Treatment Options for Refractory Asthma
For patients with refractory asthma, a stepwise approach is recommended, starting with high-dose inhaled corticosteroids plus long-acting beta-agonists, followed by leukotriene receptor antagonists, and then systemic corticosteroids if needed, with consideration of biologic therapies for those who remain uncontrolled. 1
Definition of Refractory Asthma
Refractory asthma is characterized by:
Major Characteristics (one or both required):
- Continuous or near-continuous (>50% of year) oral corticosteroid treatment 1
- Requirement for high-dose inhaled corticosteroids (e.g., fluticasone ≥880 μg/day, beclomethasone ≥1,260 μg/day) 1
Minor Characteristics (two required):
- Daily need for additional controller medications (long-acting β-agonist, theophylline, leukotriene antagonist) 1
- Daily or near-daily short-acting β-agonist use 1
- Persistent airflow obstruction (FEV1 <80% predicted) 1
- ≥1 urgent care visit for asthma per year 1
- ≥3 oral steroid "bursts" per year 1
- Rapid deterioration with <25% reduction in corticosteroid dose 1
- History of near-fatal asthma event 1
First-Line Treatment Options
- Standard antiasthmatic regimen: Inhaled bronchodilators and high-dose inhaled corticosteroids should be the initial treatment 1
- Assessment of airway inflammation: When available, evaluate airway inflammation to identify patients who may benefit from more aggressive anti-inflammatory therapy 1
- Optimization of inhaler technique: Ensure proper inhaler technique and consider using spacer devices to improve medication delivery 2
Second-Line Treatment Options
- Leukotriene receptor antagonists (LTRAs): For patients whose asthma remains refractory to inhaled corticosteroids and bronchodilators, add an LTRA (such as zafirlukast) before escalating to systemic corticosteroids 1
- Long-acting muscarinic antagonists (LAMAs): Consider adding tiotropium for improving airflow obstruction in patients not responding to ICS/LABA 2, 3
- Systemic corticosteroids: For severe and refractory cases, a short course (1-2 weeks) of systemic corticosteroids followed by maintenance with inhaled corticosteroids 1
Advanced Treatment Options
Biologic therapies: For patients with persistent symptoms despite optimal conventional therapy 3, 4:
- Anti-IgE therapy (omalizumab): Particularly effective for allergic asthma 4, 5
- Anti-IL-5 therapy (mepolizumab, reslizumab) or anti-IL-5 receptor antibodies (benralizumab): For eosinophilic asthma 3, 4, 5
- Anti-IL-4/IL-13 therapy (dupilumab): Targets type 2 inflammation 4
- Anti-TSLP therapy (tezepelumab): May benefit patients with both type 2 and non-type 2 inflammation 6
Bronchial thermoplasty: Consider for selected patients to reduce airway smooth muscle and improve control while reducing exacerbations 3, 5
Steroid-Resistant Asthma Management
- Steroid resistance assessment: Define by administering oral prednisone 40 mg/day for 1-2 weeks and observing effect on morning pre-bronchodilator FEV1 1
- Alternative anti-inflammatory agents: Consider methotrexate, cyclosporine, or macrolide antibiotics in patients who remain symptomatic despite optimal conventional therapy 1
Important Considerations and Pitfalls
- Adherence verification: Confirm medication adherence before escalating therapy 1, 2
- Comorbidity management: Identify and treat conditions that may worsen asthma control 1, 7
- Medication interactions: Be aware of drug interactions that may affect corticosteroid metabolism (e.g., rifampin, anticonvulsants) 1
- Pharmacokinetic evaluation: Consider evaluating corticosteroid pharmacokinetics in patients unable to tolerate doses lower than 20 mg every other day 1
- Environmental trigger control: Address allergen exposure and other environmental triggers 2, 7
Monitoring Response to Therapy
- Lung function monitoring: Track FEV1 and peak flow measurements, particularly morning readings for nocturnal control 2
- Inflammatory markers: Consider using eosinophil counts, exhaled nitric oxide, or sputum eosinophils to guide therapy when available 1, 3
- Exacerbation frequency: Monitor for reduction in urgent care visits and need for oral steroid bursts 1, 5
The treatment of refractory asthma requires a systematic approach with careful phenotyping to identify the most appropriate therapeutic options for each patient's specific inflammatory pattern and clinical characteristics 3, 7.