Genes and aspergillosis: why the same fungus causes different problems in different people

Why look at genes when talking about aspergillosis?

The theme of World Aspergillus Day 2026 was “How can the genomics revolution help patients with chronic aspergillosis?”
To answer that, we need to look briefly at genes and what they tell us about how the body resists infection.

Genes are the body’s instruction manual. They help control how our immune system works, how inflammation is managed, and how well we clear infections. Humans have around 25,000 genes, with two copies of each in almost every cell — and billions of cells using these instructions every day.

Small, natural differences in genes help explain why people respond differently to Aspergillus: some develop allergy, others chronic infection, and many clear it without any illness at all. Genes don’t determine outcomes, but they help us understand why the immune response differs between people.

Many people ask an understandable question:

“If we all breathe in Aspergillus spores, why do only some people get aspergillosis – and why does it look so different from person to person?”

Part of the answer lies in genes.

Genes do not cause aspergillosis on their own, but they can influence how the immune system responds once the fungus is encountered.

A simple way to think about genes

Genes act like settings, not switches.

They can influence:

  • how strongly your immune system reacts

  • whether that reaction is allergic, chronic, or weak

  • how well fungi are cleared from the lungs

Genes do not override:

  • lung damage (asthma, bronchiectasis, old infections)

  • steroid or immunosuppressive treatment

  • mould exposure levels

They help explain patterns of illness, not certainty.

Risk stacking: why combinations matter more than any single factor

Aspergillosis rarely develops because of one single cause. Instead, it usually arises through risk stacking, where several small risk factors overlap at the same time.

Each factor may add only a little vulnerability on its own, but together they can tip the balance from resistance to disease.

This helps explain why aspergillosis often appears after years of stability, or during periods of change such as illness, medication adjustment, or increased environmental exposure.

What does risk stacking look like in practice?

A person might have:

  • mild genetic tendencies toward allergic inflammation or reduced fungal clearance

  • asthma, bronchiectasis, or old lung damage

  • long-term inhaled or oral corticosteroid treatment

  • periods of higher mould exposure (for example, damp housing or renovation work)

None of these alone guarantees illness.

But stacked together, they increase the chance that Aspergillus:

  • is recognised as an allergen rather than ignored

  • is not cleared efficiently from the lungs

  • triggers ongoing inflammation or chronic infection

Where genes fit into risk stacking

Genes usually act as background modifiers, not primary causes.

In people with healthy lungs and normal immunity, genetic differences rarely matter.

In people who already have lung disease, immune suppression, or repeated exposure, those same genetic differences can add to the overall risk stack.

This also explains why there is no single genetic test that can predict aspergillosis — risk depends on combinations, not on one gene.

Just as risks can add up, risk reduction also adds up. Improvements in airway clearance, asthma control, steroid management, and home environment can all meaningfully reduce overall risk.

Why this matters in aspergillosis

Aspergillosis is not one condition. It includes:

  • fungal sensitisation and allergy

  • chronic pulmonary infection

  • invasive disease in people with weakened immunity

Different genes influence different stages of the immune response, which helps explain why people experience very different forms of disease.

1. Genes linked to fungal allergy and sensitisation

These genes affect whether the immune system treats Aspergillus as a strong allergen.

IL-4, IL-13 and the IL-4 receptor

What they do
Control allergic inflammation, including:

  • immunoglobulin E (IgE)

  • eosinophils

  • mucus production

  • airway inflammation

What this means
Certain natural gene variants increase the likelihood of:

  • fungal sensitisation

  • asthma with fungal sensitisation

  • allergic bronchopulmonary aspergillosis (ABPA)

This fits closely with what patients experience clinically: high IgE, eosinophilia, steroid responsiveness, and response to biologic treatments.

HLA-DR and HLA-DQ

What they do
Help the immune system decide which proteins deserve attention.

What this means
Some HLA types present Aspergillus proteins in a way that:

  • encourages persistent allergic inflammation

  • increases the chance of ABPA

This helps explain why only a minority of people with asthma develop ABPA.

ITGB3 (integrin beta-3)

What it does
Helps airway and immune cells:

  • attach to surrounding tissue

  • communicate danger signals

  • interact with fungal-recognition pathways

What this means
Certain versions are linked to:

  • mould sensitisation

  • stronger immune signalling when fungal particles are present

This does not mean ITGB3 causes aspergillosis.
It helps explain why some people become sensitised more easily.

TLR2

What it does
Recognises fungal cell-wall components and triggers early immune responses.

What this means
Different versions can amplify or dampen inflammation, influencing sensitivity to fungi.

2. Genes linked to chronic pulmonary aspergillosis (CPA)

These genes influence how well fungi are cleared, especially in damaged lungs.

MBL2 (mannose-binding lectin)

What it does
Marks fungi so the immune system can remove them.

What this means
Low MBL activity may allow Aspergillus to persist once lung cavities or scarring exist.

Dectin-1 (CLEC7A)

What it does
Detects fungal cell-wall sugars and triggers antifungal responses.

What this means
Reduced detection can allow slow, long-term infection rather than allergy.

TLR4

What it does
Regulates inflammation in response to microbes.

What this means
Certain variants may influence how chronic inflammation and tissue damage evolve.

3. Genes linked to invasive aspergillosis

These matter most in people with weakened immune systems (for example, during chemotherapy or after transplant).

PTX3 (pentraxin-3)

What it does
Acts as an early fungal sensor and helps immune cells kill Aspergillus.

What this means
Reduced PTX3 activity is one of the strongest known genetic risk factors for invasive aspergillosis in high-risk medical settings.

TLR3 and interferon pathways (including CXCL10)

What they do
Coordinate immune communication and antifungal killing.

What this means
Impairment can delay fungal control and increase the risk of spread.

How do scientists know these genes are involved?

Researchers study natural genetic variations that:

  • are common in healthy people

  • are present from birth

  • usually cause small functional differences, not disease by themselves

They:

  • compare people with aspergillosis to similar people without it

  • identify gene variants linked to specific disease patterns

  • test how those genes affect fungal recognition, inflammation, or killing

  • confirm findings in laboratory and clinical studies

These are risk modifiers, not disease-causing genes.

Does this mean my family is at risk?

This is a very common concern. The reassuring answer for most people is:

No – aspergillosis does not usually run in families.

Why this is reassuring

  • These gene variants are common in the general population

  • Most people who carry them never develop aspergillosis

  • Aspergillosis requires other factors, such as lung disease, immune suppression, or heavy exposure

  • There is no consistent pattern of aspergillosis being passed from parent to child

Even strong genetic signals (such as PTX3) only increase risk in specific high-risk medical situations, not in healthy relatives.

Putting it all together

Pattern of disease Genes most often involved
Fungal sensitisation IL-4, IL-13, IL-4 receptor, ITGB3, TLR2
ABPA IL-4/IL-13 pathway, HLA-DR/DQ, TLR3
Chronic pulmonary aspergillosis MBL2, Dectin-1, TLR4
Invasive aspergillosis PTX3, interferon pathways

What this means for patients and families

  • Genetic testing is not routinely needed

  • These genes do not predict individual outcomes

  • Family members are not usually at increased risk

The most important factors remain:

  • good lung care

  • appropriate treatment

  • sensible mould exposure reduction

Genes influence risk — they do not determine destiny.

by GAtherton

⭐ Chronic Pulmonary Aspergillosis: Why Diagnosis Is Missed and Who Needs to Be More Aware

With estimated prevalence of 3–4 cases per 100,000 population, and far higher rates in high-risk groups.

Chronic Pulmonary Aspergillosis (CPA) is a slowly progressive fungal lung disease affecting an estimated 3–4 per 100,000 people in the UK, with higher estimates in global settings with greater TB prevalence. Despite this, many clinicians will go through entire careers without confidently recognising it — not because it is extremely rare, but because it almost always hides inside other long-term lung diseases.

The UK is unusual in having a nationally commissioned specialist service — the National Aspergillosis Centre (NAC), based at Wythenshawe Hospital, Manchester — offering funded diagnostics, multidisciplinary review, and long-term antifungal management. But only a fraction of expected CPA cases are ever referred. Most are simply never diagnosed.

This article explains why diagnoses are missed, who is at highest risk, which specialities need to be more alert, and the red flags that should trigger testing or referral.

⭐ How Common Is CPA? The Numbers Behind the Problem

The UK prevalence is estimated at 3–4 per 100,000 people — approximately 2,000–2,500 people with CPA at any given time.

But the risk is far higher in specific groups:

Risk Group Estimated CPA prevalence
Post-TB lung disease 6–10% in those with residual cavities
Severe COPD (GOLD III–IV) 1–3%
Bronchiectasis 1–3%
NTM disease 3–10%
Sarcoidosis with fibrosis 1–2%
Immunosuppression (steroids/biologics) Unknown, but rising

Using these figures, the true UK caseload could exceed 4,000–6,000 individuals, yet NAC receives ~500–1,000 referrals, highlighting a large diagnostic gap.

⭐ Why CPA Is So Often Missed

1. Symptoms mimic common chronic lung diseases

CPA presents with:

  • Persistent cough

  • Breathlessness

  • Fatigue

  • Weight loss

  • Recurrent “chest infections”

  • Haemoptysis

These overlap almost perfectly with:

  • COPD

  • bronchiectasis

  • post-TB changes

  • long COVID

  • NTM infection

  • repeatedly “slow to clear” pneumonia

Because symptoms are non-specific, clinicians rarely think fungal.

2. Interpretation of imaging is inconsistent

CPA shows:

  • one or more cavities

  • pleural thickening

  • nodules

  • progressive changes over months

  • fungal balls

Common reporting pitfalls:

  • labelled “post-infective scarring”

  • misinterpreted as malignancy

  • seen but not compared longitudinally

  • incidental CT findings not acted upon

Radiology is one of the biggest missed opportunities for early detection.

3. IgG testing is not routinely requested

Aspergillus IgG is the key diagnostic biomarker — but it is:

  • often confused with IgE

  • not available in some hospitals

  • omitted from workups for recurrent infection

  • unfamiliar to non-respiratory clinicians

Without IgG, CPA is rarely diagnosed.

4. Short-term improvement with antibiotics is misleading

Patients with CPA may temporarily feel better after:

  • broad-spectrum antibiotics

  • steroids

  • physiotherapy

This transient improvement creates false reassurance.

5. CPA spans multiple specialisms — and no one owns it

Diagnosis requires combined expertise across:

  • respiratory medicine

  • infectious diseases

  • radiology

  • microbiology

  • immunology

When no one speciality takes responsibility, patients get lost.

⭐ Which Patients Are at High Risk?

CPA almost always develops on a background of existing lung damage.

1. Post-TB lung disease (PTLD)

Globally the largest CPA population.
Residual cavities are the strongest predictor.

Specialities needing awareness:

  • TB teams

  • ID physicians

  • Radiologists

  • Community TB nurses

  • Public health TB programmes

2. COPD (especially severe / emphysema)

Millions of people are potentially at risk.
Recurrent infections + bullae/cavities = fertile ground for CPA.

Specialities:

  • COPD clinics

  • Pulmonary rehab

  • Acute medicine (frequent admissions)

3. Bronchiectasis

Damaged airways enable persistent Aspergillus colonisation and inflammation.

Specialities:

  • Bronchiectasis MDTs

  • Severe asthma & NTM clinics

  • Respiratory physiotherapy

4. Sarcoidosis and ILD

Fibrosis and traction bronchiectasis develop cavities over time.

5. Post-COVID or post-influenza structural disease

Emerging risk group, especially in patients with:

  • ventilatory lung injury

  • persistent CT abnormalities

  • chronic steroid exposure

6. Chronic steroid or immunomodulator use

While invasive aspergillosis is linked to profound immunosuppression, CPA often affects those with milder, chronic immune dysfunction:

  • systemic steroids

  • high-dose inhaled steroids

  • biologics affecting eosinophils

  • poorly controlled diabetes

  • chronic kidney disease

  • malnutrition

⭐ Which Specialities Need to Be More Alert?

  • Respiratory Medicine – primary detection, but awareness varies greatly

  • Infectious Diseases – especially post-TB and persistent infection clinics

  • Radiology – key to spotting early changes

  • Primary Care – sees patients repeatedly with “ongoing chest infections”

  • Emergency & acute medicine – haemoptysis presentations

  • Bronchiectasis and NTM services – strong overlap

  • Severe asthma and biologics teams – ABPA → CPA evolution

  • TB clinics – highest prevalence globally, often least recognised

The National Aspergillosis Centre should be the referral point for any complex or uncertain case.

⭐ Red Flags: When to Suspect CPA

1. Cavities on CT (thin-, thick-walled, evolving, or multiple)

Especially with pleural thickening.

2. Haemoptysis

CPA is one of the most common causes of haemoptysis in people with cavities.

3. Symptoms lasting >3 months

Chronic cough, fatigue, weight loss, breathlessness.

4. “Recurrent infections” that never fully resolve

5. Post-TB patient with any new or worsening symptoms

6. Bronchiectasis patient with new cavity or Aspergillus culture

7. High or rising Aspergillus IgG

8. ABPA patient who deteriorates off antifungals

⭐ The Cost of Missed Diagnoses

When CPA is not recognised early, the consequences are severe:

  • irreversible lung damage

  • repeated hospitalisations

  • emergency haemoptysis events

  • prolonged antifungal therapy with more toxicity

  • reduced quality of life

  • avoidable deaths

For systems like the NHS, late diagnosis increases costs:

  • unplanned admissions

  • repeated CT imaging

  • prolonged antibiotics

  • intensive care during haemoptysis

  • complex surgery (lobectomy/pneumonectomy)

Early referral to specialist centres like the National Aspergillosis Centre prevents many of these harms.

⭐ Conclusion

CPA is not rare within the populations most likely to develop it.
Missed diagnoses are common, predictable, and preventable.

By increasing awareness across Respiratory, Infectious Diseases, Radiology, Primary Care, TB services, and severe asthma pathways — and by using simple tools such as Aspergillus IgG and careful CT interpretation — clinicians can dramatically reduce the diagnostic delay that damages lungs, quality of life, and survival.

The UK is fortunate to have the National Aspergillosis Centre as a nationally commissioned referral service. Recognising CPA early and referring appropriately has the power to save lives, reduce system costs, and improve long-term outcomes.

by GAtherton