severe asthma

Asthma that remains uncontrolled despite optimised step 4–5 therapy (medium-high dose ICS-LABA), confirmed adherence, correct technique, and treated comorbidities. Affects ~5–10% of patients with asthma but accounts for nearly half of asthma-related healthcare costs. Phenotyping with biomarkers guides biologic selection.

definitions

Term	Definition
Difficult-to-treat asthma	Uncontrolled on medium/high-dose ICS-LABA — but modifiable factors (adherence, technique, comorbidities) have not been fully addressed
Severe asthma	Uncontrolled despite optimised step 4–5 therapy and resolution of modifiable factors — or asthma that worsens when stepping down

Most “difficult-to-treat” patients do not have true severe asthma. Systematic assessment of modifiable factors is mandatory before escalating to biologics.

before labelling “severe” — the systematic check

Confirm the diagnosis — re-examine objective evidence of asthma; consider asthma mimics
Adherence — prescription refill records, electronic monitoring; self-report overestimates adherence
Inhaler technique — demonstrate and observe; re-assess at every visit
Comorbidities — treat the unholy trinity (rhinosinusitis, GERD, OSA) and others (obesity, anxiety/depression, VCD)
Ongoing triggers — allergen exposure, occupational sensitisers, smoking/vaping, medications (beta-blockers, ASA/NSAIDs)
Reassess after 3–6 months — only if still uncontrolled → severe asthma

phenotyping

T2-high (eosinophilic and/or allergic)

The majority (~50–70%) of severe asthma. Driven by IL-4, IL-5, IL-13 via Th2 lymphocytes and ILC2 cells.

Biomarkers:

Biomarker	Threshold suggesting T2-high	Notes
Blood eosinophils	≥ 0.15 × 10⁹/L (biologic-eligible); ≥ 0.3 strongly T2	Suppressed by OCS — check before or after wash-out
FeNO	≥ 20 ppb (suggestive); ≥ 50 ppb (strongly T2)	Reduced by ICS, smoking; elevated in atopy
Total IgE	30–1500 IU/mL	Required for omalizumab dosing; not a standalone phenotyping tool
Sputum eosinophils	≥ 2–3%	Gold standard but limited availability

T2-low (non-eosinophilic)

Neutrophilic or paucigranulocytic. Fewer biologic options. Consider:

Azithromycin 250 mg 3×/week (reduces exacerbations regardless of inflammatory profile)
LAMA add-on
Bronchial thermoplasty (limited evidence, rarely performed)
Tezepelumab (the only biologic with demonstrated efficacy in T2-low subgroup)

biologic selection

All biologics require referral to a specialist and pre-treatment biomarker assessment (CHEST 2025, GINA 2024).

Biologic	Target	Key biomarker	Dosing	Landmark trial
Omalizumab	Anti-IgE	Total IgE 30–1500 + positive skin prick/specific IgE	Weight & IgE-based, SC q2–4wk	INNOVATE (2004)
Mepolizumab	Anti-IL-5	Blood eos ≥ 0.15	100 mg SC q4wk	DREAM (2012), MENSA (2014)
Benralizumab	Anti-IL-5Rα	Blood eos ≥ 0.3	30 mg SC q4wk ×3, then q8wk	CALIMA (2016)
Dupilumab	Anti-IL-4Rα (blocks IL-4 + IL-13)	Blood eos ≥ 0.15 or FeNO ≥ 25	Loading 400–600 mg, then 200/300 mg SC q2wk	LIBERTY QUEST (2018)
Tezepelumab	Anti-TSLP	Effective across phenotypes (broadest eligibility)	210 mg SC q4wk	NAVIGATOR (2021)

biomarker-guided selection

Clinical scenario	First-line biologic	Alternative
Allergic + eosinophilic (high IgE + high eos)	Dupilumab or omalizumab	Mepolizumab
Eosinophilic, non-allergic (high eos, normal IgE)	Anti-IL-5/5Rα or dupilumab	Tezepelumab
High FeNO, moderate eos	Dupilumab	Tezepelumab
Comorbid atopic dermatitis or nasal polyps	Dupilumab (treats all three)	—
AERD (aspirin-exacerbated)	Dupilumab	Mepolizumab
OCS-dependent, very high eos (> 1.5)	Anti-IL-5/5Rα (steroid-sparing)	Dupilumab
T2-low / low eosinophils / low FeNO	Tezepelumab	Consider azithromycin
Allergic asthma + eos ≥ 0.15, recurrent exacerbations requiring hospitalisation	Dupilumab over omalizumab (conditional recommendation, very low certainty — CHEST 2025)	Omalizumab if eos < 0.15

OCS reduction with biologics

A primary goal of biologic therapy is OCS elimination. All anti-IL-5 agents and dupilumab have demonstrated OCS-sparing effects. Do not start a biologic and leave the patient on chronic OCS — systematically taper once the biologic is established (typically after 4–6 months).

response assessment

Evaluate at 4–6 months (CHEST 2025)
Good response: fewer exacerbations (≥ 50% reduction), improved control, OCS reduction/elimination, improved FEV1
Inadequate response → switch to alternative biologic (different mechanism of action preferred)
Before switching: re-confirm adherence, re-check biomarkers, reconsider diagnosis

workup before starting biologics

Confirm severe asthma (systematic check above)
Blood eosinophils (ideally not on OCS), FeNO, total IgE, specific IgE or skin prick testing
Sputum cell counts (if available)
CT chest (exclude bronchiectasis, interstitial lung disease, other pathology)
Consider eosinophilic lung disease if eosinophils > 1.5 × 10⁹/L (ABPA, EGPA, parasitic)
Screen for Strongyloides in at-risk populations before anti-IL-5 therapy (risk of hyperinfection with eosinophil depletion)

Strongyloides screening

Anti-IL-5 agents deplete eosinophils, which are a key defence against Strongyloides stercoralis. Unrecognised infection can progress to hyperinfection syndrome. Screen patients from endemic regions (tropical/subtropical) with Strongyloides serology before starting mepolizumab or benralizumab.

key trials summary

Trial	Year	Agent	Key result
INNOVATE	2004	Omalizumab	Reduced severe exacerbations in allergic asthma
DREAM	2012	Mepolizumab	48% reduction in exacerbations in eosinophilic asthma
MENSA	2014	Mepolizumab	53% exacerbation reduction; pivotal for regulatory approval
CALIMA	2016	Benralizumab	28–51% exacerbation reduction (eos ≥ 300)
LIBERTY QUEST	2018	Dupilumab	48% exacerbation reduction; FEV1 improvement; effective across eosinophilic and high-FeNO subgroups
NAVIGATOR	2021	Tezepelumab	56% exacerbation reduction; effective regardless of baseline eosinophils