16th January 2024

Allergic bronchopulmonary aspergillosis (ABPA)

Background

Epidemiology

Allergic bronchopulmonary aspergillosis (ABPA) is a type of hypersensitivity immune response respiratory disorder specifically associated with the Aspergillus fungus. The main species responsible is usually Aspergillus fumigatus, but other species, such as Aspergillus flavus, have also been identified as causative agents of ABPA. Other associated hypersensitivity respiratory disorders include HP and IgE mediated asthma. ABPA normally only occurs in those with cystic fibrosis (CF) or asthma– in those with asthma, prevalence ranges from 1-5%, and in those with CF, prevalence is approximately 1-9%. The main affected age group tends to be teenagers (if they have CF) or young adults (with asthma). It can also affect children and older patients, but occurrence is less common within these age groups.

ABPA is an emerging condition in India, and there is high prevalence in the Southwest areas of America also. Under recognition of signs and symptoms of the disease means rates may be much higher worldwide than is currently known.

References

• Akuthota, P. (2022) Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis, UpToDate. Edited by C. Kauffman, P. Barnes, and P. Dieffenbach. UpToDate. Available at: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-allergic-bronchopulmonary-aspergillosis?search=abpa&source=search_result&selectedTitle=1~57&usage_type=default&display_rank=1 (Accessed: January 15, 2023).
• Jack, J. and Bajaj, T. (2022) Allergic Bronchopulmonary Aspergillosis, Allergic Bronchopulmonary Aspergillosis. StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK542329/ (Accessed: January 15, 2023).
• Radojicic, C. (2020) Allergic bronchopulmonary aspergillosis, Allergic bronchopulmonary aspergillosis – Symptoms, diagnosis and treatment | BMJ Best Practice. BMJ Best Practice. Available at: https://bestpractice.bmj.com/topics/en-gb/836/pdf/836/Allergic%20bronchopulmonary%20aspergillosis.pdf (Accessed: January 15, 2023).

Pathophysiology

ABPA is an IgE and IgG immune-mediated hypersensitivity response to Aspergillus fumigatus fungus. It is not a systemic nor invasive fungal infection, and the fungi can be found in multiple environmental sources, including soil, grass and sewage. The spores are airborne and must be inhaled.

Exposure in individuals without atopy does not usually lead to antibody formation. However, in those with atopy, such as asthmatics, antibody formation after exposure to the fungal allergen is common. Conditions like asthma and CF tend to cause impaired mucus secretion and clearance, increasing the likelihood that spores will become trapped in these individuals’ airways and allow colonisation.

Once in the airway, the presence of fungal spores triggers an intense inflammatory response on top of existing inflammation caused by underlying asthma or CF. Th2 cells are recruited to release interleukin (IL)-5, which stimulates eosinophil and B cell recruitment. The presence of fungal enzymes causes IL-8 release, which stimulates neutrophil recruitment. These interleukins also stimulate synthesis of IgG and IgE antibodies, as do B cells. The inflammatory products released by the eosinophils and neutrophils recruited cause the bronchi and bronchioles to fill with eosinophilic plugs and hyphae, which leads to bronchiectasis and obstruction, and the signs and symptoms associated with the disease.

References

• Akuthota, P. (2022) Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis, UpToDate. Edited by C. Kauffman, P. Barnes, and P. Dieffenbach. UpToDate. Available at: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-allergic-bronchopulmonary-aspergillosis?search=abpa&source=search_result&selectedTitle=1~57&usage_type=default&display_rank=1 (Accessed: January 15, 2023).
• Jack, J. and Bajaj, T. (2022) Allergic Bronchopulmonary Aspergillosis, Allergic Bronchopulmonary Aspergillosis. StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK542329/ (Accessed: January 15, 2023).
• Moss, R.B. (2005) “Pathophysiology and immunology of allergic bronchopulmonary aspergillosis,” Medical Mycology, 43(s1), pp. 203–206. Available at: https://doi.org/10.1080/13693780500052255.
• Radojicic, C. (2020) Allergic bronchopulmonary aspergillosis, Allergic bronchopulmonary aspergillosis – Symptoms, diagnosis and treatment | BMJ Best Practice. BMJ Best Practice. Available at: https://bestpractice.bmj.com/topics/en-gb/836/pdf/836/Allergic%20bronchopulmonary%20aspergillosis.pdf (Accessed: January 15, 2023). 
• Tillie-Leblond, I. and Tonnel, A.-B. (2005) “Allergic bronchopulmonary aspergillosis,” Allergy, 60(8), pp. 1004–1013. Available at: https://doi.org/10.1111/j.1398-9995.2005.00887.x.

Presentation 

The condition is clinically hard to distinguish from CF, and for these patients, the symptoms associated with ABPA may be no different to their usual symptoms other than potentially more pronounced. A careful history and examination will be needed alongside relevant investigations to determine if ABPA is the cause of their symptoms. In those with asthma, ABPA tends to only develop after asthma treatment is begun. Symptoms of the disease can include:

• Upper airway symptoms, e.g., in keeping with rhinitis or sinusitis
• Shortness of breath if fibrosis is present
• Wheeze – may not always be present
• Productive cough
• Haemoptysis
• Pleuritic chest pain
• Malaise
• Fever

In advanced disease, signs such as finger clubbing, cyanosis and peripheral oedema can occur. Crackles may also be heard if fibrosis is present on auscultation.

References

• Akuthota, P. (2022) Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis, UpToDate. Edited by C. Kauffman, P. Barnes, and P. Dieffenbach. UpToDate. Available at: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-allergic-bronchopulmonary-aspergillosis?search=abpa&source=search_result&selectedTitle=1~57&usage_type=default&display_rank=1 (Accessed: January 15, 2023).
• Jack, J. and Bajaj, T. (2022) Allergic Bronchopulmonary Aspergillosis, Allergic Bronchopulmonary Aspergillosis. StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK542329/ (Accessed: January 15, 2023).
• Radojicic, C. (2020) Allergic bronchopulmonary aspergillosis, Allergic bronchopulmonary aspergillosis – Symptoms, diagnosis and treatment | BMJ Best Practice. BMJ Best Practice. Available at: https://bestpractice.bmj.com/topics/en-gb/836/pdf/836/Allergic%20bronchopulmonary%20aspergillosis.pdf (Accessed: January 15, 2023).

Diagnosis

ABPA should be suspected in any patient with CF or asthma presenting with several exacerbations, upper zone bronchiectasis, eosinophilia and raised IgE. It is rare to develop the condition without the underlying disease of CF or asthma. A number of investigations are needed to rule in or out a diagnosis of ABPA as follows:

1. Bloods
   • Eosinophilia – can be seen in blood tests and histology results. May be absent if steroids are taken regularly.
   • Total serum IgE – also usually raised in ABPA
   • Specific serum IgE and IgG to Aspergillus fumigatus may also be raised
2. Imaging
   • A chest X-ray will likely show non-specific features, and if ABPA is suspected, CT imaging should be performed.
   • HRCT of the chest can show bronchiectasis (mainly in the central lobes), mucus plugging, centrilobular nodules and bronchial wall thickening and dilatation.
3. Other investigations
   • Sputum culture – may be positive for presence of Aspergillus fumigatus but can also show no growth.
   • Skin test – to establish if an individual is sensitised to the fungus (type 1 hypersensitivity reaction occurs if so).
   • HLA-DR molecules – this gene marker is associated with ABPA, but it is not a routine clinical test.
   • Lung function tests – in ABPA, an obstructive pattern is usually seen, with reduced FEV1 and increased residual volume. However, fibrosis and/or bronchiectasis can cause a mixed or restrictive pattern to occur as well.

References

• Akuthota, P. (2022) Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis, UpToDate. Edited by C. Kauffman, P. Barnes, and P. Dieffenbach. UpToDate. Available at: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-allergic-bronchopulmonary-aspergillosis?search=abpa&source=search_result&selectedTitle=1~57&usage_type=default&display_rank=1 (Accessed: January 15, 2023).
• Jack, J. and Bajaj, T. (2022) Allergic Bronchopulmonary Aspergillosis, Allergic Bronchopulmonary Aspergillosis. StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK542329/ (Accessed: January 15, 2023).
• Nawaz Khan, A. (2020) Pulmonary Aspergillosis Imaging, Practice Essentials, Radiograph, CT Scanning. Medscape. Available at: https://emedicine.medscape.com/article/353200-overview (Accessed: January 15, 2023).
• Radojicic, C. (2020) Allergic bronchopulmonary aspergillosis, Allergic bronchopulmonary aspergillosis – Symptoms, diagnosis and treatment | BMJ Best Practice. BMJ Best Practice. Available at: https://bestpractice.bmj.com/topics/en-gb/836/pdf/836/Allergic%20bronchopulmonary%20aspergillosis.pdf (Accessed: January 15, 2023).

Differentials 

ABPA is a rare condition; however, the clinical presentation and imaging may be misleading and equally suggestive of other conditions also. The list below details some of the main differentials to consider when working a patient up for a possible diagnosis of ABPA.

• Eosinophilic pneumonia – this condition is more common in non-smoking women and not specific to the asthma or CF population. A chest X-ray may show bilateral infiltrates peripherally, and a biopsy would show alveolar eosinophils with minimal fibrosis.
• Eosinophilic granulomatosis with polyangiitis (EGPA) – EGPA is a type of vasculitis rather than a hypersensitivity condition; therefore, other organ systems are involved and contribute to the clinical presentation, whereas ABPA presents with purely respiratory symptoms.
• Severe asthma or CF exacerbation alone – haemoptysis would be unlikely, a skin prick test for Aspergillus fumigatus would be negative, serum IgE would not be elevated (unless the patient is on oral steroids), and specific IgE and IgG for Aspergillus fumigatus would not be elevated. 
• Parasite infection – acute eosinophilia on blood testing could be indicative of parasitic infection and should be explored if symptoms and signs do not fit with ABPA. Infectious disease opinion may be needed.

References

• Akuthota, P. (2022) Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis, UpToDate. Edited by C. Kauffman, P. Barnes, and P. Dieffenbach. UpToDate. Available at: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-allergic-bronchopulmonary-aspergillosis?search=abpa&source=search_result&selectedTitle=1~57&usage_type=default&display_rank=1 (Accessed: January 15, 2023).
• Jack, J. and Bajaj, T. (2022) Allergic Bronchopulmonary Aspergillosis, Allergic Bronchopulmonary Aspergillosis. StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK542329/ (Accessed: January 15, 2023).
• O’Connell, E.M. and Nutman, T.B. (2015) “Eosinophilia in infectious diseases,” Immunology and Allergy Clinics of North America, 35(3), pp. 493–522. Available at: https://doi.org/10.1016/j.iac.2015.05.003.
• Radojicic, C. (2020) Allergic bronchopulmonary aspergillosis, Allergic bronchopulmonary aspergillosis – Symptoms, diagnosis and treatment | BMJ Best Practice. BMJ Best Practice. Available at: https://bestpractice.bmj.com/topics/en-gb/836/pdf/836/Allergic%20bronchopulmonary%20aspergillosis.pdf (Accessed: January 15, 2023).

Management

Management will depend on what stage of disease an affected patient is at during diagnosis. Five distinct stages of disease have been proposed; table 4 below summarises each stage and the associated recommended management for it.

As part of overall management for ABPA, appropriate monitoring for medications such as steroids and azole antifungals must occur, as both can cause adrenal suppression, and azole antifungals can be hepatotoxic. Yearly spirometry is advised, and total IgE should be checked every 2 months after acute treatment for at least one year. Chest physiotherapy and oxygen therapy may need to be considered as part of optimising symptoms especially in the later stage of disease.

Table 4: Summary of management algorithm for ABPA. Adapted from: Radojicic, C. (2020) Allergic bronchopulmonary aspergillosis, Allergic bronchopulmonary aspergillosis – Symptoms, diagnosis and treatment | BMJ Best Practice. BMJ Best Practice. Available at: https://bestpractice.bmj.com/topics/en-gb/836/pdf/836/Allergic%20bronchopulmonary%20aspergillosis.pdf (Accessed: January 15, 2023) and Akuthota, P. and Weller, P. (2022) Treatment of allergic bronchopulmonary aspergillosis, UpToDate. Edited by C. Kauffman et al. UpToDate. Available at: https://www.uptodate.com/contents/treatment-of-allergic-bronchopulmonary-aspergillosis?search=abpa&source=search_result&selectedTitle=2~57&usage_type=default&display_rank=2 (Accessed: January 15, 2023). 

References

• Akuthota, P. and Weller, P. (2022) Treatment of allergic bronchopulmonary aspergillosis, UpToDate. Edited by C. Kauffman et al. UpToDate. Available at: https://www.uptodate.com/contents/treatment-of-allergic-bronchopulmonary-aspergillosis?search=abpa&source=search_result&selectedTitle=2~57&usage_type=default&display_rank=2 (Accessed: January 15, 2023).
• Jack, J. and Bajaj, T. (2022) Allergic Bronchopulmonary Aspergillosis, Allergic Bronchopulmonary Aspergillosis. StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK542329/ (Accessed: January 15, 2023).
• Jacobs, K. and Kligerman, S. (2019) “Immune-mediated lung diseases,” Seminars in Ultrasound, CT and MRI, 40(3), pp. 213–228. Available at: https://doi.org/10.1053/j.sult.2018.11.011.
• Radojicic, C. (2020) Allergic bronchopulmonary aspergillosis, Allergic bronchopulmonary aspergillosis – Symptoms, diagnosis and treatment | BMJ Best Practice. BMJ Best Practice. Available at: https://bestpractice.bmj.com/topics/en-gb/836/pdf/836/Allergic%20bronchopulmonary%20aspergillosis.pdf (Accessed: January 15, 2023).