 inflammation biomarkers

3. Mepolizumab:

   • Targets IL-5, reducing blood eosinophils 7
   • Indicated for eosinophilic asthma phenotype 7
   • Would not benefit a patient without T2 inflammation biomarkers

Treatment Algorithm for Severe Asthma with Oral Corticosteroid Dependence

1. Identify asthma phenotype:

   • T2-high (eosinophilic) vs. T2-low (non-eosinophilic)
   • This patient has T2-low asthma (no T2 inflammation biomarkers)

2. For T2-low severe asthma:

   • Ensure optimal adherence to triple therapy
   • Add azithromycin as macrolide therapy
   • Start with 250-500 mg three times weekly
   • Monitor for QT prolongation and hearing changes

3. For T2-high severe asthma (not applicable to this patient):

   • Consider biologics (mepolizumab, dupilumab) based on specific biomarkers

Monitoring and Follow-up

• Assess clinical response after 3 months of azithromycin therapy
• Monitor for potential side effects (QT prolongation, hearing changes, GI symptoms)
• If response is adequate, attempt gradual prednisone taper (e.g., 2.5 mg reduction every 2-4 weeks)
• Continue to monitor lung function and symptoms during taper

Important Considerations

• Azithromycin has anti-inflammatory properties beyond antimicrobial effects
• Long-term macrolide therapy requires periodic assessment of cardiovascular risk
• Patients with severe asthma should be managed in conjunction with a specialist
• The goal is to minimize or eliminate oral corticosteroid use while maintaining asthma control

This approach prioritizes addressing the patient's non-T2 inflammatory pathway while attempting to reduce dependence on systemic corticosteroids, which carry significant long-term risks.