What is the treatment for Allergic Bronchopulmonary Aspergillosis (ABPA)?

Clinical Features, Diagnosis, and Treatment of ABPA

Clinical Features

ABPA presents as poorly controlled asthma with characteristic expectoration of brownish mucus plugs, chronic cough, wheezing, and dyspnea. 1

Key clinical manifestations include:

• Uncontrolled asthma despite inhaled corticosteroids and long-acting β2 agonists 2
• Expectoration of brownish mucus plugs (pathognomonic when present) 1
• Chronic cough and wheezing 1
• Progressive dyspnea 1
• Recurrent pulmonary infiltrates 1

Diagnostic Criteria

Diagnosis requires a combination of elevated serum total IgE (>1000 IU/mL or >500 IU/mL with other criteria), elevated Aspergillus fumigatus-specific IgE, and characteristic CT findings. 3

Essential Diagnostic Components:

Immunological markers:

• Serum total IgE >1000 IU/mL is the cornerstone marker 3
• If IgE is 500-1000 IU/mL, additional supportive criteria are required 3
• Aspergillus fumigatus-specific IgE elevation using FEIA platform or equivalent automated assays is essential 3

Radiological evaluation:

• High-resolution CT chest is mandatory and superior to chest radiography 3
• Common findings include fleeting pulmonary infiltrates, bronchiectasis, and mucus impaction 1

Radiological Classification

ABPA is classified into five distinct radiological categories: 4, 3

• ABPA-S (Serological): No bronchiectasis on CT 4
• ABPA-B (Bronchiectasis): Presence of bronchiectasis 4
• ABPA-MP (Mucus Plugging): Bronchiectasis with mucus plugs 4
• ABPA-HAM (High-Attenuation Mucus): High-attenuation mucus plugs (>70 HU on mediastinal windows) - pathognomonic and predicts severe disease 4, 3
• ABPA-CPF (Chronic Pleuropulmonary Fibrosis): Two or more of: pulmonary fibrosis, fibro-cavitary lesions, fungal ball, pleural thickening 4

Treatment of Acute ABPA

For newly diagnosed acute ABPA, initiate oral prednisolone 0.5 mg/kg/day for 2-4 weeks, then taper over 4 months OR oral itraconazole for 4 months. 4, 3

First-Line Treatment Options:

Glucocorticoid regimen (preferred for rapid control):

• Prednisolone 0.5 mg/kg/day for 2-4 weeks 4, 3
• Taper by 5 mg every 2 weeks until discontinuation at 4 months 4, 3
• Monitor plasma glucose, blood pressure, body weight, and mental status during therapy 3
• This regimen is FDA-approved for allergic bronchopulmonary aspergillosis 5

Itraconazole alternative:

• Use as initial therapy where systemic glucocorticoids are contraindicated 4
• Duration: 4 months 4
• Requires therapeutic drug monitoring 6

Critical caveat: Do NOT use combination itraconazole and glucocorticoids as first-line therapy 4. However, a short course of glucocorticoids (<2 weeks) may be used initially along with oral itraconazole 4.

Warning: Methylprednisolone combined with oral itraconazole carries higher risk of exogenous Cushing's syndrome and adrenal insufficiency 4. Similarly, inhaled budesonide or fluticasone combined with itraconazole can cause exogenous Cushing's syndrome 4.

Treatment Response Assessment (8-12 weeks):

Assess response using three parameters: 3

• Clinical symptoms improvement ≥50% (using Likert scale or visual analog scale) 3
• Serum total IgE reduction ≥35% from baseline (not absolute value) 3
• Chest radiograph improvement 3

Special Populations:

ABPA-S (Serological only):

• Do NOT routinely treat with systemic therapy if asymptomatic 4
• Treat only if poor asthma control or recurrent exacerbations despite optimal asthma management 4
• Manage like asthma with ICS and bronchodilators 4

Asymptomatic ABPA:

• Do NOT treat with systemic therapy 4

Ineffective Therapies:

Do NOT use the following as primary therapy for acute ABPA:

• High-dose ICS alone 4
• Nebulized amphotericin B 4
• Biological agents as first-line 4
• Voriconazole, posaconazole, or isavuconazole as first-line 4

Treatment of ABPA Exacerbations

ABPA exacerbations are characterized by sustained worsening (≥2 weeks) of clinical symptoms or new infiltrates on chest imaging, with serum total IgE increase ≥50% above the "new baseline" IgE during clinical stability. 4

Treat acute ABPA exacerbations the same as newly diagnosed ABPA using either prednisolone or itraconazole 4.

For recurrent exacerbations (≥2 in the last 1-2 years), especially with extensive bronchiectasis, use combination oral prednisolone and oral itraconazole. 4

Differential diagnosis of worsening symptoms:

• ABPA exacerbation: New infiltrates + IgE increase ≥50% 4
• Asthma exacerbation: No IgE increase, no new infiltrates - treat with short-course oral glucocorticoids 4
• Bronchiectasis (infective) exacerbation: No IgE increase ≥50%, positive sputum cultures - treat with antibiotics 4

Treatment-Dependent ABPA

Treatment-dependent ABPA (10-25% of patients) requires ongoing therapy to maintain disease control despite initial treatment. 7

For treatment-dependent ABPA, use long-term itraconazole, nebulized amphotericin B, or biological agents - with dupilumab (anti-IL-4Rα) emerging as the preferred biologic. 4, 3, 7

Biological Agent Selection:

Dupilumab (anti-IL-4Rα):

• Preferred biologic based on current evidence 3, 7
• Targets type 2 immune response 4

Omalizumab (anti-IgE):

• Most extensively studied biologic in ABPA 4, 7, 6
• Rational choice given ABPA's hallmark elevated IgE levels 7, 6
• Proven safe even with very high IgE levels 7
• Reduces exacerbations, asthma hospitalizations, improves lung function, and reduces oral steroid doses 4, 6
• One crossover RCT (13 patients) showed less frequent exacerbations and decreased basophil reactivity to A. fumigatus 4
• Effective and safe regardless of comorbid chronic respiratory tract infections (P. aeruginosa, nontuberculous mycobacteria) 8

Other biologics:

• Mepolizumab (anti-IL-5): Improves FEV1, radiological findings, and quality of life; not restricted by total IgE level like omalizumab 4, 9
• Benralizumab (anti-IL-5R) 4
• Tezepelumab (anti-TSLP) 4

Continuous low-dose glucocorticoids should be the last option in managing treatment-dependent ABPA. 4

Management During Remission

During remission, manage underlying asthma and bronchiectasis per standard guidelines with ICS, long-acting bronchodilators, nebulized saline, and antibiotics as needed. 4, 3

Monitoring schedule:

• Every 3-6 months for the first year with clinical review, serum total IgE levels, and lung function tests 4, 3
• Every 6-12 months thereafter 4, 3

Remission can be prolonged by using long-term itraconazole, nebulized amphotericin B, or biological agents, especially in those with treatment-dependent ABPA. 4

Nebulized amphotericin B for maintenance:

• Nebulized liposomal amphotericin B (25 mg weekly) significantly prolongs time-to-first exacerbation 4
• Nebulized amphotericin B deoxycholate (10 mg twice daily, three times a week) reduces ABPA exacerbations at 1 year 4

Management of Advanced ABPA with Extensive Bronchiectasis

For extensive bronchiectasis, use nebulized hypertonic saline (3-7%, 4-5 mL) to reduce sputum viscosity and ease expectoration of mucus plugs. 4

Important precautions:

• Precede with nebulized salbutamol to minimize bronchospasm risk 4
• Administer first dose under supervision 4

For frequent infective exacerbations:

• Nebulized antibiotics and long-term azithromycin therapy improve outcomes 4
• Caution: Azithromycin with itraconazole can cause QTc prolongation 4

For chronic type 2 respiratory failure:

• Long-term oxygen therapy (LTOT) for resting hypoxemia (PaO2 ≤55 mmHg) reduces pulmonary hypertension and improves survival 4
• No role for LTOT in mild hypoxemia (PaO2 >55 mmHg at rest) or nocturnal oxygen desaturation 4

Vaccination:

• Administer influenza and pneumococcal vaccines before initiating glucocorticoid therapy 4
• ABPA patients respond poorly to 23-valent pneumococcal polysaccharide vaccine compared to healthy adults 4