🧬 How Biologics Are Reshaping Our Understanding of ABPA Subtypes

For many years, Allergic Bronchopulmonary Aspergillosis (ABPA) was viewed as a single condition:

An allergic reaction to Aspergillus fumigatus in the lungs, treated primarily with steroids and sometimes antifungal medication.

Biologic therapies are changing that picture.

They are not just new treatments — they are helping us understand that ABPA may not be one uniform disease, but a spectrum of related inflammatory patterns.

🧠 The Traditional View of ABPA

Historically, ABPA has been defined by:

• Asthma (or cystic fibrosis)

• High total IgE

• Sensitisation to Aspergillus

• Raised eosinophils

• Characteristic CT changes (e.g. bronchiectasis, mucus plugging)

The dominant biological explanation was:

A Type 2 (allergic) immune overreaction driven by eosinophils and IgE.

Steroids were used to suppress this immune response.

This model assumed that most patients had broadly similar immune drivers.

💊 What Are Biologics?

Biologics are targeted antibody therapies designed to block specific immune pathways.

In asthma and ABPA, the main targets are:

• IL-5 (drives eosinophils)

• IL-5 receptor

• IL-4 / IL-13 (drive allergic inflammation)

• IgE

Examples include:

• Anti–IL-5 therapies (e.g. mepolizumab, benralizumab)

• Anti–IL-4/IL-13 therapy (e.g. dupilumab)

• Anti-IgE therapy (e.g. omalizumab)

Instead of broadly suppressing immunity like steroids, they selectively block parts of the allergic pathway.

🔍 What Biologics Are Teaching Us

As biologics have been used in ABPA (often off-label or in specialist centres), an interesting pattern has emerged:

Not all ABPA behaves the same way.

Some patients respond dramatically to anti–IL-5 therapy.
Others respond better to anti–IL-4/IL-13 therapy.
Some show strong IgE-driven disease.
Others appear more mucus-dominant.

This suggests that ABPA may include different inflammatory endotypes (biological subtypes), even if outward symptoms look similar.

🧩 Possible Emerging ABPA Subtypes

While research is ongoing, clinicians are beginning to recognise patterns such as:

1️⃣ Strongly Eosinophilic-Dominant ABPA

• Very high eosinophils

• Frequent exacerbations

• Often responds well to IL-5 blockade

2️⃣ IgE-Heavy Allergic ABPA

• Extremely high total IgE

• Prominent allergic features

• May respond to anti-IgE therapy

3️⃣ Mucus-Plug Dominant ABPA

• Recurrent thick mucus impaction

• Radiological plugging

• May involve additional inflammatory drivers

4️⃣ Steroid-Dependent ABPA

• Relapses when steroids reduced

• Biologics may allow steroid-sparing strategies

These patterns are not yet formal categories, but biologics are revealing that ABPA is biologically more complex than once thought.

🧪 Blood Eosinophils vs Airway Inflammation

Biologics have also highlighted another key insight:

Blood eosinophil levels do not always perfectly reflect what is happening in the lungs.

Some patients:

• Have modest blood eosinophils

• But still show eosinophilic airway activity

Biologic response patterns are helping refine how we interpret these markers.

🧠 Moving From “Diagnosis” to “Endotype”

Traditionally, medicine focused on:

Diagnosis (ABPA vs not ABPA)

Biologics are pushing us toward:

Endotype (which immune pathway is dominant in this patient?)

This matters because targeted therapy works best when matched to the dominant pathway.

In future, ABPA may be classified not just by clinical features, but by molecular drivers.

🫁 What This Means for Patients

Biologics offer:

• Reduced steroid dependence

• Fewer exacerbations

• Improved lung function in selected patients

• Potential improvement in mucus burden

But they also help answer deeper questions:

• Why do some patients relapse frequently?

• Why do some have extreme eosinophilia?

• Why do others have more mucus plugging than inflammation?

They are helping personalise ABPA care.

⚖ Important Caveats

• Biologics are not currently licensed specifically for ABPA in many countries.

• Evidence is growing but still developing.

• They are usually considered in specialist centres.

• They are not appropriate for every patient.

Steroids and antifungals remain core treatments.

🔭 The Future

Over the next decade, we may see:

• Better classification of ABPA subtypes

• Biomarker-guided treatment selection

• Reduced long-term steroid exposure

• Improved understanding of mucus plug biology

• Trials specifically designed for ABPA (rather than extrapolated from asthma)

Biologics are not just new drugs.

They are acting as scientific tools that are reshaping how we think about ABPA itself.

🧠 Key Takeaway

ABPA is no longer seen as one single uniform allergic condition.

Biologic therapies are revealing that:

ABPA is likely a spectrum of related inflammatory patterns — and treatment may increasingly be tailored to the dominant pathway in each individual.

References

Agarwal R, Sehgal IS, Muthu V, Denning DW, Chakrabarti A, Soundappan K, Garg M, Rudramurthy SM, Dhooria S, Armstrong-James D, Asano K, Gangneux JP, Chotirmall SH, Salzer HJF, Chalmers JD, Godet C, Joest M, Page I, Nair P, Arjun P, Dhar R, Jat KR, Joe G, Krishnaswamy UM, Mathew JL, Maturu VN, Mohan A, Nath A, Patel D, Savio J, Saxena P, Soman R, Thangakunam B, Baxter CG, Bongomin F, Calhoun WJ, Cornely OA, Douglass JA, Kosmidis C, Meis JF, Moss R, Pasqualotto AC, Seidel D, Sprute R, Prasad KT, Aggarwal AN. Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses. Eur Respir J. 2024 Apr 4;63(4):2400061. doi: 10.1183/13993003.00061-2024. PMID: 38423624; PMCID: PMC10991853.

by GAtherton