What are the diagnostic criteria and treatment options for invasive aspergillosis?

Diagnosis of Invasive Aspergillosis

The diagnosis of invasive aspergillosis requires a combination of histopathological documentation, culture confirmation, radiological findings, and non-culture-based biomarker testing, with bronchoscopy and tissue sampling being the cornerstone diagnostic procedures for definitive diagnosis. 1

Diagnostic Categories

• Invasive aspergillosis is categorized into three levels of diagnostic certainty: proven, probable, and possible 1
• Proven aspergillosis requires histopathological documentation of infection and a positive culture from a normally sterile site 1
• Probable aspergillosis requires fulfillment of criteria in three categories: host factors, clinical manifestations, and microbiological evidence 1
• These definitions were developed by the European Organization for Research in Treatment of Cancer–Mycoses Study Group for standardized research purposes but provide a framework for clinical diagnosis 1

Microbiological Diagnosis

• Culture confirmation is important to differentiate aspergillosis from other filamentous fungal infections like fusariosis and scedosporiosis 1
• Aspergillus species grow well on standard fungal media and can be identified to species level in most laboratories 1
• Blood cultures have limited utility as they are often negative even in disseminated infection 1
• Specimens should be cultured on fungal media for optimal growth of Aspergillus species 1
• False-negative culture results may occur in patients already receiving antifungal therapy or when sampling cannot be performed directly in the affected area 1

Invasive Diagnostic Procedures

• Bronchoalveolar lavage (BAL), transthoracic percutaneous needle aspiration, or video-assisted thoracoscopic biopsy are standard procedures for establishing diagnosis 1, 2
• BAL should be performed at a segmental bronchus supplying an area with radiographic abnormalities 2
• Fluid and tissue specimens may reveal characteristic angular dichotomously branching septate hyphae on direct microscopic examination 1
• Direct microscopy with calcofluor white stain allows rapid visualization of fungal elements 2
• Invasive procedures may be impractical in patients who are hemodynamically unstable, severely hypoxic, or have low platelet counts 1

Radiological Diagnosis

• High-resolution CT scan is the diagnostic imaging method of choice and should be performed within 24 hours of clinical suspicion 2
• The "halo sign" and "air-crescent sign" on CT are characteristic but not diagnostic of invasive pulmonary aspergillosis 1
• These radiological features are more commonly seen in neutropenic hosts with hematologic conditions 1
• Other angioinvasive filamentous fungi and certain bacteria may cause similar radiological features 1
• In pediatric patients, cavitation and the air crescent or halo signs are less frequently observed compared to adults 3

Non-Culture-Based Biomarker Testing

• Galactomannan enzyme immunoassay (EIA) has been validated as a surrogate marker for invasive aspergillosis 1, 2
• Serum galactomannan testing has sensitivity of 74% and specificity of 85% at a cutoff of 0.5 2
• Galactomannan can also be detected in CSF samples from patients with CNS aspergillosis and in BAL fluid specimens 1, 2
• Beta-D-glucan (BDG) testing in serum has sensitivity of 50-70% and specificity of 91-99% in patients with hematological malignancies 2
• BDG testing should not be relied upon as the sole diagnostic test due to its limitations in specificity 2
• Serial assessment of galactomannan antigenemia may facilitate therapeutic monitoring, though this remains investigational 1

Molecular Diagnostic Methods

• Aspergillus PCR testing of blood or BAL samples can be valuable in immunocompromised patients 2
• PCR tests can detect fungal DNA even after antifungal treatment has been initiated 2
• Lack of standardization across laboratories limits inclusion of PCR as a standard mycological criterion for diagnosis 1, 2

Diagnostic Pitfalls and Considerations

• False-positive galactomannan results may occur in patients undergoing chemotherapy or with mucositis 2
• No single test has sufficient sensitivity to rule out invasive aspergillosis; multiple complementary tests are needed 2, 4
• In immunocompromised patients with hematological malignancies, multiple diagnostic tests should be performed simultaneously due to high mortality risk 2, 5
• Sensitivity of fungal cultures from BAL is limited (30-60%) 2, 4

Diagnostic Algorithm

1. Perform high-resolution CT scan within 24 hours of clinical suspicion 2
2. Obtain serum galactomannan and beta-D-glucan tests 1, 2
3. Perform bronchoscopy with BAL for direct microscopy, culture, and galactomannan testing 1, 2
4. Consider tissue biopsy for histopathology when feasible 1
5. Interpret results in the context of host factors and clinical manifestations 1
6. Consider molecular testing (PCR) as an adjunctive diagnostic tool 2