What is the role of beta-D-glucan (Beta-D-glucan) in diagnosing and treating invasive fungal infections?

Beta-D-Glucan Testing for Invasive Fungal Infections

Beta-D-glucan (BDG) testing is a useful adjunctive diagnostic tool for invasive candidiasis and other fungal infections in immunocompromised patients, but should never be used as a standalone test due to significant false-positive rates, particularly in ICU settings. 1

Diagnostic Performance

Overall Accuracy

• Sensitivity: 75-80% and specificity: approximately 80% for diagnosing invasive candidiasis in meta-analyses 1
• The negative predictive value is high (>90%), making it most useful for ruling out invasive fungal infections rather than confirming them 2
• Positive predictive value is limited, especially in ICU patients where false positivity is common 1

Spectrum of Detection

• BDG detects cell wall components from Candida species, Aspergillus species, Pneumocystis jirovecii, and several other fungi 1
• Does NOT detect Mucorales (mucormycosis) or Cryptococcus species, as these fungi have low or absent BDG in their cell walls 1
• This limitation is critical: a negative galactomannan with positive clinical suspicion should raise concern for mucormycosis, not be reassured by negative BDG 1

Critical Causes of False-Positive Results

High-Risk Scenarios (Avoid Testing or Interpret with Extreme Caution)

• Hemodialysis (odds ratio 4.78 for false positivity) 2
• Intravenous albumin or immunoglobulin administration 1, 2
• Intravenous amoxicillin-clavulanate (not available in US) 1
• Mucositis or gastrointestinal mucosal disruption allowing bacterial/fungal translocation 1
• Surgical gauze or glucan-containing materials 1
• Gram-positive or gram-negative bacteremia 1

Poor Specificity in Certain Populations

• In one lung transplant study, 90% of patients had at least one positive result with sensitivity/specificity of only 64%/9% 1
• ICU patients have markedly higher false-positive rates compared to healthy controls 1

Clinical Application Algorithm

When to Order BDG Testing

1. Immunocompromised patients (neutropenia, hematologic malignancy, stem cell/solid organ transplant) with unexplained fever or clinical signs of invasive fungal infection 1
2. Serial testing (at least twice weekly) is superior to single measurements 1
3. Avoid in patients with multiple false-positive risk factors listed above unless clinical suspicion is extremely high 1

Interpreting Results

Positive BDG (≥80 pg/mL cutoff for Fungitell):

• Requires additional diagnostic confirmation before initiating therapy 1
• Obtain blood cultures, site-specific cultures, and consider additional biomarkers (mannan/anti-mannan if available) 1
• Assess for false-positive causes systematically 1, 2
• Two consecutive positive results improve specificity over single measurement 1

Negative BDG:

• High negative predictive value (>90%) makes this useful for excluding invasive fungal infection 2
• However, consider mucormycosis if galactomannan also negative but clinical/radiologic suspicion remains 1

Treatment Decision Framework

Do NOT treat based on BDG alone. Initiate antifungal therapy when: 1, 3

• Positive BDG PLUS clinical signs of infection PLUS high-risk factors (neutropenia, recent abdominal surgery, ICU with multiple risks)
• OR positive blood culture for Candida
• OR evidence of deep-seated candidiasis on imaging/biopsy

Specific Fungal Infections

Invasive Candidiasis

• BDG can detect candidemia days to weeks before positive blood cultures 1
• Combined with mannan/anti-mannan antibody testing, diagnostic sensitivity increases to 83% (versus 58-59% for either alone) 1
• In hepatosplenic candidiasis, BDG or mannan was positive median 16 days before radiological detection 1

Invasive Aspergillosis

• BDG sensitivity for invasive aspergillosis ranges 68-85% depending on the study 4
• Galactomannan testing is preferred for aspergillosis diagnosis, but BDG may detect cases missed by galactomannan 1, 4
• In hematologic malignancy patients, BDG showed higher sensitivity than galactomannan for invasive aspergillosis in some studies 1

Pneumocystis jirovecii

• BDG shows 100% sensitivity for Pneumocystis pneumonia in multiple studies 4
• This is a major advantage over more specific fungal tests 4

Impact of Antifungal Therapy

• Prophylactic or empiric antifungal treatment reduces diagnostic sensitivity 1
• However, empirical systemic antifungal treatment did not completely eliminate BDG sensitivity in one large study 2
• Decreasing BDG levels may correlate with treatment response, making serial monitoring potentially useful 1

Key Pitfalls to Avoid

1. Never use BDG as sole criterion for starting antifungal therapy - the false-positive rate is too high 1, 3
2. Do not test patients on hemodialysis or receiving albumin/IVIG without understanding results will likely be uninterpretable 1, 2
3. Do not assume negative BDG rules out mucormycosis - these organisms lack BDG 1
4. Do not treat Candida colonization (e.g., respiratory secretions) based on positive BDG 3
5. Optimal cutoff values and number of positive tests required remain uncertain - heterogeneity across studies prevents definitive recommendations 1, 5

Pediatric Considerations

• Limited data exist for children 1
• Mean BDG levels are slightly higher in healthy children than adults 1
• Current recommendation: do not use BDG to guide pediatric clinical decision-making until more data available 1

Testing in Non-Serum Samples

• CSF BDG: 100% sensitivity and 95-98% specificity for non-Candida fungal CNS infections 1
• Bronchoalveolar lavage: poor positive predictive value for fungal pneumonia 1
• Limited case report data for other body sites 1