What is the diagnosis of invasive aspergillosis (Invasive Aspergillus infection)?

From the Guidelines

Diagnosis of invasive aspergillosis requires a combination of clinical, radiological, and microbiological approaches, with chest CT imaging and bronchoalveolar lavage (BAL) being crucial for obtaining samples for culture and microscopy, as recommended by the 2018 ESCMID-ECMM-ERS guideline 1.

Diagnostic Approach

The diagnostic approach for invasive aspergillosis should include:

• Chest CT imaging to identify nodular lesions with a halo sign or cavitation
• Bronchoalveolar lavage (BAL) to obtain samples for culture and microscopy
• Galactomannan antigen testing on serum or BAL fluid, with a cutoff index of ≥0.5 in serum or ≥1.0 in BAL fluid considered positive
• PCR testing for Aspergillus DNA to provide additional diagnostic support
• Histopathological examination of tissue samples showing septate hyphae with 45-degree angle branching, which is definitive
• Beta-D-glucan assay, while less specific, can serve as a supportive test

Diagnosis Categorization

Diagnosis is categorized as:

• Proven (tissue invasion with hyphae plus positive culture)
• Probable (host factors plus clinical features plus mycological evidence)
• Possible (host factors plus clinical features without mycological confirmation)

Importance of Early Diagnosis

Early diagnosis is essential as mortality rates for invasive aspergillosis remain high, particularly in immunocompromised patients, as highlighted in the 2016 IDSA guideline 1. The diagnostic approach should be tailored to the patient's immune status, with more aggressive tissue sampling in patients who can tolerate invasive procedures.

Additional Considerations

The 2018 ESCMID-ECMM-ERS guideline 1 also recommends the use of direct microscopy, preferably using optical brighteners, histopathology, and culture for diagnosis, as well as the use of serum and BAL galactomannan measures as markers for the diagnosis of IA. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates.

In terms of treatment, the 2008 IDSA guideline 1 recommends early initiation of antifungal therapy in patients with strongly suspected invasive aspergillosis, with voriconazole being the preferred agent for primary treatment. The 2018 ESCMID-ECMM-ERS guideline 1 also recommends isavuconazole and voriconazole as the preferred agents for first-line treatment of pulmonary IA.

Overall, the diagnosis of invasive aspergillosis requires a comprehensive approach that incorporates clinical, radiological, and microbiological findings, with a focus on early diagnosis and tailored treatment to improve patient outcomes, as supported by the highest quality evidence from the 2018 ESCMID-ECMM-ERS guideline 1.

From the FDA Drug Label

To be included in the study, patients with pulmonary disease must have had definite (positive tissue histopathology or positive culture from tissue obtained by an invasive procedure) or probable (positive radiographic or computed tomography evidence with supporting culture from bronchoalveolar lavage or sputum, galactomannan enzyme-linked immunosorbent assay, and/or polymerase chain reaction) invasive aspergillosis. Patients with extrapulmonary disease had to have definite invasive aspergillosis.

The diagnosis of invasive aspergillosis can be made by:

• Definite diagnosis: positive tissue histopathology or positive culture from tissue obtained by an invasive procedure
• Probable diagnosis: positive radiographic or computed tomography evidence with supporting culture from bronchoalveolar lavage or sputum, galactomannan enzyme-linked immunosorbent assay, and/or polymerase chain reaction 2

From the Research

Diagnosis of Invasive Aspergillosis

• Invasive aspergillosis is an infection with high morbidity and mortality that affects mostly immunocompromised individuals, and early identification and targeted treatment of the infection is essential to improve survival of affected patients 3.
• Traditional diagnostic approaches, such as histopathology and culture, are still considered the gold standard but lack sufficient sensitivity 3.
• Newer serologic techniques, such as galactomannan (GM) and beta-glucan, have already been incorporated into clinical guidelines, but recent evidence suggests that their performance might be limited in certain clinical settings 3, 4.

Diagnostic Tests

• Galactomannan antigen detection is a rather reliable diagnostic test for invasive aspergillosis, particularly when a lower threshold of sensitivity is used 5.
• Beta-D-glucan assay was more sensitive than galactomannan assay (91.6% versus 80.67%) whereas galactomannan assay was more specific than beta-D-glucan assay (86.44% versus 76.27%) in the diagnosis of invasive aspergillosis 4.
• Combining both positive results of GM and BDG assays leaded to high specificity and positive likelihood ratio, but low sensitivity and negative likelihood ratio 6.

Combination of Diagnostic Tests

• The combined performance of GM and BDG or LFD assays is inconsistent in various studies, and further studies with sufficient sample size should focus on the diagnostic performance and cost-effectiveness of these combined tests in clinical setting 6.
• Both positive results of GM and LFD leaded to high sensitivity, similar specificity, low positive likelihood ratio and negative likelihood ratio 6.
• At least one positive result of GM or LFD conferred great sensitivity and low negative likelihood ratio, and both negative results of GM and LFD were beneficial to rule out IA 6.

Clinical Applications

• Tests for detection of galactomannan- (GM) and 1,3-β-d-glucan (BDG) are useful adjunctive tools for the early diagnosis of IA and may have a role in monitoring response to therapy 7.
• The sensitivity and specificity of these fungal biomarkers are not optimal and variations between patient populations are observed 7.
• Diagnostic algorithms that incorporate both GM and PCR have proven to be effective in early randomized trials as screening methods and can reduce the use of antifungal agents 3.