Allergic Bronchopulmonary Aspergillosis & Aspergillus Lung Disease

The clinically useful spectrum

The same environmental mould can produce different syndromes, but the spectrum must not be collapsed into one diagnosis. Aspergillus sensitisation means a positive fungus-specific IgE without meeting ABPA criteria. Severe asthma with fungal sensitisation (SAFS) is severe asthma with fungal sensitisation but without ABPA; total IgE below 1000 IU/mL is no longer a valid separator. ABPA is an allergic bronchopulmonary disease caused by Aspergillus spp. ABPM is the analogous disease caused by a non-Aspergillus fungus. Aspergilloma, chronic pulmonary aspergillosis (CPA) and invasive aspergillosis are separate structural, chronic-infective and invasive syndromes.[1][7][8]

[1] [7] [8] [1] [7] [8]

Who develops ABPA?

The revised criteria no longer make asthma or cystic fibrosis obligatory. A patient may have asthma, cystic fibrosis, COPD or bronchiectasis, or may instead have a compatible clinico-radiological presentation such as mucus-plug expectoration, finger-in-glove opacities, fleeting infiltrates or lung collapse. This broadens case-finding without making sensitisation alone diagnostic.[1]

The current screening recommendation is specific: evaluate all newly diagnosed adult asthmatics in tertiary care for A. fumigatus sensitisation, but screen children only when asthma is difficult to treat. The best interval for repeating a previously negative A. fumigatus-specific IgE is unresolved. In cystic fibrosis, older consensus practice screens annual total IgE from age over 6 years and proceeds to Aspergillus sensitisation testing when total IgE is at least 500 IU/mL; routine annual IgG is not the screening test.[1]

Indian studies show a substantial burden of Aspergillus sensitisation and ABPA among people with asthma, but prevalence varies by setting, referral pattern and criteria. Use local laboratory methods and population-specific Aspergillus IgG cut-offs rather than transferring one country's threshold uncritically.[9][1]

Pathophysiology and presentation

Inhaled conidia persist in susceptible airways and supply fungal antigen without tissue invasion. Airway antigen presentation drives a type-2 response: IL-4 and IL-13 promote IgE production, while IL-5 supports eosinophils. Mast-cell and eosinophil mediators cause eosinophilic bronchitis, tenacious mucus, mucus plugging and bronchiectasis. Macrophages and neutrophils are both innate antifungal effectors.[10]

[10] [1]

Suspect ABPA when asthma or chronic airway disease becomes difficult to control and is accompanied by brown or black mucus plugs, fleeting or recurrent opacities, lobar collapse, eosinophilia or markedly raised total IgE. Fever, purulent sputum and haemoptysis require assessment for infection, bronchiectasis exacerbation, CPA or a fungal ball rather than automatic attribution to allergic relapse.[1]

Revised 2024 ISHAM diagnosis

Serum A. fumigatus-specific IgE is preferred to skin testing because its sensitivity is about 99–100% versus 88–94% for the skin test. Therefore, a negative skin-prick test does not exclude ABPA. Total IgE is non-specific, but it is essential for diagnosis and follow-up; A. fumigatus-specific IgE, IgG and eosinophils are not reliable response markers.[1]

Regional IgG caveat: the 2024 guideline gives example A. fumigatus-IgG thresholds of at least 27 mgA/L in India, 60 mgA/L in Japan and 40 mgA/L in the UK. Use a validated population threshold or the manufacturer's recommendation when local data are unavailable.[1]

ABPM: the non-Aspergillus allergic mycosis

Consider ABPM when the presentation resembles ABPA but A. fumigatus-specific IgE is below 0.35 kUA/L. The essentials are elevated IgE to the implicated non-Aspergillus fungus and total IgE at least 500 IU/mL, plus any two of fungus-specific IgG, eosinophils at least 500/microL, repeated culture evidence, or compatible imaging. Culture evidence means the same causative fungus in two sputum cultures or one BAL culture. HAM remains pathognomonic. Absent IgE to recombinant Asp f1, f2 and f4 supports ABPM over ABPA.[1]

Sputum fungal culture has low diagnostic accuracy for ABPA, although it may identify species or resistance before azole therapy; repeated culture is central to ABPM. Bronchoscopy is not routine. Reserve it for uncertain diagnosis, suspected ABPM with unavailable or uninformative sputum, unexplained haemoptysis, or suspected chronic infection before systemic glucocorticoids.[1]

Serum galactomannan is not recommended for diagnosing ABPA. It belongs to the invasive-aspergillosis work-up, where performance depends on host, specimen and assay context.[1][7]

Imaging and radiological class

Thin-section non-contrast CT at diagnosis defines bronchiectasis and mucus. Central bronchiectasis is predominant, but disease may extend peripherally; it is wrong to require exclusively central disease. HAM means mucus visually denser than paraspinal skeletal muscle on mediastinal windows and is pathognomonic; do not infer its chemical cause from attenuation alone.[1]

[1] [1]

Clinical activity, response and remission

The old numbered I–V or ARESF stages are obsolete. The 2024 system uses five unnumbered states: acute ABPA, response, remission, treatment-dependent ABPA and advanced ABPA.[1]

[1]

Asthma exacerbation: respiratory symptoms worsen for at least 48 hours without ABPA immunological or radiological deterioration. Infective bronchiectasis exacerbation: at least 48 hours of worsening cough, breathlessness, sputum amount/consistency or purulence, fatigue, malaise, fever or haemoptysis, again without ABPA immunological or radiological deterioration. Sputum bacterial culture helps when infection is suspected.[1]

Acute treatment: choose one first-line systemic option

Asymptomatic ABPA is generally not treated systemically. Individualise when CT already shows bronchiectasis or persistent mucus plugging or lung function worsens; if observing, optimise asthma and review symptoms, chest radiograph and total IgE every 3–6 months. Treat ABPA-S systemically only for poor asthma control or recurrent exacerbations despite appropriate asthma therapy.[1]

For symptomatic acute ABPA, the revised guideline recommends oral prednisolone monotherapy or oral itraconazole monotherapy. Itraconazole is especially useful when glucocorticoids are contraindicated. Routine prednisolone–itraconazole combination therapy is not first-line: the large trial did not reduce overall exacerbations and produced more adverse events. A glucocorticoid course shorter than 2 weeks may bridge a patient starting itraconazole.[1][3][4]

[1] [4]

Prednisolone regimen and safety

Use prednisolone 0.5 mg/kg/day orally for 2–4 weeks, then taper to complete about 4 months. One evidence-based low-dose schedule is 0.5 mg/kg/day for 2 weeks, then the same dose on alternate days for 8 weeks, followed by a 5 mg reduction every 2 weeks to stop over 3–5 months. An alternative is 0.5, 0.25 and 0.125 mg/kg/day for 4 weeks each, then reduce by 5 mg every 2 weeks. Lower-dose therapy causes fewer adverse events than prolonged high-dose therapy.[1][2]

Monitor glucose, blood pressure, weight, infection, psychiatric symptoms, ocular and bone risk, and adrenal suppression. Bone and gastric protection are individualised. Itraconazole raises methylprednisolone exposure more than prednisolone exposure; combining itraconazole with inhaled budesonide or fluticasone can cause iatrogenic Cushing syndrome and adrenal suppression.[1]

Itraconazole regimen, TDM and interactions

Use conventional itraconazole capsules 400 mg/day orally in two divided doses for 4 months (maximum 600 mg/day) with meals. Super-bioavailable itraconazole is 260 mg/day in two divided doses for 4 months (maximum 390 mg/day) on an empty stomach; PPIs and antacids do not materially reduce that formulation's exposure.[1]

Perform therapeutic drug monitoring at about 2 weeks and 3 months, and during clinical deterioration; target trough at least 0.5 mg/L. Monitor liver tests. Conventional capsules need gastric acidity, while rifampicin can make levels undetectable. Itraconazole is a potent interaction perpetrator and has a boxed heart-failure warning/negative inotropic effect: review the complete medication list, including inhaled steroids, calcineurin inhibitors, vincristine, selected statins, sedatives and QT-active drugs.[1]

Salvage azoles

Voriconazole is not preferred first-line acute ABPA. If glucocorticoids are contraindicated and itraconazole is not tolerated, fails or encounters resistance, use voriconazole 400 mg/day in two divided doses (maximum 600 mg/day) on an empty stomach with TDM; target trough at least 1 mg/L. Monitor hepatotoxicity, visual and neuropsychiatric effects, photosensitivity and skin cancer risk, QT prolongation and interactions.[1]

Posaconazole and isavuconazole are salvage options, not routine first-line acute therapy. Posaconazole delayed-release tablets are 300 mg once daily after loading per product regimen; the older oral suspension is 800 mg/day divided and food-dependent. If exposure is being optimised, the guideline uses a target trough of at least 1 mg/L for posaconazole and isavuconazole. Isavuconazole shortens QT and is contraindicated in familial short-QT syndrome. Use specialist dosing, interaction review and product-specific loading where relevant; do not transfer invasive-disease loading regimens into ABPA teaching.[1]

Recurrent and treatment-dependent disease

Treat an ordinary ABPA exacerbation like newly diagnosed disease with prednisolone or itraconazole. Use prednisolone plus itraconazole for recurrent exacerbations — at least two in the preceding 1–2 years, especially with extensive bronchiectasis. This is the correct place for combination therapy.[1][4]

For treatment-dependent ABPA, options are long-term itraconazole, maintenance nebulised amphotericin B or a biologic; continuous low-dose oral glucocorticoids are last-line. Nebulised amphotericin is maintenance, not acute therapy: deoxycholate 10 mg twice daily 3–6 times weekly or liposomal amphotericin 25–50 mg once or twice weekly may be used, with bronchospasm precautions.[1]

Omalizumab has the largest biologic evidence base and can reduce exacerbations and oral steroid exposure in stable treatment-dependent ABPA, but ABPA use is off-label and it is not first-line for acute disease. Dose by weight and baseline IgE, not exceeding 375 mg subcutaneously twice monthly in the guideline table; observe anaphylaxis precautions. Mepolizumab 100 mg monthly, benralizumab 30 mg every 4 weeks for three doses then every 8 weeks, dupilumab 600 mg loading then 300 mg every 2 weeks, and tezepelumab 210 mg every 4 weeks have lower-level case-series evidence.[1][5]

The 2021 Cochrane CF review did not establish anti-IgE efficacy or safety: it found one prematurely terminated 14-participant trial with incomplete efficacy data and an adverse-event imbalance. Do not cite it as proof that omalizumab is particularly effective in CF-ABPA.[6]

Monitoring

Assess initial response after 8–12 weeks with symptoms, total IgE and chest radiograph. The formal response state at 8 weeks requires symptom improvement at least 50% plus either radiological-opacity improvement over 50% or total IgE decline at least 20%. Do not use A. fumigatus-specific IgE, IgG or eosinophils as response markers.[1]

During remission, review symptoms, total IgE and lung function every 3–6 months in the first year and then every 6–12 months. A total IgE rise of at least 50% from the last stable value is meaningful only when paired with sustained clinical or radiological worsening and after competing causes are excluded.[1]

Special populations and regional practice

Boundaries with other Aspergillus lung disease

Simple aspergilloma and CPA

A simple aspergilloma is a single mobile fungal ball in a stable pre-existing cavity with limited surrounding disease. The air around a mobile intracavitary ball is often called the Monod sign; do not confuse it with the air-crescent sign of recovering invasive aspergillosis. Observe an asymptomatic stable lesion. If a fit patient has significant symptoms or haemoptysis from a single lesion, surgical resection is definitive.[7]

CPA requires at least 3 months of symptoms or radiological progression, characteristic cavitation/pleural thickening or fungal ball, microbiological or serological Aspergillus evidence, and exclusion of alternatives. It commonly complicates structural lung disease or subtle immunocompromise. CPA often requires long-term antifungal therapy; therefore, the statement that azoles have no role because a cavity is avascular is unsafe. Exclude CPA when ABPA-CPF contains a fungal ball or fibro-cavitary change.[8][1]

Major haemoptysis is defined by physiological threat, not one volume threshold. Place the bleeding side down, activate experienced airway, interventional-radiology and thoracic teams, and use a large-bore single-lumen tube with bronchoscopic positioning or a bronchial blocker when lung isolation is needed. Bronchial-artery embolisation controls acute bleeding but recurrence is common unless the underlying lesion is definitively managed.[7][8]

Invasive pulmonary aspergillosis

In a high-risk host with suspected or probable invasive disease, start mould-active therapy early while CT, culture, bronchoscopy and galactomannan/PCR work-up proceeds. Voriconazole is a primary option: in adults, IV loading is 6 mg/kg every 12 hours for two doses, then 4 mg/kg every 12 hours; oral dosing for at least 40 kg is 200 mg every 12 hours and may be increased with specialist TDM. Isavuconazonium is an alternative: 372 mg (equivalent to 200 mg isavuconazole) every 8 hours for six doses, then 372 mg once daily; liposomal amphotericin B is another alternative. Echinocandin monotherapy is not routine primary treatment. Treat for at least 6–12 weeks, individualised to site, response and immunosuppression.[7]

Exam traps

[1]

Why does a 60% IgE rise not automatically prove ABPA exacerbation?

The rise must be from the last stable total-IgE value and must accompany either sustained clinical worsening for over 14 days or radiological worsening. Asthma exacerbation, infective bronchiectasis exacerbation and other causes must be excluded. A laboratory rise alone is not the clinical state.[1]

Why is high-attenuation mucus special?

HAM is mucus visually denser than paraspinal skeletal muscle on non-contrast CT mediastinal windows. It is pathognomonic for ABPA/ABPM and may confirm the diagnosis even if other components are missing. It is a diagnostic and prognostic feature, not an automatic mandate for steroid–azole combination therapy.[1]

References

1. [1]Agarwal R, Sehgal IS, Muthu V, Denning DW, Chakrabarti A, et al. Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses Eur Respir J, 2024.PMID 38423624
2. [2]Agarwal R, Aggarwal AN, Dhooria S, Singh Sehgal I, Garg M, Saikia B, Behera D, Chakrabarti A. A randomised trial of glucocorticoids in acute-stage allergic bronchopulmonary aspergillosis complicating asthma Eur Respir J, 2016.PMID 26585431
3. [3]Agarwal R, Dhooria S, Singh Sehgal I, Aggarwal AN, Garg M, Saikia B, Behera D, Chakrabarti A. A Randomized Trial of Itraconazole vs Prednisolone in Acute-Stage Allergic Bronchopulmonary Aspergillosis Complicating Asthma Chest, 2018.PMID 29331473
4. [4]Agarwal R, Muthu V, Sehgal IS, Dhooria S, Prasad KT, Garg M, Aggarwal AN, Chakrabarti A. A randomised trial of prednisolone versus prednisolone and itraconazole in acute-stage allergic bronchopulmonary aspergillosis complicating asthma Eur Respir J, 2022.PMID 34503983
5. [5]Jin M, Douglass JA, Elborn JS, Agarwal R, Calhoun WJ, Lazarewicz S, Jaumont X, Yan M. Omalizumab in Allergic Bronchopulmonary Aspergillosis: A Systematic Review and Meta-Analysis J Allergy Clin Immunol Pract, 2023.PMID 36581073
6. [6]Jat KR, Walia DK, Khairwa A. Anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis Cochrane Database Syst Rev, 2021.PMID 34550603
7. [7]Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, Bennett JE. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America Clin Infect Dis, 2016.PMID 27365388
8. [8]Denning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, Ullmann AJ, Dimopoulos G, Lange C. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management Eur Respir J, 2016.PMID 26699723
9. [9]Agarwal R, Muthu V, Sehgal IS, Dhooria S, Prasad KT, Soundappan K, Rudramurthy SM, Aggarwal AN, Chakrabarti A. Prevalence of Aspergillus sensitization and Allergic Bronchopulmonary Aspergillosis in bronchial asthma: A systematic review of Indian studies Lung India, 2023.PMID 37961961
10. [10]Agarwal R, Muthu V, Sehgal IS, Dhooria S, Prasad KT, Aggarwal AN. Allergic Bronchopulmonary Aspergillosis Clin Chest Med, 2022.PMID 35236565