GAtherton

Voriconazole in Aspergillosis

A balanced guide for patients and clinicians

Voriconazole is a broad-spectrum triazole antifungal used in:

  • Chronic pulmonary aspergillosis (CPA)

  • Allergic bronchopulmonary aspergillosis (ABPA) (selected cases)

  • Invasive aspergillosis

  • Azole-resistant or itraconazole-intolerant cases

It is available orally and intravenously and is often used when a stronger or more reliably absorbed azole is required.

1️⃣ What Voriconazole Does

Voriconazole works by blocking fungal ergosterol synthesis (CYP51 inhibition), which disrupts the fungal cell membrane.

Compared with itraconazole:

  • More potent against Aspergillus

  • More predictable oral absorption

  • More central nervous system penetration

It often produces symptom improvement over weeks, though some effects (e.g. visual symptoms) may occur quickly.

2️⃣ How Long Is Treatment?

In CPA

  • Often 6–12 months or longer

  • Sometimes used as second-line or after intolerance to itraconazole

  • Long-term suppressive therapy may be required

In ABPA

  • Used in selected steroid-dependent or refractory cases

In invasive disease

  • Typically several months depending on response and immune status

3️⃣ Why Blood Level Monitoring Is Essential

Voriconazole has non-linear pharmacokinetics.

Small dose changes can cause large blood level shifts.

Two patients on the same dose may have very different levels due to:

  • Liver metabolism (CYP2C19 genetic variation is important)

  • Drug interactions

  • Age

  • Weight

  • Liver function

If Levels Are Too Low

  • Treatment failure

  • Persistent fungal activity

  • Risk of resistance

If Levels Are Too High

  • Liver toxicity

  • Neurological side effects

  • Visual disturbances

  • Increased interaction risk

Typical Target (Trough)

  • Generally 1–5.5 mg/L (lab dependent)

  • Toxicity risk increases >5–6 mg/L

Levels are usually checked:

  • 5–7 days after starting

  • After dose adjustments

  • If side effects occur

  • If clinical response is inadequate

4️⃣ Common Side Effects (Often Mild & Reversible)

Visual Disturbances (Very Common but Usually Harmless)

  • Blurred vision

  • Altered colour perception

  • Light sensitivity

  • “Wavy” vision

These typically:

  • Occur within 30–60 minutes of dosing

  • Last less than an hour

  • Reduce over time

Patients should avoid night driving initially until they understand their response.

Photosensitivity

  • Increased sensitivity to sunlight

  • Sunburn risk

  • Long-term risk of skin damage with prolonged therapy

Sun protection is important.

Gastrointestinal

  • Nausea

  • Abdominal discomfort

5️⃣ Less Common but Important Effects

Neurological

  • Headache

  • Vivid dreams

  • Hallucinations (usually at high levels)

  • Confusion (dose-related)

These are generally reversible with dose adjustment.

Liver Abnormalities

Routine liver function monitoring is required.

Most abnormalities are mild and resolve with dose modification.

Cardiac Effects

Voriconazole can prolong the QT interval.

Caution in patients with:

  • Known arrhythmias

  • Electrolyte imbalance

  • Other QT-prolonging drugs

ECG monitoring may be appropriate in higher-risk patients.

Skin Cancer Risk (Long-Term Use)

With prolonged use (especially >1–2 years):

  • Increased risk of skin squamous cell carcinoma

  • Particularly in transplant recipients

Sun protection and dermatology review are advised for long-term therapy.

6️⃣ Food & Drug Advice

  • Avoid grapefruit

  • Avoid St John’s Wort

  • Take tablets at least 1 hour before or after meals (food reduces absorption)

Voriconazole has many CYP-mediated interactions and requires careful medication review.

7️⃣ Comparison With Itraconazole (Simple Overview)

Feature Itraconazole Voriconazole
Absorption variability High More predictable
Visual side effects Rare Common but mild
Photosensitivity Rare More common
QT prolongation Minimal Possible
TDM needed Yes Yes (essential)

Balanced Summary for Patients

Voriconazole is a strong antifungal used when more reliable or potent treatment is needed. Most side effects are manageable and reversible, and blood monitoring keeps treatment safe.

Clinician Checklist

  • Confirm indication and prior azole exposure

  • Check baseline LFTs

  • Review ECG if cardiac risk present

  • Assess drug interactions (CYP2C19, 2C9, 3A4)

  • Arrange trough level at day 5–7

  • Counsel regarding visual symptoms and sun protection

by GAtherton

Why Can Aspergillus Infection Be Hard to Clear — Even When Tests Say It’s “Sensitive”?

Many patients ask:

“If my lab report says the fungus is sensitive to the antifungal drug, why is my condition not improving quickly?”

This is a very reasonable question.

The short answer is: fungi are biologically adaptable, and we are still learning how they adjust inside the lung.

Recent research involving scientists working with the National Aspergillosis Centre (NAC), including work led by Dr. Weaver and colleagues, is helping us understand this better.

You can read the scientific abstract here:
🔗 https://pubmed.ncbi.nlm.nih.gov/41673015/

1️⃣ What Does “Sensitive” Mean in the Lab?

When Aspergillus is tested against a drug (such as itraconazole or voriconazole), laboratories measure the minimum inhibitory concentration (MIC).

This tells us the drug level needed to stop fungal growth in a controlled lab setting.

If the MIC is low, the fungus is labelled “sensitive.”

But the laboratory environment is very different from a lung cavity.

2️⃣ The Lung Is Not a Uniform Environment

In chronic pulmonary aspergillosis (CPA), the fungus often lives inside:

  • Cavities

  • Scarred lung tissue

  • Fungal balls

  • Thick mucus

Within these areas there can be:

  • Low oxygen

  • Variable iron levels

  • Uneven drug penetration

  • Different levels of immune activity

This means that different parts of the same infection can behave differently at the same time.

3️⃣ New Research: Fungi Have Fine-Tuned Control Systems

Recent work from researchers collaborating with NAC, including Prof. Bowyer’s group, has shown that Aspergillus contains additional regulatory elements in its genome called long non-coding RNAs (lncRNAs).

These do not make proteins.
Instead, they help fine-tune how nearby genes behave under stress.

In laboratory studies, some of these regulatory elements appear to influence how the fungus responds to antifungal drugs — even when there is no classic resistance mutation.

This suggests:

  • Aspergillus can adjust how strongly certain pathways (like ergosterol production) are activated.

  • These adjustments may help the fungus survive stressful conditions.

  • This survival does not always show up as “resistance” in standard lab testing.

This does not mean the drug does not work.
It means the biological response can be more subtle and layered than we previously understood.

4️⃣ Resistance vs Tolerance — An Important Difference

Resistance

  • Caused by stable genetic mutations.

  • The drug becomes much less effective.

  • MIC levels rise clearly.

Tolerance

  • The fungus survives but grows slowly.

  • MIC may still appear “sensitive.”

  • The fungus adapts temporarily to stress conditions.

The new regulatory findings may help explain tolerance — not necessarily resistance.

5️⃣ Why This Matters for CPA

CPA is a chronic condition.

Inside lung cavities:

  • Drug levels may vary.

  • Oxygen levels fluctuate.

  • Stress signals are ongoing.

This environment encourages survival strategies.

Research like the Weaver study helps us understand why:

  • Treatment response may be gradual.

  • Cultures can be intermittently positive.

  • Stability may be the goal rather than rapid clearance.

6️⃣ How Could This Research Help in the Future?

It is important to be realistic: this research is still at an early stage.

However, understanding these regulatory systems opens new possibilities.

Instead of thinking only about killing the fungus directly, future approaches might aim to:

  • Weaken its survival responses.

  • Reduce its ability to enter protective stress states.

  • Make existing antifungal drugs work more effectively.

For example, research in fungal biology has already shown that interfering with certain stress-buffering pathways can increase azole effectiveness in laboratory models.

In the longer term, this type of work could lead to:

🔹 Better Diagnostics

Tests that detect not only resistance mutations, but also stress-adapted or tolerance states.

🔹 More Personalised Treatment

Identifying strains that rely heavily on stress adaptation and adjusting therapy accordingly.

🔹 Combination Strategies

Using antifungal drugs together with agents that reduce fungal stress tolerance, helping prevent persistence.

These ideas are still under investigation, and no lncRNA-based treatments exist yet.
But this research expands the way scientists think about fungal treatment.

7️⃣ Encouraging News

The important message is this:

NAC is actively involved in research that improves our understanding of how Aspergillus behaves under treatment.

This work:

  • Does not suggest current treatments are ineffective.

  • Does not mean patients are resistant.

  • Does highlight why long-term management can be complex.

  • Represents steady progress in understanding fungal biology.

Understanding these regulatory systems is a step toward:

  • Better diagnostics

  • More personalised treatment strategies

  • Improved long-term outcomes

A Reassuring Perspective

If progress feels slow, it is not because you or your clinicians have failed.

It reflects the adaptable survival biology of a fungus living in a complex lung environment.

And importantly, NAC and its research partners — including groups such as Dr. Weaver’s — are working to understand this biology in order to improve care.

by GAtherton

Aspergillosis Literature Update: Week 5

This week’s aspergillosis research highlights evolving management of life-threatening haemoptysis in Chronic Pulmonary Aspergillosis (CPA), new insights into antifungal resistance mechanisms, and continued evidence linking post-tuberculosis lung disease with CPA risk. Notably, species beyond Aspergillus fumigatus — including Aspergillus flavus and Aspergillus udagawae — feature prominently, reinforcing the importance of accurate species identification and susceptibility testing in complex or refractory disease.

Weekly Aspergillosis Literature Update
9–15 February 2026

1️⃣ Clinical Complications & Interventional Management

Refractory Massive Haemoptysis in Chronic Pulmonary Aspergillosis

Superselective Pulmonary Artery Embolization for Refractory Massive Hemoptysis Post-Bronchial Artery Embolization: A Bail-Out Measure
Cardiovasc Intervent Radiol (Feb 15, 2026)
🔗 https://pubmed.ncbi.nlm.nih.gov/41692834/

Focus: Advanced haemoptysis management in Chronic Pulmonary Aspergillosis (CPA)

  • 6 of 7 patients had CPA

  • All had failed prior bronchial artery embolization (BAE)

  • Pulmonary artery embolization used as salvage therapy

Why this matters:
Suggests a potential pathway for CPA patients with persistent life-threatening bleeding when conventional embolization fails.

2️⃣ Antifungal Resistance & Drug Sensitivity Mechanisms

Novel Caspofungin Resistance in Aspergillus flavus

Ubiquinone-based gene mutation and protein compactness of CoQ5 may contribute to a novel caspofungin resistance mode in Aspergillus flavus
Diagn Microbiol Infect Dis (Feb 9, 2026)
🔗 https://pubmed.ncbi.nlm.nih.gov/41690241/

Focus: Echinocandin resistance biology

  • Suggests mitochondrial/ubiquinone-linked mechanism

  • Moves beyond classical cell wall mutation models

  • Highlights increasing importance of non-fumigatus species

Why this matters:
Resistance biology is becoming more complex — molecular surveillance may need to expand.

Long Non-Coding RNAs and Antifungal Sensitivity

Genome-wide discovery and phenotyping of non-coding transcripts in A. fumigatus reveals lncRNAs with a role in antifungal drug sensitivity
Nat Commun (Feb 11, 2026)
🔗 https://pubmed.ncbi.nlm.nih.gov/41673015/

Focus: Regulatory genomics in antifungal response

  • Identifies long non-coding RNAs influencing drug sensitivity

  • Suggests new regulatory layers in antifungal resistance

  • Opens potential future therapeutic targets

Why this matters:
Signals a shift from single-gene resistance thinking toward systems-level regulation.

3️⃣ Species-Specific Virulence & Emerging Pathogens

Virulence of Aspergillus flavus and Relatives

Virulence of Aspergillus flavus and relatives using the Galleria mellonella model
Virulence (Epub Feb 13, 2026)
🔗 https://pubmed.ncbi.nlm.nih.gov/41685886/

Focus: Comparative pathogenicity

  • Demonstrates variability in virulence among related species

  • Reinforces need for accurate species identification

Why this matters:
Species differentiation has prognostic and potentially therapeutic implications.

Fatal Dissemination from Cryptic Species

Fatal Fungal Peritonitis Caused by Aspergillus udagawae: An Autopsy Case Report
Intern Med (Feb 10, 2026)
🔗 https://pubmed.ncbi.nlm.nih.gov/41672531/

Focus: Disseminated disease from chronic pulmonary infection

  • Multidrug-resistant A. udagawae

  • Autopsy-confirmed fatal fungal peritonitis

  • Highlights invasive potential of cryptic species

Why this matters:
Supports advanced diagnostics and susceptibility testing in refractory cases.

4️⃣ Structural Lung Disease & Secondary Aspergillosis

CPA Following Cavities and Prednisolone

Chronic pulmonary aspergillosis as a complication of lung cavities and prednisolone treatment
Ugeskr Laeger (Feb 9, 2026)
🔗 https://pubmed.ncbi.nlm.nih.gov/41685454/

Focus: Steroids + cavitation as CPA risk factors

  • Imaging and microbiology confirmed diagnosis

  • Long-term azole therapy successful

  • IgG normalisation observed

Why this matters:
Reinforces the structural lung disease + corticosteroid risk interaction.

Post-Tuberculosis Lung Disease and CPA

Post-tuberculosis lung disease and pulmonary aspergillosis management: challenges and considerations
Expert Rev Anti Infect Ther (Feb 12, 2026)
🔗 https://pubmed.ncbi.nlm.nih.gov/41674445/

Focus: Global burden interface

  • Post-TB structural damage predisposes to CPA

  • Major diagnostic and management challenges highlighted

Why this matters:
Post-tuberculosis lung disease remains one of the largest global drivers of CPA.

5️⃣ Mixed & Extrapulmonary Presentations

Abdominal Wall Aspergillosis

Letter: Abdominal Wall Aspergillosis
Surg Infect (Feb 12, 2026)
🔗 https://pubmed.ncbi.nlm.nih.gov/41680095/

Focus: Extrapulmonary aspergillosis

  • Uncommon presentation

  • Reinforces need for broad diagnostic awareness

Mixed Tuberculosis and Aspergillus Infection

Milky Tea-Colored Pleural Effusion: Empyema Complicated by Pneumothorax Due to Mixed Infection With Mycobacterium tuberculosis and Aspergillus fumigatus
Am J Case Rep (Feb 10, 2026)
🔗 https://pubmed.ncbi.nlm.nih.gov/41664446/

Focus: Dual infection

  • Structural damage enables mixed infection

  • TB diagnosis does not exclude concurrent aspergillosis

Overall Themes This Week

  • 🔴 Haemoptysis management continues to evolve in advanced CPA

  • 🧬 Resistance mechanisms are becoming increasingly complex

  • 🌍 Post-tuberculosis lung disease remains central to global CPA burden

  • 🧫 Species identification is clinically important

  • ⚠ Mixed and disseminated infections continue to challenge diagnosis

by GAtherton

Looking further into the future - could we control lung damage, preserve healthy lung tissue better?

Can Lungs Repair Themselves?

What New Research Means for People with CPA (and Other Aspergillosis)

A recent scientific discovery has helped researchers understand how certain lung cells decide whether to focus on repairing damage or defending against infection. The work, highlighted by the Mayo Clinic and published in Nature Communications, describes a molecular “switch” inside specialised lung cells that influences this balance.

For people living with Chronic Pulmonary Aspergillosis (CPA) — and also those with Allergic Bronchopulmonary Aspergillosis (ABPA) — this kind of research is relevant. But it needs careful explanation.

This is not about rebuilding destroyed lungs.
It is about understanding how to better protect and preserve the lung tissue that remains.

The Discovery: A “Repair vs Defence” Switch

Researchers identified a regulatory circuit in alveolar type II (AT2) cells — specialised cells that:

  • Produce surfactant (which keeps air sacs open)

  • Act as a reserve “repair” population in the lung

  • Can regenerate other essential lung cells after injury

The study showed that these cells operate under tight control. When infection is present, they prioritise defence. When injury needs healing, they can switch into repair mode.

The key insight is that this switch is biologically regulated. It is not random. That means, in theory, it may one day be possible to influence it.

What “Repair” Means — and What It Does Not Mean

When we talk about lung repair in this context, we must be very clear.

It does not mean:

  • Lung cavities caused by CPA will close in the foreseeable future

  • Established fibrosis will melt away

  • Bronchiectasis will reverse

  • Severely distorted lung architecture will rebuild

CPA cavities represent major structural remodelling — destruction of alveoli, scarring, altered blood supply, and thickened pleura. Reconstructing that complex architecture is biologically extremely challenging and not currently realistic within the next decade.

What repair does realistically mean

In chronic lung disease, “repair” is more likely to mean:

  • Supporting survival of remaining alveoli

  • Preventing excessive fibrotic signalling

  • Helping lung lining cells recover more efficiently after inflammation

  • Reducing cumulative injury from repeated infection

  • Slowing progression of structural change

In other words:

Not rebuilding what is gone — but better protecting what remains.

For many people with CPA, this is a crucial distinction.

Why Preservation Is a Major Goal in CPA

CPA usually develops in lungs already weakened by conditions such as tuberculosis, non-tuberculous mycobacteria, chronic obstructive pulmonary disease, or severe pneumonia.

Over time, CPA can lead to:

  • Expanding cavities

  • Progressive scarring

  • Reduced gas exchange

  • Reduced exercise tolerance

Many patients have limited lung reserve. Even small additional losses of functioning lung tissue can significantly increase breathlessness or fatigue.

If future therapies could slow the rate of progression — even modestly — that would meaningfully affect long-term outcomes.

Flattening the decline curve is not trivial. It changes quality of life.

Why This Also Matters in ABPA

In ABPA, repeated inflammatory episodes can lead to:

  • Airway remodelling

  • Mucus plugging

  • Development or progression of bronchiectasis

Better control of inflammatory signalling — combined with improved epithelial recovery — could reduce long-term airway damage.

Again, this is about preservation rather than reversal.

Where Development Has Reached

The current research is still laboratory-based. It used advanced techniques such as:

  • Single-cell sequencing

  • Imaging of lung tissue

  • Preclinical models of injury

No human treatments based on this discovery are yet available.

However, the significance lies in identifying:

  • A defined molecular pathway

  • A controllable regulatory mechanism

  • A clearer understanding of why repair fails in chronic inflammation

That foundational knowledge is what eventually allows targeted drug development.

The Balance Challenge in Aspergillosis

There is an additional complexity in fungal lung disease.

Any attempt to promote repair must not weaken antifungal defence.

The immune system must:

  • Control Aspergillus

  • Avoid causing excessive inflammatory damage

Future therapies would need to strike that balance carefully.

What This Means for Patients Now

This discovery does not change current treatment.

The most effective preservation strategies today remain:

  • Consistent antifungal therapy when indicated

  • Careful inflammatory control

  • Biologic therapies where appropriate

  • Airway clearance

  • Vaccination and infection prevention

  • Avoiding damp and mould exposure

  • Pulmonary rehabilitation

These measures are already forms of lung preservation.

A Realistic and Hopeful Perspective

It is unlikely that cavities from CPA will be repaired in the near future.

It is realistic that within the next 5–10 years we may see improved strategies aimed at:

  • Slowing structural progression

  • Supporting endogenous repair cells

  • Reducing fibrotic signalling

  • Improving recovery after exacerbations

For people living long-term with CPA or ABPA, even incremental preservation could significantly affect independence and quality of life.

The science is still early — but understanding how the lung decides to repair itself is an important step forward.

Reference

Sawhney, A.S., Deskin, B.J., Cai, J. et al. A molecular circuit regulates fate plasticity in emerging and adult AT2 cells. Nat Commun 16, 8924 (2025). https://doi.org/10.1038/s41467-025-64224-1

by GAtherton

🧬 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

🧬 Could Antibody-Driven Dissolving of Charcot–Leyden Crystals Help ABPA?

Researchers have recently discovered that Charcot–Leyden crystals (CLCs) — the needle-shaped structures formed from the eosinophil protein galectin-10 — are not just debris.

In laboratory studies, specially designed antibodies can dissolve these crystals.

This has raised two important questions:

  1. Could dissolving the crystals reduce airway inflammation?

  2. Could dissolving them make mucus plugs easier to clear?

Here is what we currently know.

1️⃣ Could dissolving crystals reduce airway inflammation?

What we know

Laboratory and animal studies have shown:

  • Charcot–Leyden crystals can activate immune cells (especially macrophages).

  • They can stimulate inflammatory pathways (including inflammasome signalling).

  • In mouse models, antibodies targeting galectin-10 dissolved the crystals.

  • When crystals were dissolved, airway inflammation decreased.

This suggests that the crystals themselves may amplify inflammation, rather than simply mark it.

What this means biologically

In ABPA and eosinophilic asthma:

  • Eosinophils release galectin-10.

  • Galectin-10 crystallises.

  • Crystals may trigger further immune activation.

  • That leads to more inflammation → more eosinophils → more crystals.

Dissolving the crystals could theoretically interrupt this feedback loop.

How likely is this to help inflammation in humans?

Moderately plausible, but not yet proven.

The biological mechanism is strong.
The animal data are encouraging.
But no human clinical trials have yet shown reduced inflammation through crystal dissolution.

If developed successfully, this approach could:

  • Reduce airway immune activation

  • Lower exacerbation risk

  • Potentially reduce steroid dependence

But at present, it remains investigational.

2️⃣ Could dissolving crystals make mucus plugs easier to cough up?

This is more speculative — but still biologically reasonable.

Why mucus plugs are so thick in ABPA

ABPA mucus plugs contain:

  • Gel-forming mucins

  • DNA from inflammatory cells

  • Dead cells

  • Fungal fragments

  • Eosinophil proteins

  • Charcot–Leyden crystals

The crystals are:

  • Rigid

  • Needle-shaped

  • Structurally stable

When embedded in mucus, they likely increase:

  • Mechanical stiffness

  • Plug density

  • Resistance to deformation

From a physics perspective:

Removing rigid crystalline structures from a gel should reduce stiffness and improve flow.

Do we have direct evidence?

No.

There are currently:

  • No human studies measuring mucus clearance after crystal dissolution

  • No trials showing improved plug expectoration from crystal-targeting therapy

So while it is plausible that dissolving crystals could soften plugs, this has not yet been demonstrated in patients.

3️⃣ How strong is the overall case?

Outcome Evidence strength Likelihood
Reduced inflammation Strong biological rationale + animal data Moderately promising
Easier mucus clearance Biophysical plausibility only Possible but unproven

Inflammation reduction is the more evidence-supported target.
Improved plug clearance is plausible but currently theoretical.

4️⃣ How does this compare to existing treatments?

Current therapies (e.g., anti-IL-5 biologics) reduce eosinophils upstream.

That leads to:

  • Less galectin-10 release

  • Fewer crystals forming

  • Reduced inflammation

  • Often improved mucus plugging

So biologics already indirectly reduce crystal burden.

A crystal-dissolving antibody would act downstream, targeting the structural product directly.

This could theoretically:

  • Accelerate resolution of existing plugs

  • Reduce residual inflammatory signalling

But again, this remains in early research stages.

5️⃣ Practical take-home message

At present:

  • Dissolving Charcot–Leyden crystals reduces inflammation in animal models.

  • It is biologically plausible that this could also soften mucus plugs.

  • There is no human clinical proof yet.

  • No approved therapy currently targets the crystals directly.

The concept is scientifically credible — but still under development.

🔭 The Bigger Picture

ABPA is increasingly understood as a condition driven by:

  • Eosinophils

  • Allergic immune signalling

  • Abnormal mucus biology

  • Structural plug formation

Crystal-targeting therapies may eventually become part of a more precise approach to treating eosinophilic airway disease.

But for now, they remain a promising research direction rather than a clinical option.

by GAtherton

🔬 Charcot–Leyden Crystals in ABPA and Asthma

What are they? Why do they form? Do they matter?

If you live with Allergic Bronchopulmonary Aspergillosis (ABPA) or severe asthma, you may see the term Charcot–Leyden crystals in a sputum or pathology report.

They can sound worrying.

They are:

  • Not fungus

  • Not infection

  • Not cancer

They are a sign of a particular type of allergic inflammation in the airways.

🧬 What Are Charcot–Leyden Crystals?

Charcot–Leyden crystals are microscopic, needle-shaped structures found in mucus.

They are made from a protein called galectin-10, which is stored inside a type of white blood cell called an eosinophil.

Eosinophils are immune cells involved in:

  • Allergic asthma

  • ABPA

  • Severe asthma with fungal sensitisation

  • Parasitic infections

When eosinophils are activated and break down, they release galectin-10.
If enough of this protein accumulates in thick airway mucus, it crystallises into visible crystals.

So the crystals are made from your immune cells, not from Aspergillus.

🫁 Why Do They Appear in ABPA?

In ABPA:

  1. The immune system overreacts to Aspergillus fumigatus.

  2. This triggers a strong allergic (Type 2) immune response.

  3. Large numbers of eosinophils move into the airways.

  4. Eosinophils break down and release galectin-10.

  5. The protein crystallises inside mucus plugs.

The crystals are therefore a footprint of intense allergic inflammation, not fungal invasion.

🌡 Is Most ABPA Eosinophilic?

Yes — almost all classical ABPA is eosinophilic.

ABPA is fundamentally a Type 2 allergic condition, driven by immune pathways involving:

  • IL-4

  • IL-5

  • IL-13

  • IgE

  • Eosinophils

IL-5 in particular stimulates eosinophil production and survival.
Because of this, eosinophils are central to the disease process.

Historically, raised blood eosinophils have been part of diagnostic criteria.

However:

  • Eosinophil counts can fluctuate

  • Steroids can suppress blood levels

  • Eosinophils may still be present in airway mucus even if blood counts appear normal

So ABPA is biologically eosinophilic — even if a single blood test does not show a high count.

True non-eosinophilic ABPA would be unusual and would prompt clinicians to reconsider the diagnosis.

❓ Are Crystals Caused by Aspergillus Infection?

No.

They are caused by the immune reaction to Aspergillus — not by the fungus itself.

They can also be seen in:

  • Severe eosinophilic asthma

  • Parasitic infections

  • Other allergic lung conditions

They reflect eosinophil activity, not fungal growth.

🧠 Why Don’t All People with Asthma Develop These Crystals?

Asthma is not one single disease. It has different inflammatory patterns.

Type 2 (Eosinophilic) Asthma

This involves high eosinophils and allergic pathways.

Common in:

  • Allergic asthma

  • ABPA

  • Severe eosinophilic asthma

These patients can develop Charcot–Leyden crystals.

Non–Type 2 (Non-Eosinophilic) Asthma

This includes:

Neutrophilic asthma

Driven by neutrophils rather than eosinophils.

Paucigranulocytic asthma

Very few inflammatory cells present.

In these forms:

  • Eosinophils are low

  • Galectin-10 is not released in large amounts

  • Crystals are unlikely to form

🧱 Do Charcot–Leyden Crystals Make Mucus Plugs Worse?

Possibly.

Research suggests they may:

  • Increase mucus thickness

  • Contribute mechanically to airway blockage

  • Stimulate further inflammation

For many years they were thought to be harmless debris.
Modern studies suggest they may actively amplify inflammation when present in large amounts.

🎯 Do They Have a Purpose?

Eosinophils evolved mainly to help fight parasitic infections.

Galectin-10 probably has immune signalling roles inside cells.

However, when large amounts are released into thick airway mucus, crystallisation appears to be a by-product of excessive immune activity rather than a useful defence.

In ABPA and allergic asthma, they are more likely part of the problem than part of the solution.

💧 Can Their Formation Be Reduced?

Hydration alone does not stop them forming.

Drinking fluids helps:

  • Keep mucus less sticky

  • Support airway clearance

But it does not prevent eosinophils releasing galectin-10.

What reduces crystal formation?

Reducing eosinophilic inflammation:

  • Corticosteroids

  • Anti-IL-5 biologics

  • Anti-IL-4/IL-13 biologics

When eosinophil numbers fall:

→ Less galectin-10 is released
→ Fewer crystals form

Antifungal treatment in ABPA may indirectly help by reducing allergic stimulation, but the main driver is the immune response.

📊 Do They Change Treatment?

Not directly.

Doctors base treatment on:

  • Symptoms

  • Blood eosinophils

  • Total IgE

  • Imaging

  • Lung function

  • Exacerbation history

Crystals support the diagnosis of eosinophilic inflammation but do not determine treatment alone.

🔎 What Do They Tell Us?

Charcot–Leyden crystals tell us:

  • The airway inflammation is eosinophilic.

  • The immune response is strongly allergic.

  • Mucus plugging risk may be higher.

They are a marker of immune overreaction, not infection severity.

🧠 Key Points to Remember

  • They are made from proteins released by eosinophils.

  • They are not Aspergillus.

  • They do not mean invasive fungal infection.

  • Most classical ABPA is eosinophilic.

  • They are unlikely in non-eosinophilic asthma.

  • Reducing eosinophils reduces their formation.

  • Hydration helps clearance but does not prevent formation.

In simple terms:

Charcot–Leyden crystals are microscopic signs that the immune system is working too hard in the airways.

by GAtherton

Event: 📸 Science is Open: A Photo Journey of Research Lab Samples

Have you ever wondered what happens to samples used in research?

The KHP Centre for Translational Medicine is inviting people living with a lung condition to take part in a unique behind-the-scenes experience:

Science is Open: A Photo Journey of Research Lab Samples

This is a rare opportunity to:

  • Go inside a working research laboratory

  • Learn how lung samples are processed and studied

  • Capture the experience through photography

  • Help tell the story of research from a patient perspective

📍 When and Where?

Date: Monday 16th February
Time: Afternoon (exact timing provided after registration)
Location: Central London – Lab tour at Guy's Hospital (London Bridge)

🔬 On the Day You Will:

  • Tour a research lab at Guy’s Hospital

  • Hear directly from researchers about how lung tissue samples are handled and studied

  • Take photographs during the visit (you will be provided with a simple, easy-to-use camera)

  • Receive guidance from a professional photographer

  • Help create a visual story to share with other lung health communities

No previous research or photography experience is needed — just bring yourself.

💷 Reimbursement

  • Travel expenses will be covered

  • Payment for your time: £27.50 per hour (NIHR standard rate)

✉ How to Express Interest

To register your interest, please email Emily and include:

  • A few sentences about your experience with lung health

  • Why you would like to be involved

  • Why you feel your perspective is important

Email Emily to express your interest.

Places are limited and events like this do not come around often.

🌍 Other Opportunities

The team are also running similar events for people living with:

  • Cancer

  • Arthritis

  • Cardiovascular conditions

  • Child and maternal health conditions

If any of these areas are of interest to you, your friends, or family members, please contact Emily for further details.

Event organised by the KHP Centre for Translational Medicine
Shared with thanks to Catherine, Senior Research Impact Officer, Asthma + Lung UK.

by GAtherton

How to Join Our Microsoft Teams Meetings - Troubleshooting

(For patients, carers and external guests)

You do not need a Microsoft account to join.

Most people can join easily using their internet browser.

✅ The Easiest Way to Join (Laptop or Desktop)

  1. Click the meeting link we sent you.

  2. When prompted, choose:
    “Continue in this browser”
    (You do NOT need to download Teams.)

  3. Type your name.

  4. Click Join now.

  5. If asked, allow access to your microphone and camera.

Please wait in the lobby until we admit you.

📱 Joining on a Phone or Tablet

  • Tap the meeting link.

  • If you already have the Microsoft Teams app, it will open automatically.

  • If not, you can download the free Teams app from your app store.

  • Enter your name and join.

Phones often work even if laptops have problems.

⚠️ If You Are Asked to Sign In

You do not need to sign into Microsoft.

If you see a sign-in screen:

  • Look for “Join as guest”

  • Or close the page and reopen the link

  • Or choose “Continue in this browser”

Avoid signing in with a work or NHS account unless you are sure it allows external meetings.

🔧 If It Doesn’t Work on Your Laptop

Try one of these:

  • Open the link in a Private / Incognito window

  • Try a different browser (Chrome or Edge usually work best)

  • Make sure you are not already signed into multiple Microsoft accounts

If you are using a work or NHS laptop, security settings may block external meetings. In that case:

👉 Try your personal laptop or your phone.

🎤 Audio & Camera Tips

  • If your microphone does not work, leave the meeting and rejoin.

  • If you prefer, you can turn your camera off.

  • You can also use the chat box to type questions.

📞 Still Having Trouble?

If you cannot join:

  • Try using your phone instead.

  • Or contact us before the meeting and we will help where we can.

by GAtherton

Health effects: why aspergillosis patients are higher-risk

Home › Knowledge Hub › Damp, mould and aspergillosis › Health effects

This page explains what damp and mould can do to the lungs and how to recognise patterns that suggest your home is contributing to symptoms.

How damp buildings can affect the lungs

Damp homes can increase exposure to airborne particles including fungal spores and fragments. For many people this causes irritation; for people with chronic lung disease it can trigger significant exacerbations.

  • Worsening cough, wheeze, breathlessness
  • Increased mucus and reduced airway clearance
  • More frequent chest infections / antibiotic courses
  • Allergic-type reactions in sensitised individuals

Why aspergillosis and severe airways disease are different

If you have Aspergillus-related disease or severe asthma/bronchiectasis, your airways may react strongly to fungal material and irritants. Some patients also require systemic or inhaled corticosteroids, which can increase susceptibility to infections and complicate symptom control.

Important nuance: a damp home does not automatically “cause” aspergillosis, but it can be a powerful driver of persistent symptoms and repeated flares.

Patterns that support a housing contribution

  • Time-and-place pattern: symptoms worsen at home and improve when away (even partially).
  • Multi-person effects: more than one household member develops respiratory/allergic symptoms.
  • Post-disturbance worsening: symptoms worsen after “repairs” or “remediation”.
  • Escalating medication use: increased reliever inhaler/nebuliser use, repeated steroid bursts, more antibiotics.

Simple symptom timeline template (copy/paste)

Keeping a short, factual timeline helps clinicians and councils understand risk.

Date(s):
Where damp/mould is present:
What changed (rain event, leak, repair work, return after decant):
Symptoms (breathlessness/wheeze/cough/fever/skin/eyes/nose):
Medication change (inhalers, steroids, antibiotics):
Healthcare use (GP/A&E/hospital):
Improves when away from home? (yes/no, how quickly):

What to ask your clinician to document

  • Diagnosis (e.g., Chronic pulmonary aspergillosis, allergic bronchopulmonary aspergillosis, asthma, bronchiectasis)
  • That symptoms are consistent with environmental triggers or worsened by damp/mould exposure (they do not need to prove causation)
  • Any vulnerability factors (steroid use, immunosuppression, reduced lung function)

by GAtherton