In a patient with knee swelling and a positive Lyme disease ELISA (enzyme‑linked immunosorbent assay) but negative IgG (immunoglobulin G) and IgM (immunoglobulin M) Western‑blot antibodies, what is the appropriate next step in diagnosis and management?

Diagnosis and Management of Positive Lyme ELISA with Negative Western Blot

This patient does NOT have serologic evidence of Lyme disease and should not be treated for Lyme disease based on these test results. 1

Understanding the Two-Tiered Testing Algorithm

The standard diagnostic approach for Lyme disease requires sequential testing, where a positive screening test (ELISA) must be confirmed by Western blot before reporting a positive serological result. 1

Interpretation of Your Patient's Results

• Positive ELISA with negative IgG and IgM Western blot = Negative for Lyme disease 1
• The negative confirmatory Western blot overrides the positive screening test, indicating this is a false-positive ELISA 1
• Studies confirm that screen-negative samples (and by extension, those with negative confirmatory tests) do not require further Lyme-specific testing 2

Why False-Positive ELISA Results Occur

False-positive screening tests are common and can result from: 3

• Cross-reactivity with other spirochetes (Treponema pallidum, relapsing fever Borrelia) 1, 3
• Viral infections (Epstein-Barr virus, Cytomegalovirus) 3
• Rheumatoid factor 3
• Other bacterial infections 3

This is precisely why the two-tiered system was implemented—to reduce false-positive results from ELISA alone. 4

Clinical Decision-Making for Knee Swelling

If Clinical Suspicion for Lyme Arthritis Remains High

Consider repeat serologic testing in 2-4 weeks ONLY if: 5

• Symptoms have been present for less than 4 weeks (antibodies may not yet be detectable) 5
• The patient has documented tick exposure in an endemic area 6
• The clinical presentation is consistent with Lyme arthritis (intermittent oligoarticular arthritis, especially knee involvement) 6

Important timing considerations: 5

• Antibodies develop approximately 2 weeks after symptom onset 5
• Maximum titers occur 3-4 weeks from onset 5
• Early antibiotic treatment can blunt antibody response 5

Alternative Diagnoses to Pursue

With negative confirmatory testing, you should actively investigate other causes of knee swelling: 7

• Septic arthritis (especially if monoarticular, fever, elevated WBC >12,500/mm³, ESR >40 mm/h, severe pain with passive range of motion) 7
• Reactive arthritis
• Juvenile idiopathic arthritis
• Other inflammatory arthropathies

Key clinical differentiators: 7

• Lyme arthritis typically presents with polyarticular involvement (especially ankle/knee together in 87% of cases) 7
• Minimal pain with passive range of motion suggests Lyme over septic arthritis 7
• One or fewer Kocher criteria favors Lyme 7

Critical Pitfalls to Avoid

• Do NOT treat based on positive ELISA alone—this leads to overdiagnosis, unnecessary antibiotic exposure, and delays in correct diagnosis 3, 4
• Do NOT interpret persistent antibodies as active infection—antibodies persist for months to years after treated or untreated infection 8, 9
• Do NOT order additional Lyme testing if Western blot is negative, as this is sufficient to rule out Lyme disease 2, 4
• Do NOT confuse cross-reactivity with true infection—consider testing for Treponema pallidum if syphilis is in the differential 1

Recommended Next Steps

1. Report the result as NEGATIVE for Lyme disease 1
2. Perform joint aspiration for cell count, Gram stain, culture, and crystal analysis 7
3. Consider PCR testing of synovial fluid if Lyme remains in differential despite negative serology (though this scenario represents seronegative Lyme borreliosis, which is rare and typically occurs with very short disease duration) 1
4. Pursue alternative diagnoses based on clinical presentation and joint fluid analysis 7