Allergic bronchopulmonary aspergillosis (ABPA) is a fungal infection of the lung due to a hypersensitivity reaction to antigens of Aspergillus fumigatus after colonization into the airways. Predominantly it affects patients with bronchial asthma and those having cystic fibrosis. It characteristically presents with bronchospasm, pulmonary infiltrates, eosinophilia, and immunologic evidence of allergy to the antigens of Aspergillus species.
Aspergillus species are molds that are present ubiquitously in the environment, especially in the organic matter. There are over 100 species worldwide, but most of the illness is caused by Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus, and Aspergillus clavatus. An infection by Aspergillus species causes a broad spectrum of illnesses in humans and depends on the immune status of the host, ranging from hypersensitivity reactions to direct angioinvasion.
Aspergillus fumigatus is the most common ubiquitous airborne fungus causative organism for ABPA.Aspergillus conidia, because of its small diameter (2 to 3 micrometers), easily reach the pulmonary alveoli and deposits there.
ABPA affects people who are asthmatic or have cystic fibrosis and are allergic to Aspergillus. The thick mucus in the airways of these patients makes it difficult to clear up the Aspergillus spores when inhaled. Genetic association: HLA-DR molecules DR2, DR5, and possibly DR4 or DR7 contribute to susceptibility; whereas, HLA-DQ2 contributes to resistance, and a combination of these may determine the outcome of ABPA in CF and asthma.
Allergic bronchopulmonary aspergillosis commonly presents in the third to fifth decade of life. It is also common in children. It usually found in severe asthmatics and patients with cystic fibrosis.
Allergy to Aspergillus, as shown by a positive skin prick test to Aspergillus antigen, is present in almost 25% asthmatics and 50% of cystic fibrosis patients, but ABPA is not that much prevalent. The prevalence of ABPA in asthma and cystic fibrosis is about 13% and 9%, respectively. Worldwide, more than 4 million people are affected by ABPA.
A. fumigatus is the most common organism that causes ABPA, and the fungus requires dead organic matter to survive. The highest incidence of the infection is known to be in the winter season around the world (secondary to fallen leaves).
The pathogenesis of allergic bronchopulmonary aspergillosis remains incompletely understood. A. fumigatus spores that get inhaled in sufficient quantities behave as allergens. Normally a low level of IgG against fungal antigens in the circulation and the low antifungal secretory IgA in bronchoalveolar fluid suggest that healthy individuals can effectively eliminate fungal spores. In contrast, exposure of atopic individuals to fungal spores or mycelial fragments results in the formation of IgE and IgG antibodies.
Th2 cells (Helper T cells) play an essential role in the hypersensitivity reaction caused by the A. fumigatus antigen. It manifests as IgE production, eosinophilia, mast cell degranulation, and bronchiectasis.
A. fumigatus proteases release proinflammatory cytokines, such as IL-8, which causes epithelial cell damage and disruption of protective barriers, which triggers the hypersensitivity reaction. It also releases cytokines interleukin (IL)-4, IL-5, and IL-13, which increases blood and airway eosinophils as well as IgE.
Histopathologically, there is chronic bronchial inflammation, eosinophilia (leading to the development of an area of parenchymal scarring), airway remodeling, and bronchiectasis. Bronchi may show impacted mucus plug containing fungal hyphae, fibrin, Charcot-Leyden crystals, Curschmann spirals. The dichotomous branching of hyphae occurs at 45-degree angles.
On physical examination:
There is no individual test that establishes the diagnosis of allergic bronchopulmonary aspergillosis. The diagnosis is based on classic clinical manifestations, radiographic findings, and immunological findings.
Aspergillus skin test:
Radiological manifestations of ABPA:
The following shadows may present radiologically:
Revised radiologic classification of allergic bronchopulmonary aspergillosis based on findings on a high-resolution computed tomography of the chest.
Pulmonary function tests:
Bronchoscopy: Mucoid impaction may be evident, and bronchial brushings may reveal mucus that contains aggregates of eosinophils, fungal hyphae, and eosinophil-derived Charcot–Leyden crystals. The finding of hyphae-filled mucus plugs is considered pathognomonic for ABPA. BAL fluid analysis from patients with ABPA: moderate eosinophilia (especially in steroid-naive patients) and increased levels of Aspergillus-specific IgE and IgA, but not IgG.
Sputum cultures for A. fumigatus: It is not diagnostic, but if it reveals an organism, then it helps in drug susceptibility test.
The following criteria are used for the diagnosis and typing of ABPA.
1) Rosenberg-Patterson criteria: It has five major and three minor criteria.
2) Criteria proposed by ISHAM working group :
Cystic Fibrosis Foundation has revised the criteria for the diagnosis of ABPA in patients with cystic fibrosis. ABPA is diagnosed and should be treated if the following are present:
1. Deterioration of cough, wheeze, sputum, or deterioration in pulmonary functions
2. Total serum IgE level more than 1000 IU/ml or greater than twofold from baseline
3. Aspergillus precipitins or increased Aspergillus specific IgG or IgE
4. New infiltrates on chest radiograph or CT scan
If patients have new radiographic findings, symptoms, or an increase in baseline IgE to more than 500 IU/ml, even then treatment of ABPA should be given to cystic fibrosis patients.
The main aim of the treatment of allergic bronchopulmonary aspergillosis is to control episodes of acute inflammation and to limit progressive lung injury.
Goals of treatment:
• Controlling symptoms • Preventing exacerbations • Preserving normal lung function
Drugs used for the treatment of ABPA:
Corticosteroids: Systemic corticosteroids are the primary therapy for ABPA. The steroids help to relieve the symptoms and decrease airflow obstruction, decrease serum IgE and reduce peripheral blood eosinophils. Moreover, there is a resolution of pulmonary inflammation, pulmonary infiltrates, and it prevents irreversible lung damage.
Oral antifungal agents: Antifungal agents act by decreasing the fungal load that reduces inflammatory activity and act as steroid-sparing agents. Antifungal therapy may help to decrease exacerbations.
Antibiotics: To prevent or treat an associated secondary bacterial infection.
Omalizumab: An anti-IgE recombinant humanized monoclonal antibody which prevents binding of IgE to Fc-epsilon RI receptor on mast cells and basophils.
Differential Diagnosis of allergic bronchopulmonary aspergillosis:
ABPA mimics many diseases that involve both airway and lung parenchyma. Undiagnosed lung infiltrates, pneumonia, bronchiectasis make a long list of differential diagnoses. Following are few diseases which should be carefully ruled out while making a diagnosis of ABPA:
Itraconazole interferes with the hepatic metabolism of several medications, including cyclosporine, oral hypoglycemics, tacrolimus, terfenadine, cisapride, and midazolam. Deranged liver function test results, rash, headache, edema, nausea, vomiting, and diarrhea are the most common side effects. Impaired absorption is most significant with proton pump inhibitors.
Glucocorticoids side effects: Weight gain, osteopenia, acne, skin atrophy, diabetes mellitus, glaucoma, cataracts, avascular necrosis of bone, infection, hypertension, and growth retardation in children.
Omalizumab side effects: The most common reaction is swelling and redness at the injection site. Anaphylaxis may occur in asthmatics.
New Proposed clinical staging of allergic bronchopulmonary aspergillosis in asthmatic patients:
Stage 0: Asymptomatic
Stage 1: Acute
Stage 2: Response
Stage 3: Exacerbation
Stage 4: Remission
Sustained clinical-radiological improvement and
Stage 5a: Treatment-dependent ABPA
Stage 5b: Glucocorticoid-dependent asthma
Stage 6: Advanced ABPA
EPR-3: third expert panel report; GINA: global initiative against asthma.
The natural history, progression, remission, and recurrences of ABPA are not well understood. Patients without central bronchiectasis at the time of diagnosis tend to maintain their lung function despite occasional exacerbations. With appropriate treatment, long-term control of ABPA is feasible, and durable remissions are common.
Treatment of Stage 1 disease using corticosteroids typically results in decreased sputum production, improved control of bronchospasm, over 35% reduction in total IgE within 8 weeks, clearing of precipitating antibodies, and resolution of radiographic infiltrates. IgE levels typically do not completely normalize, but it decreases by approximately one-half of peak levels seen in the acute stage.
Progression of Stage 5 disease to pulmonary fibrosis may be preventable if patients maintain therapy on low-dose steroids. Persons with an FEV1 persistently under 0.8 L have a worse prognosis.
Patients with allergic bronchopulmonary aspergillosis have to be more conscious about the worsening of their symptoms. If the worsening of respiratory symptoms occurs on treatment or new respiratory symptoms develops on stage 2 and stage 3, then immediately consult a pulmonologist.
Patients with ABPA-CB have a higher chance of getting a secondary infection and complications related to bronchiectasis. If fever or hemoptysis occurs, then immediately consult a pulmonologist.
If a patient is receiving long-term oral corticosteroids, all adverse drug effects should be properly understood. Screening should be performed for corticosteroid adverse effects of osteoporosis/osteopenia (by bone density measurement) and cataracts (by eye exams) regularly.
Patients bronchiectasis should receive training on sputum clearance techniques. Recommendations are for influenza and pneumococcal immunizations.
Avoid areas and environmental conditions with high mold counts, such as decomposing organic materials, and moldy indoor environments.
Allergic bronchopulmonary aspergillosis is a fungal infection of the lung secondary to a hypersensitivity reaction to antigens of Aspergillus fumigatus. This disease process is uncommon; however, routine screening is necessary for asthmatic and cystic fibrosis patients. The interprofessional approach of pulmonologists, infectious diseases, primary care physicians, pharmacists, and other healthcare professionals is essential to educate and improve patient outcomes. [Level V] A focused history and physical examination along with appropriate imaging with a high-resolution chest tomography of the chest are critical to establish an early diagnosis and initiate early treatment to prevent the development of bronchiectasis or pulmonary fibrosis. As targeted immunotherapy is evolving, there may be new treatment options in the near future.
The nurse place an important role in monitoring the patient for progression or worsening symptoms that must be reported back to the interprofessional team leader. As drug therapy and monitoring are complex in these patients, a pharmacist should evaluate for drug-drug interactions and coordinate drug therapy, assisting in monitoring for compliance and side effects and reporting to the clinical team leader if untoward complications arise. The nurse practitioner, a physician assistant, must coordinate care and patient and family education together so that they are aware of the need to monitor treatment, follow up regularly, and return for reassessment if unexpected complications occur. This disease is challenging to treat, and only through coordinated interprofessional care will the best outcomes be achieved. [Level V]
|||Oguma T,Taniguchi M,Shimoda T,Kamei K,Matsuse H,Hebisawa A,Takayanagi N,Konno S,Fukunaga K,Harada K,Tanaka J,Tomomatsu K,Asano K, Allergic bronchopulmonary aspergillosis in Japan: A nationwide survey. Allergology international : official journal of the Japanese Society of Allergology. 2018 Jan; [PubMed PMID: 28546015]|
|||Sehgal IS,Choudhary H,Dhooria S,Aggarwal AN,Bansal S,Garg M,Behera D,Chakrabarti A,Agarwal R, Prevalence of sensitization to Aspergillus flavus in patients with allergic bronchopulmonary aspergillosis. Medical mycology. 2019 Apr 1; [PubMed PMID: 29566248]|
|||Vitte J,Ranque S,Carsin A,Gomez C,Romain T,Cassagne C,Gouitaa M,Baravalle-Einaudi M,Bel NS,Reynaud-Gaubert M,Dubus JC,Mège JL,Gaudart J, Multivariate Analysis As a Support for Diagnostic Flowcharts in Allergic Bronchopulmonary Aspergillosis: A Proof-of-Concept Study. Frontiers in immunology. 2017; [PubMed PMID: 28878778]|
|||Chauhan B,Santiago L,Kirschmann DA,Hauptfeld V,Knutsen AP,Hutcheson PS,Woulfe SL,Slavin RG,Schwartz HJ,Bellone CJ, The association of HLA-DR alleles and T cell activation with allergic bronchopulmonary aspergillosis. Journal of immunology (Baltimore, Md. : 1950). 1997 Oct 15 [PubMed PMID: 9378997]|
|||Chauhan B,Santiago L,Hutcheson PS,Schwartz HJ,Spitznagel E,Castro M,Slavin RG,Bellone CJ, Evidence for the involvement of two different MHC class II regions in susceptibility or protection in allergic bronchopulmonary aspergillosis. The Journal of allergy and clinical immunology. 2000 Oct [PubMed PMID: 11031343]|
|||Bhankhur D,Singla N,Aggarwal D,Chander J, Prevalence of allergic bronchopulmonary aspergillosis among patients with severe bronchial asthma in a tertiary care hospital in Northern India. Indian journal of pathology [PubMed PMID: 30706871]|
|||Agarwal R,Sehgal IS,Dhooria S,Aggarwal AN, Developments in the diagnosis and treatment of allergic bronchopulmonary aspergillosis. Expert review of respiratory medicine. 2016 Dec; [PubMed PMID: 27744712]|
|||Gago S,Denning DW,Bowyer P, Pathophysiological aspects of Aspergillus colonization in disease. Medical mycology. 2019 Apr 1; [PubMed PMID: 30239804]|
|||Stevens DA,Moss RB,Kurup VP,Knutsen AP,Greenberger P,Judson MA,Denning DW,Crameri R,Brody AS,Light M,Skov M,Maish W,Mastella G, Allergic bronchopulmonary aspergillosis in cystic fibrosis--state of the art: Cystic Fibrosis Foundation Consensus Conference. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2003 Oct 1 [PubMed PMID: 12975753]|
|||Greenberger PA,Smith LJ,Hsu CC,Roberts M,Liotta JL, Analysis of bronchoalveolar lavage in allergic bronchopulmonary aspergillosis: divergent responses of antigen-specific antibodies and total IgE. The Journal of allergy and clinical immunology. 1988 Aug [PubMed PMID: 3042837]|
|||Kauffman HF,Tomee JF,van der Werf TS,de Monchy JG,Koëter GK, Review of fungus-induced asthmatic reactions. American journal of respiratory and critical care medicine. 1995 Jun [PubMed PMID: 7767565]|
|||Agarwal R,Khan A,Gupta D,Aggarwal AN,Saxena AK,Chakrabarti A, An alternate method of classifying allergic bronchopulmonary aspergillosis based on high-attenuation mucus. PloS one. 2010 Dec 15; [PubMed PMID: 21179536]|
|||Shah A,Panjabi C, Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy, asthma [PubMed PMID: 27126721]|
|||Chishimba L,Niven RM,Cooley J,Denning DW, Voriconazole and posaconazole improve asthma severity in allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. The Journal of asthma : official journal of the Association for the Care of Asthma. 2012 May; [PubMed PMID: 22380765]|
|||Nové-Josserand R,Grard S,Auzou L,Reix P,Murris-Espin M,Brémont F,Mammar B,Mely L,Hubert D,Durieu I,Burgel PR, Case series of omalizumab for allergic bronchopulmonary aspergillosis in cystic fibrosis patients. Pediatric pulmonology. 2017 Feb; [PubMed PMID: 27717223]|
|||Collins J,Devos G,Hudes G,Rosenstreich D, Allergic bronchopulmonary aspergillosis treated successfully for one year with omalizumab. Journal of asthma and allergy. 2012; [PubMed PMID: 23204847]|
|||Voskamp AL,Gillman A,Symons K,Sandrini A,Rolland JM,O'Hehir RE,Douglass JA, Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis. The journal of allergy and clinical immunology. In practice. 2015 Mar-Apr; [PubMed PMID: 25640470]|
|||Greenberger PA, Clinical aspects of allergic bronchopulmonary aspergillosis. Frontiers in bioscience : a journal and virtual library. 2003 Jan 1; [PubMed PMID: 12456338]|
|||Jaruratanasirikul S,Sriwiriyajan S, Effect of omeprazole on the pharmacokinetics of itraconazole. European journal of clinical pharmacology. 1998 Apr; [PubMed PMID: 9626921]|
|||Vlahakis NE,Aksamit TR, Diagnosis and treatment of allergic bronchopulmonary aspergillosis. Mayo Clinic proceedings. 2001 Sep; [PubMed PMID: 11560305]|
|||Agarwal R, Allergic bronchopulmonary aspergillosis. Chest. 2009 Mar; [PubMed PMID: 19265090]|
|||Maturu VN,Agarwal R, Acute Invasive Pulmonary Aspergillosis Complicating Allergic Bronchopulmonary Aspergillosis: Case Report and Systematic Review. Mycopathologia. 2015 Oct; [PubMed PMID: 26045286]|
|||Lowes D,Chishimba L,Greaves M,Denning DW, Development of chronic pulmonary aspergillosis in adult asthmatics with ABPA. Respiratory medicine. 2015 Dec; [PubMed PMID: 26507434]|
|||Gibson PG, Allergic bronchopulmonary aspergillosis. Seminars in respiratory and critical care medicine. 2006 Apr; [PubMed PMID: 16612769]|