What is the diagnostic approach for Lyme disease?

Diagnostic Approach for Lyme Disease

Primary Diagnostic Strategy

For patients with erythema migrans (EM) rash in endemic areas, diagnose clinically and treat immediately without serologic testing. 1, 2 The presence of EM is sufficient for diagnosis, and laboratory confirmation is unnecessary and may delay appropriate treatment. 3, 4

Two-Tiered Serologic Testing Protocol

When serologic testing is indicated, use the CDC-recommended two-tiered approach: initial enzyme immunoassay (EIA/ELISA) followed by confirmatory Western immunoblot only if the first test is positive or equivocal. 1, 2

First-Tier Testing

• Perform IgG-EIA and IgM-EIA (or IFA if ELISA unavailable) as initial screening 1, 2
• ELISA is more reliable than IFA 1
• Do not proceed to Western blot if first-tier test is negative 1

Second-Tier Western Immunoblot Interpretation

• IgM positive: ≥2 of 3 bands (21-24,39,41 kDa) 1
• IgG positive: ≥5 of 10 bands (18,21-24,28,30,39,41,45,58,66,93 kDa) 1
• Critical pitfall: Never interpret fewer bands as positive—the 41-kDa band alone was found in 43% of healthy controls and cross-reacts with other bacterial flagellar proteins 1

When to Test vs. When NOT to Test

Test When:

• Intermediate pretest probability: Patient from endemic area with disseminated disease manifestations (arthritis, cranial neuropathies, carditis, meningitis) but no EM rash 1
• Endemic area exposure: Patients in or recently traveled to endemic regions with compatible symptoms 1, 2
• Facial paralysis in endemic areas: Up to 25% of facial paralysis cases in endemic regions are due to Lyme disease 1

Do NOT Test When:

• EM rash present: Clinical diagnosis is sufficient 1, 2
• Low pretest probability: Patients in non-endemic areas without travel history have only 10% positive predictive value, making false-positives more likely than true disease 1, 2
• Nonspecific symptoms alone: Fatigue, headache, myalgias without objective findings have poor predictive value 5, 3

Timing Considerations for Serologic Testing

Sensitivity varies dramatically by disease stage: 2, 3

• Early disease (first 2-4 weeks): Only 30-40% sensitive—negative serology does NOT exclude Lyme disease 2, 5
• Disseminated disease: 70-100% sensitive 2

For samples drawn >4 weeks after symptom onset, test IgG only; IgM-positive/IgG-negative results at this stage likely represent false-positive IgM. 5, 3

Alternative Diagnostic Methods (Limited Utility)

PCR Testing

• Synovial fluid: >75% sensitive for Lyme arthritis—useful adjunct 1
• CSF: Only 38% sensitive for early neuroborreliosis—not recommended as primary test 1
• Blood: Poor sensitivity, high contamination risk—not standardized for routine use 1
• Exception: PCR useful for novel species (B. miyamotoi, B. mayonii) 1

CSF Antibody Testing

• In the United States, serum two-tiered testing is preferred for neuroborreliosis 1
• Intrathecal antibody production testing (CSF/serum IgG ratio >1.0) may confirm diagnosis in high seroprevalence regions 1
• Must collect CSF and serum same day, diluted to match total protein 1

Culture

• Not recommended—labor-intensive, poor sensitivity 1

Critical Pitfalls to Avoid

Never use unvalidated alternative laboratory tests or non-standard interpretation criteria—these have 58% false-positive rates in healthy controls. 1 Only use FDA-cleared tests with CDC-recommended interpretation criteria. 1

Do not misinterpret persistent antibodies as active infection—antibodies persist for months to years after successful treatment and cannot indicate disease activity. 2, 5

Avoid testing patients with low pretest probability—even highly specific tests yield more false-positives than true-positives when pretest probability is low. 1

For suspected reinfection, obtain acute and convalescent sera to detect rising titers or increasing band numbers, as baseline antibodies persist from prior infection. 1

Geographic Considerations

Exposure history is the single most crucial factor determining pretest probability. 1 In non-endemic states, only 0.7% of patients with disseminated disease signs (arthritis, cranial neuropathies, meningitis) without endemic area travel actually had Lyme disease. 1

Consider alternative diagnoses in non-endemic regions: Southern tick-associated rash illness (STARI) can mimic EM in southeastern United States. 1