What tests should I order for a patient with a positive beta-D-glucan (BDG) test?

Diagnostic Workup for Positive Beta-D-Glucan

When you encounter a positive beta-D-glucan (BDG) result, immediately repeat the test within 3-5 days and obtain blood cultures, as two consecutive positive BDG results significantly improve diagnostic accuracy and a single positive result has poor specificity. 1

Immediate Assessment Steps

Repeat Beta-D-Glucan Testing

• Obtain a second BDG test within 3-5 days to confirm persistent positivity, as two consecutive positive results increase specificity from approximately 60% to 78% 2, 1
• A single positive result has limited positive predictive value, particularly in ICU settings where false positivity is common 2

Obtain Blood Cultures

• Draw at least two sets of blood cultures from different sites before initiating antifungal therapy 1, 3
• Blood culture sensitivity for invasive fungal infections ranges from only 21-71%, so negative cultures do not exclude infection 2, 3
• Blood cultures may take 2-5 days to become positive, but remain essential for species identification and susceptibility testing 2

Order Complementary Fungal Biomarkers

• Obtain serum galactomannan (GM) testing if aspergillosis is suspected, as GM has higher specificity than BDG for mold infections 2, 1
• The combination of positive blood culture OR positive BDG has 79% sensitivity for invasive candidiasis, while positive blood culture OR positive PCR reaches 98% sensitivity 2
• Consider Candida PCR if available, which has pooled sensitivity of 95% and specificity of 92% for invasive candidiasis 2

Imaging Studies

High-Resolution Chest CT

• Obtain high-resolution chest CT (HRCT) if pulmonary involvement is suspected, as early fungal infiltrates are often missed on conventional chest X-rays 2, 1
• Look for the "halo sign" (nodules 1-3 cm surrounded by ground-glass opacification), which suggests perifocal hemorrhage from angioinvasive fungal infection 2
• The "hypodense sign" (central hypodensity within nodules) is highly specific for fungal angiotropism with hemorrhagic infarction 2
• Cavitations and air-crescent signs typically appear during or after neutrophil recovery 2

Baseline CT Before Therapy

• Perform baseline chest CT in high-risk patients before starting intensive chemotherapy, as 38% of patients have pre-existing abnormalities that complicate later interpretation 4

Site-Specific Cultures

Obtain Cultures from Sterile Sites

• Collect cultures from any normally sterile site with clinical suspicion of infection, including cerebrospinal fluid, pleural fluid, peritoneal fluid, joint fluid, or tissue biopsies 2, 1
• For suspected intra-abdominal candidiasis, BDG becomes positive a median of 5-6 days before positive intra-abdominal cultures 2
• Tissue biopsy with histopathology provides definitive diagnosis when accessible 4

Do NOT Culture Respiratory Secretions

• Never use Candida isolation from respiratory secretions (sputum, tracheal aspirates) to guide antifungal treatment, as this represents colonization, not infection 5, 3

Assess for False Positive Causes

Common Confounding Factors

Before acting on a positive BDG, evaluate for these causes of false positivity:

• Hemodialysis with cellulose-containing membranes 2, 1, 5
• Administration of albumin or intravenous immunoglobulin products 2, 1, 5
• Antibiotics, particularly piperacillin-tazobactam or amoxicillin-clavulanate 2, 1
• Gram-positive or gram-negative bacteremia (10 of 14 bacteremic patients had false positive BDG) 1, 6
• Surgical gauze or glucan-containing medical materials 2, 1
• Mucositis or gastrointestinal mucosal disruption 1
• Fungal colonization without invasive disease 1

Risk Stratification

High-Risk Features Requiring Aggressive Workup

Assess for these risk factors that increase likelihood of true invasive fungal infection:

• Neutropenia (especially >10 days) or hematologic malignancy 2, 1, 4
• Hematopoietic stem cell or solid organ transplantation 1
• Prolonged ICU stay with multiple risk factors 1
• Recent abdominal surgery with complications 1
• Monocytopenia >10 days 4
• Karnofsky score <90 4
• Persistent fever despite broad-spectrum antibiotics 1

Additional Diagnostic Tests

Ophthalmologic Examination

• Perform dilated fundoscopic examination to rule out Candida endophthalmitis in all patients with candidemia 5

Consider Bronchoalveolar Lavage

• Obtain bronchoalveolar lavage (BAL) with GM testing if pulmonary aspergillosis is suspected, as BAL GM has higher sensitivity than serum GM 1

Special Population Considerations

Avoid BDG in Certain Populations

• Do not use BDG for clinical decision-making in pediatric patients, as optimal thresholds are not established and mean BDG levels are higher in uninfected children 1
• BDG has extremely poor performance in lung transplant recipients (specificity only 9%, positive predictive value 14%), with 90% having at least one false positive result 1

Patients on Antifungal Prophylaxis

• Recognize that BDG sensitivity may be reduced in patients receiving mold-active antifungal prophylaxis 1
• Echinocandins may cause false-negative BDG results by inhibiting β-D-glucan synthase 2

Critical Limitations of BDG Testing

Fungi NOT Detected by BDG

• BDG does NOT detect mucormycosis (Zygomycetes) 1, 5
• BDG does NOT reliably detect Cryptococcus species 2, 1
• If mucormycosis is suspected (negative GM, clinical presentation), BDG negativity increases likelihood of this diagnosis 1

Fungi Detected by BDG

• BDG detects Candida species, Aspergillus species, Pneumocystis jirovecii, Fusarium, Trichosporon, Saccharomyces, and Acremonium 2, 5, 7
• BDG cannot differentiate between these fungal species, requiring additional testing for species identification 2, 5

When to Initiate Empiric Antifungal Therapy

Start Treatment While Awaiting Results If:

• Patient is critically ill with septic shock and high clinical suspicion for invasive candidiasis 1
• Patient is neutropenic with persistent fever despite broad-spectrum antibiotics and high-risk features 1
• Clinical deterioration with radiographic findings suggestive of invasive fungal infection 1
• Two consecutive positive BDG results plus clinical signs of infection plus high-risk factors 2, 1

Preferred Empiric Regimen

• Echinocandin is first-line for suspected invasive candidiasis: caspofungin 70 mg loading then 50 mg daily, micafungin 100 mg daily, or anidulafungin 200 mg loading then 100 mg daily 1, 5

Common Pitfalls to Avoid

• Never initiate antifungal therapy based solely on a single positive BDG without supporting clinical or microbiological evidence 1, 5
• Do not ignore the high negative predictive value (>90%): a negative BDG is useful for ruling out invasive fungal infection 5, 3, 6
• Do not use BDG results from respiratory secretions or colonization sites to guide treatment 5
• Remember that source control (catheter removal, abscess drainage) is essential for successful treatment 5, 3