Allergic bronchopulmonary aspergillosis (ABPA) is a common fungal infection in uncontrolled asthmatics, cystic fibrosis patients, and immunocompromised patients. Early diagnosis and rapid implementation of proper management are critical to prevent complications and/or disease progression. Diagnosis centers around classic clinical manifestations, radiographic findings, and immunological findings. This activity describes the etiology, evaluation, and management of allergic bronchopulmonary aspergillosis and highlights the role of the interprofessional team in caring for affected patients.
Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterized by an exaggerated response of the immune system (a hypersensitivity response) to the fungus Aspergillus (most commonly Aspergillus fumigatus). It occurs most often in people with asthma or cystic fibrosis. Aspergillus spores are ubiquitous in soil and are commonly found in the sputum of healthy individuals. A. fumigatus is responsible for a spectrum of lung diseases known as aspergilloses. ABPA causes airway inflammation, leading to bronchiectasis—a condition marked by abnormal dilation of the airways. Left untreated, the immune system and fungal spores can damage sensitive lung tissues and lead to scarring.
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 bronchospasm, pulmonary infiltrates, eosinophilia, and immunologic evidence of allergy to the antigens of Aspergillus species.[rx][rx]
Causes
Aspergillus species are molds that are present ubiquitously in the environment, especially in 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.[rx]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.[rx][rx]
The pathogenesis of allergic bronchopulmonary aspergillosis remains incompletely understood.[rx] 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.[rx][rx] 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.[rx]
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.
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Immunocompetent individuals easily eliminate Aspergillus conidia from the airway by the innate immune system mechanisms; therefore, there are no manifestations of pulmonary fungal infections. If isolated in respiratory secretions like sputum or bronchoalveolar lavage, then it only reflects colonization, not an infection.
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Immunocompromised individuals do not eliminate Aspergillus conidia due to host immune defense imbalance; therefore, they colonize airways and germinate into somatic hyphae that stimulate a chronic allergic inflammatory response that results in tissue injury, which ultimately leads to the clinical features of ABPA.[rx]
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In atopic individuals (asthmatics), cystic fibrosis patients, and patients with cavitary lung diseases, inhalation of Aspergillus fumigatus spores triggers an IgE-mediated hypersensitivity response in the respiratory tract that causes respiratory symptoms like cough with expectoration and breathlessness.
Symptoms
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Wheezing with radiological evidence of patchy fleeting pulmonary infiltrates and bronchiectasis. Wheezing is not always evident, and some patients present with asymptomatic pulmonary consolidation.
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Uncontrolled asthma with increased frequency and severity despite optimum asthma medications.
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Cystic fibrosis.
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A presentation of cough, dyspnea, pleuritic chest pain, blood-stained sputum, or sputum with brown mucus plugs.
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There are non-specific complaints like anorexia, fatigue, generalized aches and pains, low-grade fever, and loss of weight.
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ABPA may occur with allergic fungal sinusitis having symptoms of chronic sinusitis with purulent sinus discharge.
- Almost all patients have been clinically diagnosed with asthma, and present with wheezing (usually episodic in nature), coughing, shortness of breath, and exercise intolerance (especially in patients with cystic fibrosis).
- Moderate and severe cases have symptoms suggestive of bronchiectasis, in particular thick sputum production (often containing brown mucus plugs), as well as symptoms mirroring recurrent infection such as pleuritic chest pain and fever.
- Patients with asthma and symptoms of ongoing infection, who do not respond to antibiotic treatment, should be suspected of ABPA.[rx]
Diagnosis
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, and Curschmann spirals. The dichotomous branching of hyphae occurs at 45-degree angles.[rx]
History and Physical
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Allergic bronchopulmonary aspergillosis occurs primarily in patients with asthma or cystic fibrosis.
On physical examination
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In asthmatic patients with ABPA, wheezing, and/or rhonchi are present on auscultation.
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In cystic fibrosis patients with ABPA, crepitations present on auscultation due to bronchiectasis.
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Tachypnea may present in case of asthma exacerbation or due to a secondary lung infection.
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.[rx]
Aspergillus skin test
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Aspergillus skin test (AST) is the investigation most commonly used for diagnosing sensitization to A. fumigatus.
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It reveals immediate cutaneous hypersensitivity to A. fumigatus.
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A positive Type I Hypersensitivity reaction is typical of ABPA and represents the presence of A. fumigatus-specific IgE antibodies.
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Intradermal skin tests are more sensitive than the skin prick test for the diagnosis of Aspergillus sensitization.
Blood Abnormalities
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Elevated total serum IgE (usually over 1000 IU/mL)
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Elevated specific serum IgE to A. fumigatus (Af)
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Presence of serum precipitins (by gel diffusion) or raised specific serum IgG to A. fumigatus
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Peripheral blood eosinophilia (often absent, especially if the patient is on oral or inhaled corticosteroids)
Radiological manifestations of ABPA
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Chest X-ray has 50% sensitivity for the diagnosis of ABPA. It can show parenchymal infiltrate and bronchiectasis changes mostly in the upper lobes; however, all lobes may exhibit involvement.
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HRCT Chest is the investigation of choice to detect bronchiectasis distribution and other abnormalities that are undetectable on a chest X-ray, such as centrilobular nodules and tree-in-bud appearance.
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Patients with ABPA with no abnormalities on HRCT chest are labeled as serologic ABPA (ABPA-S).
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Patients with central bronchiectasis on HRCT are labeled as ABPA Central Bronchiectasis (ABPA-CB).
The following shadows may present radiologically
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“Finger in glove” opacity: suggestive of mucoid impaction in dilated bronchi.
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“Tramline shadows”: suggestive of parallel linear shadows extending from the hilum in bronchial distribution and reflecting longitudinal views of inflamed, edematous bronchi
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“Toothpaste shadows”: representing mucoid impaction of the bronchi
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“Ring shadows”: reflecting dilated bronchi with inflamed bronchial walls
Revised radiologic classification of allergic bronchopulmonary aspergillosis based on findings on a high-resolution computed tomography of the chest. [rx]
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ABPA-S (Serological ABPA): Fulfills the diagnostic criteria of ABPA with an absence of any radiological finding of ABPA on HRCT of the thorax.
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ABPA-B (Bronchiectasis ABPA): Satisfies the diagnostic requirements of ABPA along with the presence of bronchiectasis.
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ABPA-HAM (ABPA- High attenuation mucus): ABPA, along with the presence of high attenuation mucus on HRCT of the thorax.
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ABPA-CPF (ABPA-Chronic pleuropulmonary fibrosis): Fulfills the diagnostic criteria of ABPA with at least two radiological features suggestive of fibrosis (including fibrocavitary lesions, pulmonary fibrosis, pleural thickening) without the presence of mucoid impaction (or HAM).
Pulmonary function tests
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Aids in measuring lung function impairment severity and monitoring improvement of lung function on follow-up.
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Obstructive ventilatory defect: Stages I, III, IV, and often, V may not correlate with the duration of ABPA or asthma.
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Patients with Stage V disease typically also have a restrictive ventilatory defect and a reduced DLCO.
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 tests. The following criteria are used for the diagnosis and typing of ABPA.
1) Rosenberg-Patterson criteria: It has eight major and three minor criteria.[rx]
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Major criteria1. Asthma2. Presence of transient pulmonary infiltrates (fleeting shadows)3. Immediate cutaneous reactivity to Af (A. fumigatus)4. Elevated total serum IgE5. Precipitating antibodies against Af6. Peripheral blood eosinophilia7. Elevated serum IgE and IgG to Af8. Central/proximal bronchiectasis with normal tapering of distal bronchi
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Minor criteria1. Expectoration of golden brownish sputum plugs2. Positive sputum culture for Aspergillus species3. Late (Arthus-type) skin reactivity to Af
2) Criteria proposed by the ISHAM working group
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Predisposing conditions1. Bronchial asthma2. Cystic fibrosis
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Obligatory criteria (both should be present)1. Type I – positive Aspergillus skin test (immediate cutaneous hypersensitivity to Aspergillus antigen) or elevated IgE levels against Af2. Elevated total IgE levels (greater than 1000 IU/mL)
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Other criteria (at least two or three)1. Presence of precipitating or IgG antibodies against Af in serum2. Radiographic pulmonary opacities are consistent with ABPA3. Total eosinophil count over 500 cells/microliter in steroid naïve patients(If the patient meets all the other criteria, an IgE value less than 1000 IU/mL may be acceptable)
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:
- Deterioration of cough, wheeze, sputum, or deterioration in pulmonary functions
- Total serum IgE level more than 1000 IU/ml or greater than twofold from baseline
- Aspergillus precipitins or increased Aspergillus specific IgG or IgE
- 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.
Treatment
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
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Anti-inflammatory drugs: corticosteroids
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Antifungal drugs
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Anti IgE therapy
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Antibiotics
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, and pulmonary infiltrates, and it prevents irreversible lung damage.
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Prednisolone is a commonly used drug for treatment.
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Dose: 0.5 to 1 mg/kg a day for two weeks, followed by 0.5 mg/kg every other day for 6 to 8 weeks. A subsequent taper (by 5 to 10 mg every two weeks) over the 3 to 5 months. The duration of treatment depends upon the activity and severity of the disease. A low maintenance dose (5.0 to 7.5 mg/d) may be required long-term to control the disease and prevent recurrence in some patients.
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IgE levels should be monitored within a few months of an acute episode or exacerbation and require follow-up every two months. Escalation of steroid therapy should be an option if IgE levels rise more than 100%.
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Inhaled corticosteroids may help to control bronchospasm and may minimize the dose of systemic steroids.
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Stage 1 & 3 requires oral/intravenous corticosteroids to control the acute stage and exacerbation.
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Stage 2 disease requires careful regular follow-up.
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Stage 4 disease requires long-term steroids to control asthmatic symptoms and keep IgE levels at baseline.
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Stage 5 & 6 disease requires long-term corticosteroid use.
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.
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Itraconazole is a commonly used drug for treatment.
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Itraconazole (200 mg twice daily for 16 weeks) leads to significant reductions in corticosteroid dose, decreases IgE levels, resolves pulmonary infiltrates, improves exercise tolerance, and improves pulmonary function.
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Itraconazole treatment (200 mg/d or every other day) is generally recommended for patients with ABPA who are steroid-dependent, have frequent relapses, and where the benefits of treatment outweigh the risks.
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Other antifungal agents, including nystatin, amphotericin B, miconazole, clotrimazole, and natamycin, are generally ineffective in controlling ABPA. Ketoconazole may be effective, but hepatotoxicity limits its utility.
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Newer antifungal drug: Voriconazole (300 to 600 mg/day) or posaconazole (800 mg/day) shows clinical improvement with a reduction in the requirement of oral glucocorticoids, improvement in asthma control, and a decline in IgE levels. Cost is a major current limitation; however, the high rate of efficacy shows that treatment with these agents as second-line therapy is justified in specific patients.[rx]
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Nebulized lipid amphotericin B (AMB-L) requires further studies to determine efficacy; therefore, at this time, it is not used for the treatment of ABPA.
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.
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It is mainly used to treat uncontrolled asthma on Step 4 GINA treatment guidelines.
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Very expensive drug.
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Dosage: 375mg SC injection every two weeks for at least 4 to 6 months. The dosage depends upon the serum total IgE level. In ABPA, despite a high level of IgE, the routine dose of omalizumab is sufficient.[rx]
Supportive measures
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Airway clearance treatment for ABPA-related bronchiectasis patients should be prescribed nebulization with hypertonic saline with salbutamol and mucus clearance valves or percussion vests.
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Avoid areas and environmental conditions with high mold counts, such as decomposing organic materials and moldy indoor environments.
Differential Diagnosis of allergic bronchopulmonary aspergillosis[rx]
ABPA mimics many diseases that involve both airway and lung parenchyma. Undiagnosed lung infiltrates, pneumonia, and bronchiectasis make a long list of differential diagnoses. Following are a few diseases that should be carefully ruled out while making a diagnosis of ABPA:
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Corticosteroid-dependent asthma without ABPA
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Severe asthma with fungal sensitivity (SAFS)
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Cystic fibrosis (CF)
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Bronchiectasis
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Chronic necrotizing aspergillosis
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Chronic eosinophilic pneumonia
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Chronic obstructive pulmonary disease (COPD)
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Churg–Strauss syndrome
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Bronchocentric granulomatosis
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Acute eosinophilic pneumonia (including drug-induced pneumonitis)
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Pulmonary tuberculosis
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Parasitic infections
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Hypersensitivity pneumonitis
Staging
New Proposed clinical staging of allergic bronchopulmonary aspergillosis in asthmatic patients
Stage 0: Asymptomatic
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No previous diagnosis of ABPA
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Controlled asthma (according to GINA/EPR-3 guidelines)
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Fulfilling the diagnostic criteria of ABPA (ISHAM working group criteria)
Stage 1: Acute
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No previous diagnosis of ABPA
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Uncontrolled asthma/symptoms consistent with ABPA
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Meeting the diagnostic criteria of ABPA
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1a: With mucoid impaction – Mucoid impaction observed on chest imaging or bronchoscopy
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1b: Without mucoid impaction – Absence of mucoid impaction on chest imaging or bronchoscopy
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Stage 2: Response
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Clinical and/or radiological improvement and
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Decline in IgE by greater than or equal to 25% of baseline at 8 weeks
Stage 3: Exacerbation
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Clinical and/or radiological worsening and
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Increase in IgE by ≥ 50% from the baseline established during response/remission
Stage 4: Remission
Sustained clinical-radiological improvement and
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IgE levels persisting at or below baseline (or increase by less than 50%) for greater than or equal to 6 months off treatment
Stage 5a: Treatment-dependent ABPA
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Greater than or equal to two exacerbations within six months of stopping therapy or
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Worsening of clinical and/or radiological condition, along with immunological worsening (rise in IgE levels) on tapering oral steroids/azoles
Stage 5b: Glucocorticoid-dependent asthma
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Systemic glucocorticoids are required for the control of asthma while the ABPA activity is controlled (as indicated by IgE levels and thoracic imaging)
Stage 6: Advanced ABPA
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Extensive bronchiectasis due to ABPA on chest imaging and
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Complications (cor pulmonale and/or chronic type II respiratory failure)
EPR-3: third expert panel report; GINA: global initiative against asthma.
Complications
Complications of allergic bronchopulmonary aspergillosis include[rx][rx][rx]:
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Recurrent asthma exacerbations and steroid dependence
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Aspergilloma
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Invasive aspergillosis
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Chronic pulmonary aspergillosis
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Cavitation
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Local emphysema
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Chronic or recurrent lobar atelectasis
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Honeycomb fibrosis
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Complications related to bronchiectasis like hemoptysis, recurrent pulmonary infection
References
