1. Allergic Bronchopulmonary Aspergillosis: Management
Ritesh Agarwal, MD, DM
Professor of Pulmonary Medicine
Postgraduate Institute of Medical Education and Research
Chandigarh, India

2. Intended aims of this module
To be aware of the different stages of allergic bronchopulmonary aspergillosis (ABPA)
To be familiar with the management goals and treatment approaches for patients with ABPA
To gain an understanding of the roles of glucocorticoids, antifungals and other adjunctive management options in ABPA

3. Introduction
ABPA occurs in persons with asthma and those with cystic fibrosis
ABPA may occur in conjunction with allergic fungal sinusitis (symptoms including chronic sinusitis with purulent sinus drainage)
Patients often manifest with uncontrolled asthma, expectoration of mucus plugs, and haemoptysis
Recurrent pulmonary infiltrates ( fever) unresponsive to antibacterial therapy suggests ABPA in patients with asthma and cystic fibrosis
Patients with asthma and ABPA may have poorly controlled disease and difficulty tapering off oral corticosteroids
Agarwal et al. Clin Exp Allergy. 2013; 43:
Agarwal et al. Expert Rev Respir Med. 2016;10:

4. Diagnostic criteria for ABPA
Predisposing conditions
Bronchial asthma, cystic fibrosis
Obligatory criteria (both should be present)
Elevated A. fumigatus-specific IgE (>0.35 kUA/L)
Elevated total IgE levels (>1000 IU/mL)
Other criteria (at least two of three)
Elevated A. fumigatus-specific IgG (>27 mgA/L)
Radiographic pulmonary opacities consistent with ABPA
Eosinophil count >500 cells/µL (may be historical)
Agarwal et al. Clin Exp Allergy. 2013; 43:
Agarwal et al. Expert Rev Respir Med. 2016;10:

5. Stages of ABPA Stage Definition Features 1 Acute
Never diagnosed to have ABPA in the past; presentation with uncontrolled asthma/constitutional symptoms, and meeting the diagnostic criteria of ABPA 2
Response
Clinical and/or radiological improvement AND fall in IgE by ≥25% of baseline at eight weeks 3
Exacerbation
Clinical and/or radiological worsening accompanied by an increase in IgE by ≥50% from the ‘new’ baseline 4
Remission
Sustained clinicoradiological improvement with IgE levels remaining at or below the ‘new’ baseline (or increase by <50%) for ≥6 months off therapy 5a
Treatment-dependent ABPA
Two or more relapses within six months of stopping treatment OR deterioration in clinical and/or radiological condition and/or immunological worsening on tapering oral steroids/azoles 5b
Glucocorticoid-dependent asthma
Systemic corticosteroids required for asthma control while the ABPA activity is controlled (as indicated by IgE levels and thoracic imaging) 6
Advanced ABPA
Presence of complications (cor pulmonale and/or chronic type II respiratory failure) along with presence of extensive bronchiectasis
Agarwal et al. Clin Exp Allergy. 2013; 43:

6. Management goals
To optimise control of cystic fibrosis and exacerbation of asthma
To avoid steroid dependency
To improve airflow through reduction of mucus and obstruction
To control bacterial infection (often associated with bronchiectasis)
To control severity and exacerbation frequency of ABPA
To avoid treatment (steroids and/or antifungal) related adverse events
To control emergence of antifungal resistance
Moss et al. Eur Respir J. 2014; 43:
Denning et al. Clin Transl Allergy. 2014; 4:14.
Agarwal et al. Clin Exp Allergy. 2013; 43:

7. Management approaches
Control of the immune response
Control of airway fungal burden
Airway hypersensitivity syndrome; IgE mediated
Approach
Immunosuppression with oral steroids
Reduced inflammation
Anti-IgE therapy
? More fungus, more airway immune response
Approach
Antifungal therapy to decrease airway fungal burden
Avoiding environmental exposures to fungal organisms
Patterson et al. Clin Infect Dis. 2016; 63: e1-e60
Moss et al. Eur Respir J. 2014; 43:

8. Management: Glucocorticoids
Oral glucocorticoids reduce the inflammatory response in acute stage (stage 1) and exacerbations (stage 3) of ABPA
Mainstay of ABPA management
Inhaled steroids are not effective (can control asthma in some patients).
Many short and long-term adverse events
Relapse is frequent after discontinuation
Greenberger et al. J Allergy Clin Immunol Pract. 2014;2:
Agarwal et al. Chest. 2009;135:

9. Management: Antifungals
Adding oral itraconazole to steroids in patients with recurrent or chronic ABPA may be helpful
This may allow more rapid resolution of infiltrates and symptoms, facilitating steroid tapering or lowering the required dose of maintenance corticosteroids
Relapse after improvement during antifungal therapy is common; Long-term suppressive therapy may be necessary
Therapeutic azole monitoring is recommended to optimise ABPA control and avoid emergence of resistance
In CF patients with ABPA, the concomitant use of itraconazole and inhaled steroids may precipitate Cushing’s syndrome
Moreira et al. Clin Exp Allergy. 2014; 44:
Stevens et al. N Engl J Med. 2000; 342:

10. Management: Antifungals
Indications for itraconazole in ABPA
Recurrent exacerbations
Glucocorticoid-dependent ABPA
Transformation to CPA
Alternative to steroids in acute-stage ABPA in those at-risk for steroid complications
Itraconazole solution is preferred in CF patients because of poor absorption of capsules.
Patients who fail itraconazole, or are intolerant to itraconazole, may respond to voriconazole, posaconazole, or inhaled amphotericin B
Chang et al. Curr Allergy Asthma Rep. 2013;13:
Agarwal et al. Expert Rev Respir Med. 2016;10:

11. Management: Itraconazole vs. Placebo
Higher response in the itraconazole group (46%), compared to the placebo group (19%, P=0.04)
The rate of adverse events was similar in the two groups
Stevens et al. N Engl J Med. 2000; 342:

12. Management: Itraconazole vs. Prednisolone
Composite response was significantly higher in the prednisolone group compared with the itraconazole group (100% vs 88%; P = .007)
The rate of adverse events was higher in the glucocorticoid arm
Prednisolone was more effective in inducing response than itraconazole in acute-stage ABPA
Agarwal et al. Chest. 2018:S (18)

13. Omalizumab
13 patients with chronic ABPA randomized to 4-month treatment with omalizumab (750 mg monthly) or placebo
Exacerbations occurred less frequently
Mean FeNO decreased
Basophil sensitivity to A. fumigatus decreased significantly after omalizumab but not after placebo
Voskamp et al. J Allergy Clin Immunol Pract 2015; 3:

14. Management: Surgical care
Areas of mucoid impaction in ABPA may have a mass-like appearance and are sometimes resected as an undiagnosed lung mass; however, steroid therapy and oral itraconazole therapy are preferred.
Patients who have associated allergic fungal sinusitis benefit from surgical resection of obstructing nasal polyps and inspissated mucus in addition to corticosteroid therapy.
Nasal washes with amphotericin or itraconazole have also been employed
Allergic fungal sinusitis usually requires endoscopic sinus surgery to improve drainage

15. Other treatment additions in ABPA
Azithromycin
Reduces cough and sputum production
Nebulized hypertonic saline
May help clears sputum in some patients
Vaccination
Haemophilus influenzae / Pneumococcal vaccines
Prevents exacerbation
Kellett et al. Respir Med. 2005; 99:27–31.

16. Stage-wise management of ABPA
Stage 1: Acute
• Prednisolone 4-16 weeks
• Total IgE follow-up every 8 weeks for 1 year
Stage 2: Response
• Management of underlying CF or Asthma
Stage 3: Exacerbation
• Same management as Stage 1
• Prednisolone: daily for 2 weeks, then every other day for 8 weeks
Total serum IgE should be repeated after the initial 8 weeks of corticosteroid therapy, then every 8 weeks for 1 year
Stage 4: Remission
• Management of underlying CF or Asthma
Stage 5: Corticosteroid-dependent asthma
Oral corticosteroids, given indefinitely
Stage 6: End-stage fibrosis
• Daily oral corticosteroids
An antifungal may be considered as a corticosteroid-sparing agent at any stage from 1 to 5
Agarwal et al. Expert Rev Respir Med. 2016;10(12):
Virnig & Bush. Curr Opin Pulm Med.2007;13:67-71.
Greenberger. J Allergy Clin Immunol. 2002;110:

17. Total IgE is a useful test for monitoring treatment response in ABPA
Total IgE declines consistently from baseline to 2 months on therapy
Aspergillus specific IgE values are variable
Total IgE is a useful test in monitoring treatment responses in ABPA while A. fumigatus specific IgE has limited utility.
Agarwal et al. Mycoses. 2016;59(1):1-6.

18. High-attenuated mucus in ABPA
High-attenuation mucus (HAM) is a characteristic radiologic finding seen in patients with ABPA
HAM impaction in ABPA is associated with initial serologic severity and frequent relapses
Central bronchiectasis and HAM are independent predictors of recurrent relapses in ABPA
Therapeutic flexible or rigid bronchoscopy may be required to relieve HAM.
Agarwal et al. PLoS ONE. 2010; 5(12): e15346.

19. Summary
The treatment of ABPA is directed at the inflammatory component caused by the hypersensitivity reaction to Aspergillus fumigatus
Timely diagnosis and treatment can prevent the progression to end-stage ABPA
The underlying asthma or cystic fibrosis (CF) should also be aggressively treated
Corticosteroids are a cornerstone of therapy for exacerbations of ABPA
Antifungal interventions in ABPA improved patient and disease outcomes in both asthma and cystic fibrosis
Antifungals are considered an adjunctive but not primary therapy for APBA
For patients with corticosteroid-dependent ABPA, addition of itraconazole leads to improvement in the condition without added toxicity

20. END