What is the role of alpha defensin testing in diagnosing periprosthetic joint infections in adult patients?

Alpha Defensin Testing for Periprosthetic Joint Infection

Alpha defensin testing of synovial fluid is a highly accurate confirmatory test for periprosthetic joint infection, demonstrating 97% sensitivity and 96% specificity when used alone, and achieving near-perfect specificity (100%) when combined with synovial fluid CRP. 1

What Alpha Defensin Is and How It Works

• Alpha defensin is an antimicrobial peptide naturally released by neutrophils responding to pathogens in synovial fluid 1
• The test nearly matches the Musculoskeletal Infection Society (MSIS) definition for prosthetic joint infection in diagnostic accuracy 1
• Available as both an ELISA test and a rapid lateral flow device (Synovasure) for point-of-care testing 2, 3

Diagnostic Performance

As a Standalone Test

• Sensitivity: 81-97% across multiple studies 4, 2, 5, 3
• Specificity: 95-100% across multiple studies 4, 2, 5, 3
• The lateral flow device version shows 92.1% sensitivity and 100% specificity 2

Combined with Synovial Fluid CRP

• When both tests are positive (AND logic): 73% sensitivity, 99.3% specificity - this approach provides the highest certainty for confirming infection 5
• When either test is positive (OR logic): 91.9% sensitivity, 79.5% specificity - this approach maximizes detection but increases false positives 5
• The American College of Radiology notes that combining alpha defensin with CRP achieves 97% sensitivity and 100% specificity 1

Clinical Role: Confirmatory, Not Screening

Alpha defensin should be used as a confirmatory test rather than a screening test due to its high specificity but variable sensitivity. 3

• The test is most valuable when positive, as it provides near-certainty of infection 3
• A negative result does not reliably exclude infection, particularly in specific clinical scenarios 3
• The synovial fluid leukocyte count remains more sensitive for screening purposes, especially in chronic infections 3

Important Limitations and False Results

False Negatives (7-23% of infections missed):

• Low-virulence organisms (Cutibacterium acnes, coagulase-negative staphylococci) may not trigger sufficient neutrophil response 5
• Draining sinuses are associated with false negative results 5
• Chronic infections show lower sensitivity (44-54%) compared to acute infections 3

False Positives (4-5% of non-infected cases):

• Metallosis is the most common cause of false positive results 5
• Inflammatory arthropathies may theoretically cause false positives, though the test performed well even in populations with 23% systemic inflammatory disease 4
• Combining with synovial fluid CRP (threshold 3 mg/L) eliminates false positives without reducing sensitivity 4

Practical Clinical Algorithm

When to Order Alpha Defensin:

1. After elevated serum ESR, CRP, or IL-6 suggest possible infection 1
2. During joint aspiration workup for suspected periprosthetic joint infection 1
3. As part of comprehensive synovial fluid analysis including cell count, differential, culture, and leukocyte esterase 1

How to Interpret Results:

• Positive alpha defensin + positive synovial fluid CRP: Proceed with treatment for infection (99.3% specificity) 5
• Positive alpha defensin alone: High likelihood of infection, but consider metallosis if other findings inconsistent 5
• Negative alpha defensin: Cannot exclude infection; rely on other diagnostic criteria, especially if draining sinus present or low-virulence organism suspected 5, 3

Key Advantages

• Unaffected by concurrent antibiotic treatment, unlike cultures 4
• Rapid results with lateral flow device (can be performed at point-of-care) 2, 3
• Highly specific - particularly valuable in early postoperative period (91% specificity) when other markers may be elevated 3
• Performs well despite presence of inflammatory comorbidities 4

Evidence Quality Note

The most recent ACR Appropriateness Criteria (2023) 1 and multiple high-quality prospective studies 4, 2, 5, 3 consistently support alpha defensin's role as a highly specific confirmatory test, though sensitivity varies by infection chronicity and organism virulence.