What are the steps for investigating Lyme disease?

Lyme Disease Investigation Protocol

The most effective approach for investigating Lyme disease requires a two-tiered serologic testing algorithm consisting of an enzyme-linked immunoassay (EIA) or immunofluorescence assay (IFA), followed by a reflex Western immunoblot only if the first test is positive or equivocal. 1

Assessment of Pretest Probability

Before ordering any laboratory tests, evaluate the patient's pretest probability for Lyme disease:

• High pretest probability:

  • Presence of erythema migrans (EM) rash in endemic area
  • Recent travel to endemic regions with compatible symptoms
  • Tick exposure in endemic areas with compatible symptoms

• Intermediate pretest probability:

  • Compatible symptoms without EM in endemic areas
  • Possible tick exposure with compatible symptoms

• Low pretest probability:

  • Nonspecific symptoms in non-endemic areas
  • No history of travel to endemic regions

Diagnostic Algorithm

Step 1: Clinical Evaluation

• If classic erythema migrans (EM) is present in endemic area:

  • No laboratory testing required
  • Proceed directly to treatment 1

• If no EM but symptoms suggest Lyme disease:

  • Proceed to serologic testing

Step 2: Laboratory Testing

1. First-tier test: EIA or IFA

   • If negative → Lyme disease unlikely
   • If positive or equivocal → Proceed to second-tier test

2. Second-tier test: Western immunoblot

   • IgM Western blot (only interpret if symptoms ≤30 days)
     • Positive if ≥2 of 3 bands present
   • IgG Western blot (for all patients)
     • Positive if ≥5 of 10 bands present 1

Special Situations

Early Localized Disease (≤30 days)

• Sensitivity of serologic testing is low (30-40%) 1
• If high clinical suspicion despite negative serology:
  • Consider repeat testing in 2-4 weeks
  • Treat empirically if clinical presentation strongly suggests Lyme disease

Disseminated Disease (>30 days)

• Sensitivity of serologic testing improves to 70-100% 1
• IgM Western blot is not clinically interpretable after 6-8 weeks of symptoms 1

Neurologic Lyme Disease

• Consider CSF analysis for intrathecal antibody production
• PCR of CSF has limited sensitivity (38% for early neuroborreliosis) 1

Lyme Arthritis

• Synovial fluid PCR may be helpful (>75% sensitivity) 1

Common Pitfalls to Avoid

1. Testing patients with low pretest probability

   • False positives are more likely than true positives in non-endemic areas 1
   • Positive predictive value of testing is only 10% in low-incidence regions without travel history 1

2. Relying on IgM Western blot beyond 6-8 weeks of symptoms

   • IgM can persist and lead to false positive interpretations 1

3. Using unvalidated or non-standard laboratory tests

   • Alternative testing methods have high false-positive rates (up to 58%) 1

4. Performing Western blot without a preceding positive/equivocal EIA

   • Western blot should only be performed as a reflex test 1

5. Misinterpreting EM-like lesions in non-endemic regions

   • Southern tick-associated rash illness (STARI) can mimic EM 1

Reinfection Assessment

For patients with suspected reinfection:

• Perform thorough skin examination (most reinfections present with EM) 1
• If no EM present, serologic testing is recommended but interpret with caution
• Consider paired acute and convalescent serology to detect rising EIA titers or increasing number of immunoblot bands 1

By following this systematic approach to Lyme disease investigation, clinicians can accurately diagnose and appropriately treat patients while avoiding the pitfalls of unnecessary or misinterpreted testing.