Severe Type 2 Asthma

Severe type 2 asthma is asthma that stays uncontrolled despite high dose inhaled corticosteroid with a second controller (or needs these to stay controlled) and shows eosinophilic or allergic type 2 inflammation. It responds to biologic therapy.

Pathophysiology. Airway inflammation is driven by IL-4, IL-5, IL-13, thymic stromal lymphopoietin and IgE, with eosinophils and mast cells. This causes recurrent exacerbations, fixed airflow limitation and oral corticosteroid dependence.

It affects a small share of people with asthma and carries a large burden of exacerbations, hospital admission and corticosteroid adverse effects.

The diagnosis requires that adherence, inhaler technique, triggers and comorbidities (rhinosinusitis with nasal polyps, gastro oesophageal reflux, obesity, sleep apnoea, vocal cord dysfunction) have been addressed first.

• Frequent exacerbations needing oral corticosteroids (2 or more a year)
• Persistent symptoms despite high dose inhaled treatment
• Chronic rhinosinusitis with nasal polyps and loss of smell
• Atopic features, and blood eosinophilia
• Fixed airflow obstruction in long standing disease
• Corticosteroid effects: weight gain, diabetes, osteoporosis, cataract

• Confirm asthma and exclude mimics: spirometry with reversibility, fractional exhaled nitric oxide, and imaging of the chest and sinuses.
• Check adherence and technique: prescription records, inhaler technique review and, where available, electronic monitoring.
• Type 2 markers: blood eosinophils over 0.15 x 109/L (and over 0.3 x 109/L on 1 or more occasions in the past year), fractional exhaled nitric oxide over 25 ppb, total IgE and specific IgE or skin prick tests.
• Eosinophilic mimics: exclude eosinophilic granulomatosis with polyangiitis (ANCA, urinalysis), parasitic infection, drug reaction and hypereosinophilic syndrome when eosinophils are very high.
• Comorbidity assessment: nasal endoscopy, reflux, sleep study, and mental health.
• Fungal sensitisation: specific IgE to Aspergillus fumigatus and total IgE, with a high resolution CT if ABPA is suspected.

Differential diagnosis.

• Poor adherence or technique
• Allergic bronchopulmonary aspergillosis
• Eosinophilic granulomatosis with polyangiitis
• Vocal cord dysfunction, bronchiectasis, COPD
• Obesity related breathlessness and heart failure
• Hypereosinophilic syndrome

• Optimise baseline treatment: high dose inhaled corticosteroid with formoterol (for example budesonide with formoterol 400/12 microgram, 2 inhalations twice daily), long acting muscarinic antagonist (tiotropium 5 microgram, 2 puffs once daily), and montelukast 10 mg at night when useful.
• Biologic selection by phenotype (after 4 months of optimised treatment):
  • Omalizumab: for allergic asthma with total IgE of 30 to 1500 IU/mL, 75 to 600 mg subcutaneously every 2 or 4 weeks by weight and IgE.
  • Mepolizumab 100 mg subcutaneously every 4 weeks, for eosinophilic asthma.
  • Benralizumab 30 mg subcutaneously every 4 weeks for 3 doses, then every 8 weeks, for eosinophilic asthma.
  • Dupilumab 400 mg subcutaneously then 200 mg every 2 weeks (600 mg then 300 mg every 2 weeks for oral corticosteroid dependent asthma), for type 2 asthma with eosinophilia or raised exhaled nitric oxide.
  • Tezepelumab 210 mg subcutaneously every 4 weeks, for severe asthma across phenotypes including low eosinophils.
  • Reslizumab 3 mg/kg intravenously every 4 weeks, for eosinophilic asthma.
• Judge response at 4 months: reduction in exacerbations, symptoms and oral corticosteroid use, and stop if no benefit.
• Reduce oral corticosteroid stepwise once control is stable.
• Treat comorbidity: nasal polyps (intranasal corticosteroid, surgery, dupilumab or mepolizumab), reflux, obesity and sleep apnoea.
• Azithromycin 500 mg orally three times weekly for exacerbations in non-eosinophilic disease, after ECG shows QTc under 450 ms and sputum is clear of non-tuberculous mycobacteria.
• Corticosteroid toxicity: bone density scan, bisphosphonate when indicated, and screening for diabetes, hypertension and cataract.

Special groups.

• Pregnancy: biologic use needs individual risk assessment, and uncontrolled asthma is itself harmful.
• Children over 6 years: omalizumab, mepolizumab, dupilumab and benralizumab have paediatric dosing by weight.

Monitoring. Exacerbation count, symptom score, spirometry and blood eosinophils at every visit. Review every 3 to 4 months at first. Bone density and metabolic screening yearly in oral corticosteroid users.

Referral and escalation. Refer to a severe asthma service. Emergency for severe exacerbation.