Laboratory Studies
Because Aspergillus infection may cause colonization, allergy, or invasive infection, its manifestations are quite variable and are best considered based on the disease process.
Allergic bronchopulmonary aspergillosis (ABPA) is defined by several abnormalities, including the following:
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Asthma
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Eosinophilia
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Positive skin test result for A fumigatus
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Marked elevation of the serum immunoglobulin E (IgE) level to greater than 1000 IU/dL
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Fleeting pulmonary infiltrates
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Central bronchiectasis
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Mucoid impaction
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Positive test results for Aspergillus precipitins (primarily immunoglobulin G [IgG], but also immunoglobulin A [IgA] and immunoglobulin M [IgM])
Minor criteria for diagnosis include positive Aspergillus radioallergosorbent assay test results and culture findings for Aspergillus in sputum.
Diagnostic criteria for ABPA in persons with cystic fibrosis (CF) were revised by the Cystic Fibrosis Foundation. ABPA is considered a definite diagnosis requiring treatment if the following are noted [30] :
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Clinical deterioration, including cough, wheeze, increased sputum production, diminished exercise tolerance, or diminished pulmonary function
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Total serum IgE level greater than 1000 IU/mL or a greater than twofold rise from baseline
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Positive serology results for Aspergillus (Aspergillus precipitins or Aspergillus -specific IgG or IgE)
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New infiltrates on chest radiographs or computed tomography (CT) scans
Treatment for ABPA is also recommended in patients with CF who have new radiographic findings and symptoms and a change in baseline IgE level to greater than 500 IU/mL. [30]
Definitive diagnosis of invasive aspergillosis or chronic necrotizing Aspergillus pneumonia depends on the demonstration of the organism in tissue.
In the appropriate clinical setting of pulmonary infiltrates in a patient who is neutropenic or immunosuppressed, visualization of the characteristic fungi using Gomori methenamine silver stain or Calcofluor or a positive culture result from sputum, needle biopsy, or bronchoalveolar lavage (BAL) fluid should result in the prompt institution of therapy.
This is especially important after bone marrow transplantation because a positive Aspergillus culture result from sputum has a 95% positive predictive value for invasive disease. However, a negative fungus result from culture of sputum or BAL fluid does not exclude pulmonary aspergillosis because Aspergillus is cultured from sputum in 8-34% of patients and from BAL fluid in 45-62% of patients eventually found by biopsy or autopsy to have invasive disease.
An assay to detect galactomannan, a major component of the Aspergillus cell wall, is available. [4] Patients who are at high risk, such as those who have received stem cell transplants or who have prolonged neutropenia, may be screened for the development of invasive Aspergillus infection by monitoring serum galactomannan levels weekly. [5]
One study of serum galactomannan index (GMI) found that charting early GMI trends during the first two weeks of antifungal therapy can be helpful in predicting clinical outcomes. A reduction in GMI between baseline and week 1 predicted a good clinical response. [31]
The presence of an elevated galactomannan level in BAL fluid may also be helpful in the diagnosis of pulmonary aspergillosis in patients in whom compatible radiographic changes are present and BAL testing is performed in the suspicious area. [32] A meta-analysis and systematic review determined that the measurement of BAL-galactomannan levels may help in diagnosing invasive aspergillosis early. [33]
A study by Luong et al of 150 BAL samples from lung transplant recipients concluded that real-time polymerase chain reaction (PCR) assays could be useful in diagnosis of invasive aspergillosis in high-risk populations. Pan-Aspergillus PCR combined with BAL galactomannan testing was 97% specific and 93% sensitive for invasive pulmonary aspergillosis. Species-specific real-time PCR assays for A fumigatus and for A terreus could be used to rule out or identify the common A fumigatus and the amphotericin B-resistant A terreus. [34]
Aspergilloma does not cause many characteristic laboratory abnormalities. Aspergillus precipitin antibody test results (ie, for IgG) are usually positive. [3]
Imaging Studies
ABPA may cause variable manifestations on chest radiographs, from fleeting pulmonary infiltrates to mucoid impaction to central bronchiectasis. Mucoid impaction of bronchiectatic areas may cause a lobulated infiltrate, which has been likened to a cluster of grapes or a hand in a mitten. CT is helpful for better defining bronchiectasis, and scans may show that apparent lobulated masses are mucus-filled dilated bronchi. Areas of atelectasis related to bronchial obstruction from mucoid impaction may be present.
In aspergilloma, chest radiography reveals a mass in a preexisting cavity, usually in an upper lobe, manifested by a crescent of air partially outlining a solid mass. As the patient is moved onto his or her side or from supine to prone, the mass is typically observed to move within the cavity. CT images provide better definition of the mass within a cavity and may demonstrate multiple aspergillomas in areas of extensive cavitary disease. The scanning may be performed with the patient in the supine and prone positions to demonstrate movement of the mass within the cavity.
In invasive aspergillosis, chest radiographic features are variable, with solitary or multiple nodules, cavitary lesions, or alveolar infiltrates that are localized or bilateral and more diffuse as disease progresses. CT images may be very helpful in the early diagnosis of aspergillosis because they may demonstrate a characteristic halo sign (ie, an area of ground-glass infiltrate surrounding nodular densities). [6, 7] Later disease may show a crescent of air surrounding nodules, indicative of cavitation. Because Aspergillus is angioinvasive, infiltrates may be wedge-shaped, pleural-based, and cavitary, which is consistent with pulmonary infarction.
Other Tests
With ABPA, prick or intradermal skin testing with Aspergillus antigen results in a positive reaction manifested by wheal and flare.
Procedures
In ABPA, mucoid impaction of dilated bronchi can cause a masslike appearance, and patients with ABPA sometimes undergo transthoracic needle aspiration in an effort to obtain diagnostic information.
ABPA may be observed in association with chronic eosinophilic pneumonia or cryptogenic organizing pneumonia (COP), and patients may require transbronchial or open biopsy for diagnosis of unresolving pulmonary infiltrates with or without mucoid impaction. In the proper context, prick or intradermal skin testing to confirm immediate hypersensitivity to Aspergillus should be performed first because a negative skin test result excludes the diagnosis of ABPA. [35]
Procedures that may be helpful for the diagnosis of invasive aspergillosis include the following:
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Bronchoscopy
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Needle biopsy
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Open lung biopsy
At bronchoscopy, BAL in areas of pneumonia may provide evidence for the diagnosis. Transbronchial biopsy may be helpful, but it may not be possible, because patients are often thrombocytopenic because of bone marrow suppression. Peripheral lesions may be amenable to transthoracic needle aspiration and biopsy. Open lung biopsy through a small thoracotomy or by video-assisted thoracoscopy may be the only way to obtain tissue samples large enough to confirm the presence of Aspergillus organisms in tissue. [32, 36]
Histologic Findings
Histopathology and silver staining for persons with invasive aspergillosis demonstrate the characteristic septate hyphae, branching at acute angles, and acute inflammatory infiltrate and tissue necrosis with occasional granulomata and blood vessel invasion. The airways of patients with ABPA contain mucus filled with degenerating eosinophils and typical fungal hyphae. ABPA may occur against a background of chronic eosinophilic pneumonia and bronchiolitis, granulomatous bronchitis, bronchocentric granulomatosis, and, occasionally, COP.
Staging
No staging protocol is used for invasive aspergillosis or aspergilloma. ABPA may be progressive, and the following five stages have been described [37] :
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Acute disease
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Remission
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Exacerbation or recurrence
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Corticosteroid-dependent asthma
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End-stage fibrosis
