Type 2 airway inflammation: eosinophils, IL-4, IL-5, IL-13 and biomarkers

At a glance

• About half to two thirds of adults with asthma have type 2 (T2-high) inflammation: eosinophils, IgE and IL-13 effects in the airway.
• It starts at the epithelium. Allergens, viruses, proteases and pollutants make epithelial cells release the alarmins TSLP, IL-33 and IL-25.
• Alarmins activate dendritic cells (which prime Th2 cells) and group 2 innate lymphoid cells (ILC2s). ILC2s make IL-5 and IL-13 without any antigen, which is why non-allergic eosinophilic asthma exists.
• Three cytokines do most of the work: IL-4 (IgE class switch, Th2 differentiation), IL-5 (eosinophils) and IL-13 (mucus, hyperresponsiveness, FeNO).
• Each biomarker reads out one arm. Blood eosinophils reflect IL-5, FeNO reflects IL-13, and total and specific IgE reflect IL-4 and allergen sensitisation.
• Paper 1 links each biologic to the step it blocks and asks you to predict the biomarker response. Clinical use is in asthma.

The pathway, step by step

Step	Main players	What it produces	Drug that blocks it
Epithelial alarm	TSLP, IL-33, IL-25	Activation of dendritic cells, ILC2s, mast cells	Tezepelumab (anti-TSLP)
Th2 priming	Dendritic cell, naive CD4 T cell, IL-4, GATA3	Th2 cells in lymph node
IgE production and FcεRI loading	IL-4 and IL-13 on B cells, CD40L	Allergen-specific IgE bound to mast cells and basophils	Omalizumab (binds free IgE, so less loads onto FcεRI; doesn't stop the class switch)
Eosinophil production and survival	IL-5	Blood and tissue eosinophilia	Mepolizumab (anti-IL-5), benralizumab (anti-IL-5R alpha)
Airway remodelling	IL-13 (and IL-4) via IL-4R alpha	Goblet cell hyperplasia, mucus plugs, smooth muscle hyperresponsiveness, iNOS	Dupilumab (anti-IL-4R alpha)
Eosinophil recruitment	Eotaxins (CCL11, CCL24, CCL26), VCAM-1	Tissue eosinophils	(dupilumab reduces VCAM-1)
Mast cell mediators	Cysteinyl leukotrienes, PGD2	Bronchoconstriction, Th2 and ILC2 recruitment via CRTH2	Montelukast (CysLT1 receptor)

Eosinophils damage the airway with major basic protein, eosinophil peroxidase and cationic protein, and they form Charcot-Leyden crystals (galectin-10) that thicken mucus. Mucus plugs on CT are a marker of type 2 disease and predict response to biologics.

Why corticosteroids work so well here

Glucocorticoids switch off transcription of IL-4, IL-5 and IL-13 (via the glucocorticoid receptor recruiting HDAC2 to inflamed genes) and induce eosinophil apoptosis. Type 2 asthma is therefore steroid-responsive, and the biomarkers fall on ICS. Neutrophilic airway inflammation responds far less (see neutrophilic airway inflammation).

Aspirin-exacerbated respiratory disease

In N-ERD (asthma, nasal polyps, NSAID reactions), COX-1 inhibition removes protective PGE2. Arachidonic acid is shunted to cysteinyl leukotrienes, and mast cells release more PGD2. The reaction is not IgE-mediated, so skin tests are negative. Selective COX-2 inhibitors are usually tolerated. Montelukast and aspirin desensitisation target this pathway; dupilumab helps the polyps.

The biomarkers

Marker	What it reflects	Thresholds used
Blood eosinophils	IL-5 activity	150/µL or more suggests T2; 300/µL or more is the usual PBS cut-off for anti-IL-5 drugs (150/µL if on oral steroids)
FeNO	IL-13-driven epithelial iNOS	GINA: 20 ppb or more suggests T2 on ICS. Australian Asthma Handbook uses 40 ppb or more to support the diagnosis. ATS: under 25 low, over 50 high
Total IgE	IL-4, atopy	30 IU/mL or more for PBS omalizumab; dose by weight and IgE
Specific IgE or skin prick	Sensitisation to a named allergen	Must fit the history to matter
Sputum eosinophils	Airway eosinophilia	3% or more is eosinophilic

Pitfall: FeNO is raised by atopy and recent allergen exposure, and lowered by smoking, ICS and recent bronchoconstriction. It is not a measure of eosinophils.

Worked example: predicting the biomarker response

A 46-year-old woman with severe asthma takes high-dose budesonide-formoterol and needed prednisolone three times last year. Blood eosinophils are 0.52 × 10^9/L, FeNO 64 ppb, total IgE 85 IU/mL, house dust mite sensitised.

1. Convert units: 0.52 × 10^9/L = 520 cells/µL. Above 300, so anti-IL-5 drugs qualify.
2. FeNO 64 ppb on high-dose ICS means IL-13 activity is still high, or she isn't taking the ICS. Check adherence first.
3. What happens to each marker on each drug?

Drug	Blood eosinophils	FeNO	Total IgE
Mepolizumab	Falls by about 80%	Little change	Unchanged
Benralizumab	Falls to near zero	Little change	Unchanged
Dupilumab	Rises transiently, then settles	Falls early, by about 30 to 40%	Falls slowly over months
Omalizumab	Modest fall	Modest fall	Total IgE rises (assay counts bound complexes); free IgE falls
Tezepelumab	Falls	Falls	Falls

FeNO falling on dupilumab but not on mepolizumab is the classic demonstration that FeNO is an IL-13 signal.

How it's tested

• Mechanism to drug: "Which drug causes antibody-dependent cellular cytotoxicity of eosinophils?" (benralizumab). "Which blocks both IL-4 and IL-13?" (dupilumab, via the shared IL-4R alpha chain).
• Biomarker interpretation: a rising eosinophil count on dupilumab, a raised total IgE on omalizumab, a normal FeNO in a smoker.
• Eosinophilia that isn't asthma: before biologics or high-dose steroids, think of Strongyloides (check serology in people from endemic areas, including many Aboriginal and Torres Strait Islander communities in northern Australia), EGPA (eosinophils over 1,500/µL, neuropathy, ANCA in 30 to 40%), ABPA (total IgE over 500 IU/mL, Aspergillus-specific IgE) and drug reactions.
• Shared biology: the same pathway drives atopic dermatitis, eosinophilic oesophagitis and chronic rhinosinusitis with nasal polyps, which is why dupilumab is used in all four.
• Australian access: severe asthma biologics are Section 100 and specialist-initiated (respiratory physicians, clinical immunologists and other specialists experienced in severe asthma; check the current PBS restriction for the exact prescriber list), with ACQ-5 of 2.0 or more and exacerbation criteria. Tezepelumab was PBS-listed from 1 July 2026 for severe uncontrolled asthma in people 12 and over.

Pitfalls

• Calling asthma "non-type 2" from one eosinophil count taken on oral prednisolone.
• Reading a rising total IgE on omalizumab as treatment failure.
• Starting dupilumab when eosinophils are above 1,500/µL without excluding EGPA or hypereosinophilic syndrome; eosinophilic pneumonia and vasculitis have been reported.
• Treating eosinophilia with steroids or biologics before excluding Strongyloides, which can cause hyperinfection.
• Assuming FeNO and blood eosinophils measure the same thing. They are separate arms (IL-13 versus IL-5) and are often discordant.
• Forgetting that ILC2s make IL-5 and IL-13 without allergen, so a non-atopic patient can still have florid eosinophilic asthma.