What is the approach to an indeterminate beta-D-glucan (beta-D-glucan) result in a patient?

Approach to Indeterminate Beta-D-Glucan Results

An indeterminate beta-D-glucan result should prompt repeat testing within 3-5 days combined with comprehensive clinical assessment for invasive fungal infection risk factors, rather than triggering immediate antifungal therapy, as single positive results have poor specificity and consecutive positive results significantly improve diagnostic accuracy. 1

Understanding Indeterminate Results

• Beta-D-glucan testing has significant limitations with false positivity being a major concern, particularly when common confounding factors are present 1
• The specificity of beta-D-glucan can be improved by requiring consecutive positive results rather than relying on a single result 1
• A single indeterminate or borderline result should not be used alone to guide clinical decision-making 2, 3

Immediate Assessment Steps

Identify Confounding Factors for False Positives

Evaluate for the following causes of false positive results:

• Gram-positive or gram-negative bacteremia 1
• Hemodialysis 1, 2, 3
• Receipt of albumin or intravenous immunoglobulin products 1, 2, 3
• Certain antibiotics, particularly intravenous amoxicillin-clavulanate or piperacillin-tazobactam 1
• Exposure to surgical gauze or other materials containing glucan 1
• Mucositis or gastrointestinal mucosal disruption 1
• Fungal colonization without invasive disease 1

Assess Clinical Risk Factors for Invasive Fungal Infection

• Neutropenia or hematologic malignancy 1, 2, 3
• Hematopoietic stem cell or solid organ transplantation 3
• Prolonged ICU stay with multiple risk factors 3
• Recent abdominal surgery with complications 2
• Clinical signs of infection including persistent fever despite antibiotics 1, 2

Diagnostic Algorithm

Step 1: Repeat Beta-D-Glucan Testing

• Obtain a second beta-D-glucan test within 3-5 days to determine if results are consistently positive 1
• Two consecutive positive results significantly improve specificity compared to a single positive test 1

Step 2: Obtain Complementary Diagnostic Tests

• Blood cultures (at least two sets from different sites) 2, 3, 4
• Serum galactomannan testing if aspergillosis is suspected 1, 3
• High-resolution chest CT if pulmonary involvement is suspected (look for macronodules with halo sign, wedge-shaped lesions, or cavitary lesions) 1, 3
• Site-specific cultures from normally sterile sites when clinically indicated 2, 3, 4

Step 3: Clinical Decision-Making

Initiate antifungal therapy if:

• Two consecutive positive beta-D-glucan results PLUS clinical signs of infection PLUS high-risk factors 2, 3
• Positive blood culture for Candida or other fungi 2, 4
• Evidence of deep-seated fungal infection on imaging or biopsy 2, 3

Continue monitoring without antifungal therapy if:

• Single indeterminate result with identifiable confounding factors and low clinical suspicion 2, 3
• No clinical signs of infection and low-risk patient population 1, 2
• Repeat testing is negative 2, 3

Special Populations and Considerations

Pediatric Patients

• Beta-D-glucan testing is not currently recommended to guide pediatric clinical decision-making 1
• Mean beta-D-glucan levels are slightly higher in uninfected children compared to adults, and optimal thresholds for positivity are not established 1

Lung Transplant Recipients

• Beta-D-glucan has particularly poor performance in lung transplant recipients, with specificity as low as 9% and positive predictive value of only 14% 1
• In one study, 90% of lung transplant patients had at least one positive result, making routine surveillance testing unreliable in this population 1

Patients on Antifungal Prophylaxis

• Sensitivity of beta-D-glucan may be reduced in patients receiving mold-active antifungal prophylaxis 1, 5
• False negative results can occur with concomitant use of anti-mold antifungal agents 1

Important Caveats and Pitfalls

Test Limitations

• Beta-D-glucan does NOT detect mucormycosis (zygomycetes) or most Cryptococcus species 1, 5
• If mucormycosis is suspected based on negative galactomannan and clinical presentation, beta-D-glucan negativity increases the likelihood of this diagnosis 1
• The test detects Candida, Aspergillus, Pneumocystis, and Fusarium species but cannot differentiate between them 1, 5

Avoid Common Errors

• Do not initiate antifungal therapy based solely on a single indeterminate beta-D-glucan result without supporting clinical or microbiological evidence 2, 3
• Do not use beta-D-glucan results from respiratory secretions or colonization sites to guide treatment decisions 2
• Do not ignore the high negative predictive value (>90%): a negative result is useful for ruling out invasive fungal infection 3, 6

Optimal Cutoff Values

• Different cutoff values affect test performance: sensitivity/specificity of 95%/86% at 30 pg/mL, 85%/95% at 60 pg/mL, and 78%/98% at 80 pg/mL 6
• Higher cutoff values improve specificity but reduce sensitivity 6

When to Consider Empiric Antifungal Therapy

Start empiric therapy while awaiting repeat testing if:

• Patient is critically ill with septic shock and high clinical suspicion for invasive candidiasis 4
• Neutropenic patient with persistent fever despite broad-spectrum antibiotics and high-risk features 1, 2
• Clinical deterioration with radiographic findings suggestive of invasive fungal infection 1, 3

Preferred empiric regimens:

• Echinocandin (caspofungin 70 mg loading, then 50 mg daily; micafungin 100 mg daily; or anidulafungin 200 mg loading, then 100 mg daily) for suspected invasive candidiasis 1, 4
• Broader spectrum coverage if aspergillosis or other molds are suspected based on clinical presentation 1, 2