Key Facts

Difficult asthma refers to asthma that appears uncontrolled despite treatment at Step 4/5 of the BTS/SIGN guidelines. Systematic assessment often reveals modifiable factors. True severe refractory asthma accounts for only a subset of these patients.

Epidemiology

• ~5-10% of asthma patients have difficult-to-treat asthma
• ~3.5% (~190,000 in the UK) have truly severe refractory asthma
• Severe asthma accounts for >50% of total asthma healthcare costs
• Higher prevalence in women, obesity, late-onset disease

Aetiology

Modifiable factors (difficult asthma):

• Poor inhaler technique (~70-80% of patients have errors)
• Non-adherence to ICS (~50% of difficult asthma)
• Untreated comorbidities: GORD, rhinosinusitis, obesity, OSA, anxiety/depression
• Ongoing allergen/occupational exposure
• Smoking
• Drug triggers: NSAIDs, beta-blockers

Severe refractory asthma:

• Persistent eosinophilic inflammation despite high-dose ICS
• Neutrophilic airway inflammation (poor steroid response)
• Airway remodelling with fixed obstruction

Pathophysiology

• Heterogeneous: multiple inflammatory endotypes
• Type 2 high: eosinophilic, elevated FeNO, IgE, IL-4/5/13 driven (~50-70%)
• Type 2 low: neutrophilic or paucigranulocytic, poor steroid response
• Airway remodelling leads to irreversible obstruction over time
• Mucus plugging, subepithelial fibrosis, and smooth muscle hypertrophy persist

Typical Presentation

• Persistent symptoms despite high-dose ICS/LABA
• Frequent exacerbations (≥2 requiring OCS per year)
• Recurrent hospital admissions
• Chronic OCS dependence
• Significant impact on quality of life and daily activities

Phenotypes

• Early-onset allergic: atopy, raised IgE, eosinophilia - responds to anti-IgE
• Late-onset eosinophilic: adult-onset, nasal polyps, no atopy, high blood eosinophils - responds to anti-IL-5
• Obesity-related: female predominance, poor response to standard therapy
• Aspirin-exacerbated respiratory disease (AERD): Samter triad (asthma, nasal polyps, aspirin sensitivity)

Red Flags

• Frequent OCS courses (≥2/year) - consider biologic therapy
• Maintenance OCS requirement
• Frequent ED attendances or admissions
• Ever requiring ICU admission or ventilation
• Rapid decline in lung function on serial spirometry

Bedside

• Inhaler technique assessment: observe and correct
• FeNO: elevated (≥25 ppb) suggests eosinophilic inflammation and steroid-responsive disease
• PEF diary: assess variability and adherence
• Pulse oximetry: baseline oxygen saturation

Bloods

• Blood eosinophil count: ≥300 cells/µL supports eosinophilic phenotype and biologic eligibility
• Total IgE: elevated in allergic asthma (guides omalizumab dosing)
• Specific IgE/skin prick tests: allergen identification
• Aspergillus IgE and IgG: exclude ABPA
• ANCA: exclude EGPA if eosinophilia + systemic features

Imaging

• HRCT chest: bronchiectasis, mucus plugging, air trapping, ground-glass opacity
• CT sinuses: chronic rhinosinusitis, nasal polyps

Special Tests

• Spirometry: assess for fixed airflow obstruction (post-BD FEV₁/FVC)
• Sputum induction: eosinophil vs neutrophil predominance for phenotyping
• Prescription refill monitoring: objective adherence assessment
• Fractional exhaled NO (FeNO): suppressed FeNO in patient claiming ICS use suggests non-adherence
• Prednisolone assay: confirm OCS adherence if concerns

Non-pharmacological

• Systematic assessment (BTS Difficult Asthma Protocol):
  1. Confirm diagnosis
  2. Assess and optimise inhaler technique
  3. Monitor and improve adherence
  4. Identify and treat comorbidities
  5. Eliminate triggers
• Weight management if BMI >30
• Treat rhinosinusitis, GORD, and OSA
• Psychological support for anxiety/depression
• Breathing pattern retraining if dysfunctional breathing

Pharmacological

Before biologics - optimise Step 4/5 therapy:

• High-dose ICS/LABA (e.g. budesonide/formoterol 400/12 mcg, 2 puffs BD)
• Add LTRA (montelukast 10mg ON)
• MART regimen if appropriate
• Trial of low-dose maintenance OCS (prednisolone 5-7.5mg/day) - minimise dose

Biologic therapies (NICE-approved):

• Omalizumab (anti-IgE): severe allergic asthma, IgE 30-1500 IU/mL, positive skin prick test (NICE TA278)
• Mepolizumab 100mg SC monthly (anti-IL-5): blood eosinophils ≥300 cells/µL (NICE TA431, MENSA/MUSCA trials)
• Benralizumab 30mg SC 4-weekly then 8-weekly (anti-IL-5Rα): blood eosinophils ≥300 (NICE TA565, SIROCCO/CALIMA trials)
• Dupilumab 200mg or 300mg SC 2-weekly (anti-IL-4Rα): type 2 inflammation, eosinophils ≥150 or FeNO ≥25 (NICE TA751, LIBERTY ASTHMA trials)
• Tezepelumab (anti-TSLP): broad severe asthma (NICE TA880, NAVIGATOR trial)

Surgical/Interventional

• Bronchial thermoplasty: considered in select refractory cases (NICE IPG635)
• Sinus surgery for refractory rhinosinusitis with nasal polyps

Referral Criteria

• All patients uncontrolled on Step 4 therapy should be referred to a specialist severe asthma centre
• MDT assessment for biologic eligibility
• Biologic trial (minimum 4 months) with objective response assessment

• Severe asthma has significantly higher morbidity and mortality than mild-moderate disease
• Biologic therapies reduce exacerbations by 50-70% and allow OCS dose reduction/cessation in ~50% of patients
• Chronic OCS use causes significant morbidity: osteoporosis (30-50%), diabetes (15-20%), adrenal suppression, cataracts
• Airway remodelling may cause irreversible obstruction
• Quality of life significantly impaired; 30-40% report severe impact on daily activities
• Good outcomes with early specialist referral and biologic therapy

Biologic Eligibility Summary

Difficult Asthma Systematic Assessment