How should steroid‑resistant severe asthma in an adult who remains uncontrolled despite high‑dose inhaled corticosteroid (ICS) plus long‑acting β2‑agonist (LABA) with good adherence be evaluated and managed?

Management of Steroid-Resistant Severe Asthma

In an adult with severe asthma remaining uncontrolled despite high-dose ICS/LABA with confirmed good adherence, the priority is to systematically verify true treatment failure, add a third controller medication (preferably a LAMA such as tiotropium or umeclidinium), and refer to a severe asthma specialist for phenotyping and consideration of biologic therapy before resorting to maintenance oral corticosteroids. 1, 2, 3

Initial Verification Steps (Before Escalating Therapy)

Before concluding this is truly steroid-resistant asthma, three critical assessments must be completed:

• Confirm proper inhaler technique at every visit, as incorrect technique is a common cause of apparent treatment failure and can masquerade as steroid resistance 1, 4
• Verify medication adherence objectively by reviewing prescription refill frequency and SABA use patterns (use >2 days/week indicates inadequate control) 5, 1, 4
• Identify and address comorbidities that mimic or worsen asthma, including GERD, chronic rhinosinusitis, obstructive sleep apnea, vocal cord dysfunction, and anxiety disorders 2, 3
• Eliminate environmental triggers such as allergen exposure, tobacco smoke, occupational exposures, and irritants 5, 4

A critical pitfall: Up to one-third of patients with asthma demonstrate some degree of corticosteroid insensitivity and may not respond adequately even to high-dose therapy, but this should only be diagnosed after ruling out the above factors 5

Formal Assessment of Steroid Resistance

If the above factors are optimized and the patient remains uncontrolled, consider a formal steroid responsiveness trial:

• Administer oral prednisone 40 mg daily (divided doses) for 14 days and measure pre-bronchodilator FEV1 before and after the trial 5
• True steroid resistance is defined as failure to increase FEV1 by ≥15% (and ≥200 mL) after this course 5
• This trial also helps assess adherence to the maintenance regimen, as patients who respond to oral steroids but not inhaled therapy may have adherence issues 5

Step-Up Treatment Algorithm

First-Line Add-On: Long-Acting Muscarinic Antagonist (LAMA)

Add tiotropium (via Respimat inhaler) or umeclidinium 62.5 mcg once daily to the existing high-dose ICS/LABA regimen as the preferred third controller medication 1, 3, 6, 7

• LAMAs added to ICS/LABA significantly improve lung function, extend time to first exacerbation, and reduce severe exacerbation rates in patients with uncontrolled asthma despite high-dose ICS/LABA 6, 7
• Triple ICS/LABA/LAMA combination reduces overall exacerbation risk, with high-dose ICS showing greater effect particularly in reducing severe exacerbations, especially in patients with type 2 inflammation biomarkers 6
• Tiotropium specifically demonstrated significant lung function improvement after 6 months and extended time to first asthma exacerbation in phase III trials of patients on high-dose ICS (≥800 µg budesonide/day equivalent) plus LABA 7

Alternative Add-On Options (Less Preferred)

If LAMA is contraindicated or not tolerated:

• Leukotriene receptor antagonist (montelukast 10 mg daily) can be added, though evidence is less robust than for LAMA 5, 1, 3
• A 14-day trial in 72 adults with severe persistent asthma found no additional benefit from adding montelukast to medium-to-high-dose ICS plus LABA (85% also received theophylline or LABA, 47% received oral corticosteroids) 5
• Theophylline is the least preferred option due to narrow therapeutic window, need for serum monitoring (target 5-15 mcg/mL), and significant side effect profile 5, 8

Specialist Referral and Phenotyping

Refer to a severe asthma specialist for patients requiring Step 5-6 therapy or remaining uncontrolled despite optimized triple therapy 1, 2, 3

The specialist evaluation should include:

• Measure blood eosinophil counts to identify eosinophilic phenotype (≥300 cells/μL suggests candidacy for anti-IL-5 biologics) 9, 2
• Measure fractional exhaled nitric oxide (FeNO) as a marker of type 2 airway inflammation 1, 2
• Assess sputum granulocytic counts if available to further characterize inflammatory phenotype 2
• Perform skin testing or RAST for perennial aeroallergens to identify allergic asthma phenotype 5

Biologic Therapy Considerations

For Severe Eosinophilic Asthma

Benralizumab (anti-IL-5 receptor) or mepolizumab (anti-IL-5) should be considered for patients with:

• Blood eosinophils ≥300 cells/μL (benralizumab studied in patients with ≥150 cells/μL in oral steroid reduction trials) 9
• History of ≥2 exacerbations requiring oral/systemic corticosteroids in the past 12 months 9
• Pre-bronchodilator FEV1 <80% predicted despite high-dose ICS/LABA 9
• Benralizumab dosing: 30 mg subcutaneously every 4 weeks for first 3 doses, then every 8 weeks 9

Critical adherence consideration: Good ICS adherence (medication possession ratio >0.75) during biologic therapy predicts greater OCS dose reduction (100% vs 60% reduction, p=0.031) and exacerbation reduction compared to poor adherence 10

For Severe Allergic Asthma

Omalizumab (anti-IgE) is indicated for patients ≥12 years with:

• Moderate to severe persistent asthma inadequately controlled with ICS 5, 8
• Positive skin test or RAST to perennial aeroallergen 5, 8
• Reduces asthma exacerbations even in severe asthma, though cost is higher than other therapies 5
• Black-box warning: 0.09% risk of anaphylaxis; clinicians must be prepared to treat anaphylaxis and observe patients appropriately after each injection 5

Oral Corticosteroid Use: Last Resort

Maintenance oral corticosteroids should only be initiated after exhausting all other options including triple ICS/LABA/LAMA therapy and appropriate biologic therapy 5, 3

• Current recommendations include adding oral systemic corticosteroids only if control cannot be achieved with high-dose ICS, LABA, and additional controllers 5
• Oral corticosteroids are commonly associated with significant adverse events and comorbidities including osteoporosis, cataracts, HPA axis suppression, and increased infection risk 5, 3
• If maintenance oral steroids are required, use the minimum effective dose (typically 1-2 mg/kg/day, generally not exceeding 60 mg/day) and make repeated attempts to reduce the dose while maintaining control with high-dose inhaled therapy 5

Monitoring for Oral Corticosteroid Complications

For patients on high-dose ICS (>1 year) or frequent oral corticosteroid courses:

• Bone densitometry (DEXA scan) to assess osteoporosis risk, particularly in perimenopausal women 8
• Slit-lamp eye examination to screen for posterior subcapsular cataracts 8
• Morning plasma cortisol or 24-hour urinary cortisol if clinical concern for HPA axis suppression exists 8

Key Safety Considerations

• Never discontinue ICS when adding LAMA or other controllers, as ICS remains the foundation of therapy 1, 3
• LABAs must never be used as monotherapy due to increased risk of asthma-related deaths; always combine with ICS 1, 8
• Monitor cardiovascular status when using LAMAs in patients with recent MI (<6 months), heart failure hospitalization within past year, or unstable arrhythmias 1
• Higher ICS doses provide minimal additional benefit beyond 200 µg/day fluticasone equivalent while substantially increasing systemic side effect risk 5

Understanding True Steroid Resistance

Several mechanisms explain limited response to conventional therapy:

• Decreased glucocorticoid receptor numbers or binding affinity in association with increased receptor concentrations 5
• Altered suppression of transcription factors involved in inflammatory pathways 5
• Presence of relatively steroid-resistant neutrophils rather than eosinophils as the predominant inflammatory cell 5
• Extensive airway structural changes (remodeling) that are less responsive to anti-inflammatory therapy 5
• Rapid corticosteroid elimination due to drug interactions with rifampin, phenytoin, carbamazepine, or phenobarbital (though <25% of severe asthma patients show clinically significant increased clearance) 5