Diagnosis of Lyme Disease
The diagnosis of Lyme disease requires a combination of clinical evaluation and appropriate laboratory testing, with erythema migrans (EM) rash being sufficient for diagnosis in endemic areas without the need for laboratory confirmation. 1
Clinical Approach to Diagnosis
Early Localized Disease (0-30 days)
- Erythema migrans (EM) is the hallmark of early Lyme disease, appearing as a gradually expanding annular lesion >5 cm in diameter, often with central clearing 1
- EM occurs in 70-80% of infected persons and is sufficient for diagnosis in patients from endemic areas without laboratory testing 1
- Early EM commonly presents with homogeneous or central redness rather than the classic "bull's-eye" appearance 2
- Associated symptoms may include fever, lymphadenopathy, myalgias, arthralgias, headache, fatigue, and regional lymphadenopathy 1, 3
Early Disseminated Disease (days to weeks after infection)
- Multiple EM lesions may appear as the infection spreads hematogenously 1
- Manifestations include facial palsy, meningitis, or carditis 1
- Laboratory confirmation becomes essential for diagnosis in the absence of EM 1
Late Disseminated Disease (weeks to months after infection)
- Characterized by recurrent large-joint arthritis 1
- Neurologic manifestations may include peripheral neuropathy, encephalopathy, or encephalomyelitis 1
- Laboratory confirmation is required for diagnosis 1
Laboratory Testing Algorithm
Two-Tiered Serologic Testing (Standard of Care)
- First tier: Enzyme-linked immunoassay (EIA/ELISA) or immunofluorescence assay (IFA) 1
- Second tier: If first tier is positive or equivocal, Western immunoblot is performed 1
- Sensitivity varies by disease stage:
- Specificity is high (>95%) during all stages of disease 1
Interpretation of Serologic Results
- Consider pretest probability based on exposure history and clinical presentation 1
- False positives are more likely than true positives in low-prevalence areas 1
- Positive predictive value is only 10% in non-endemic regions without travel history to endemic areas 1
Special Diagnostic Considerations
PCR and Culture Testing
- PCR can provide specific evidence of B. burgdorferi but has limited clinical utility due to:
- Synovial fluid PCR has better sensitivity (>75%) for Lyme arthritis 1
- PCR of CSF has low sensitivity (38%) for neuroborreliosis 1
- PCR of blood may be useful for detecting novel Borrelia species (B. miyamotoi and B. mayonii) 1
Testing for Reinfection
- Antibody persistence makes diagnosis of reinfection challenging 1
- Detailed history and physical examination are essential as most reinfected patients will have EM 1
- Consider acute and convalescent serologic testing to detect increases in antibody titers or bands 1
Testing Cerebrospinal Fluid
- Testing for intrathecal antibody production may be helpful in confirming neuroborreliosis 1
- CSF and serum should be collected on the same day and diluted to match total protein or IgG concentration 1
- A CSF/serum IgG EIA optical density ratio >1.0 indicates active intrathecal antibody production 1
Common Pitfalls in Lyme Disease Diagnosis
- Inappropriate testing in low-risk populations: False positives are more likely than true positives in patients from non-endemic areas without travel history 1
- Misinterpretation of EM-like lesions: Southern tick-associated rash illness (STARI) can mimic EM in southeastern United States 1
- Using unvalidated tests: Alternative laboratory tests may have high false-positive rates (up to 58%) 1
- Bypassing the two-tiered approach: Performing Western blot without first-tier EIA is not recommended for clinical diagnosis 1
- Over-reliance on PCR: Despite high specificity, PCR has limited sensitivity for blood and CSF samples 1
Diagnostic Algorithm
Assess pretest probability based on:
If EM rash is present and patient has been in an endemic area:
If no EM but symptoms suggestive of Lyme disease with appropriate exposure history:
For suspected late manifestations (arthritis, neurologic symptoms):