What are the causes of falsely elevated galactomannan levels?

Causes of Falsely Elevated Galactomannan

The most clinically important causes of false-positive galactomannan results are piperacillin-tazobactam administration, gastrointestinal graft-versus-host disease (GVHD), and aspiration or ingestion of foods containing galactomannan, particularly in patients with compromised intestinal mucosal barriers. 1, 2

Medication-Related False Positives

β-lactam/β-lactamase combination antibiotics are the most well-established pharmaceutical cause of false-positive galactomannan assays. 1

• Piperacillin-tazobactam is the most commonly implicated antibiotic, with documented batches containing galactomannan antigen that can produce false-positive results 1, 3
• Co-amoxiclav (amoxicillin-clavulanate) has also been identified in specific batches as containing galactomannan antigen 3
• These false positives occur because certain manufacturing processes for these antibiotics can introduce fungal-derived galactomannan contamination 3

Dietary and Aspiration-Related False Positives

Food aspiration or ingestion in patients with compromised intestinal barriers represents an increasingly recognized cause of false-positive galactomannan. 4, 5, 6

• Rice aspiration can cause marked elevation in both serum and BAL galactomannan levels, as demonstrated in cases of Mendelson's syndrome 4
• Enteral nutrition solutions have been documented to contain galactomannan and can cause false-positive results in both serum and bronchoalveolar lavage fluid after aspiration 5, 6
• Common foods containing galactomannan include hospital-prepared meals (79% positive in one study), canned vegetables, pasta, and rice from health food stores 3
• Fecal galactomannan is present in concentrations of 1.2-38.4 micrograms/gram and can translocate into circulation when intestinal mucosal barriers are compromised 3

Patient-Specific Risk Factors

Gastrointestinal chronic graft-versus-host disease is the only independent significant risk factor for false-positive galactomannan antigenaemia. 2

• Patients with gastrointestinal chronic GVHD have a positive predictive value of 0% for galactomannan testing, compared to 66.7% in those without GVHD 2
• The compromised intestinal mucosal barrier in GVHD allows dietary galactomannan to enter the bloodstream 3, 2
• Early post-transplant period (first 100 days after HSCT) is associated with lower positive predictive value (37.5%) compared to beyond 100 days (58.8%) 2

Cross-Reactivity with Other Organisms

Galactomannan assays can cross-react with non-Aspergillus organisms, though this is less common. 1

• Histoplasma capsulatum has documented cross-reactivity with galactomannan assays 1
• Penicillium species (rare pathogen in the United States) will produce positive galactomannan results as they share similar cell wall components with Aspergillus 1

Antifungal Therapy Effect

Concurrent anti-mold antifungal therapy can cause false-negative (not false-positive) galactomannan results. 1

• This is mentioned for completeness as it affects test interpretation, though it reduces rather than elevates galactomannan levels 1

Clinical Pitfalls and Practical Approach

When encountering positive galactomannan results, systematically evaluate for these confounding factors before initiating antifungal therapy:

• Review medication list specifically for piperacillin-tazobactam or amoxicillin-clavulanate use 1, 3
• Assess for recent aspiration events or enteral nutrition administration 4, 5, 6
• Evaluate for gastrointestinal GVHD in transplant recipients 2
• Consider timing relative to HSCT (higher false-positive rate in first 100 days) 2
• Take a detailed aspiration history in all patients with pneumonia and elevated galactomannan, as this is frequently overlooked 4

The positive predictive value of galactomannan is only 54% even in high-risk populations, necessitating correlation with clinical findings, CT imaging, and other diagnostic modalities. 1