What is the diagnostic approach for Borrelia?

Diagnostic Approach for Borrelia Infection

The diagnosis of Borrelia infection requires a two-tiered serological testing approach, starting with a screening ELISA or IFA followed by confirmatory Western blot, with direct detection methods reserved for specific clinical scenarios. 1, 2

Clinical Diagnosis

Lyme Disease (Borrelia burgdorferi)

• Erythema Migrans (EM):

  • Pathognomonic skin lesion occurring in 60-80% of patients
  • Gradually expanding erythematous lesion (≥5 cm diameter) with partial central clearing
  • When classic EM is present in an endemic area, clinical diagnosis is sufficient without laboratory confirmation 2, 1
  • EM typically appears 3-30 days after tick bite

• Early Disseminated Disease (days to weeks after infection):

  • Multiple EM lesions
  • Neurological manifestations (meningitis, cranial nerve palsy, radiculopathy)
  • Cardiac involvement (atrioventricular block, myopericarditis)
  • Arthralgia, myalgia, fatigue, headache

• Late Disease (months to years after infection):

  • Arthritis (particularly knee)
  • Acrodermatitis chronica atrophicans (Europe, associated with B. afzelii)
  • Neurological manifestations (encephalopathy, polyneuropathy)

Tick-Borne Relapsing Fever (TBRF)

• Caused by multiple Borrelia species (not B. burgdorferi)
• Characterized by recurring episodes of high fever with septicemic symptoms
• Diagnosis primarily by direct detection of spirochetes in blood during febrile episodes 1

Laboratory Diagnosis

Serological Testing for Lyme Disease

1. First-Tier Screening:

   • ELISA or IFA for detection of antibodies against B. burgdorferi
   • Sensitivity: 85-100%; Specificity: 79-95%
   • Report as positive, negative, or equivocal 2

2. Second-Tier Confirmation (only if first-tier is positive/equivocal):

   • Western Blot (immunoblot)
   • IgM criteria: ≥2 of 3 specific bands (21-24,39,41 kDa)
   • IgG criteria: ≥5 of 10 specific bands (18,21-24,28,30,39,41,45,58,66,93 kDa)
   • Specificity >95% 2

3. Alternative Two-Tier Testing:

   • Two-EIA approach (whole-cell sonicate EIA followed by C6 EIA)
   • Higher sensitivity for early Lyme disease (61% vs. 48%) with equivalent specificity (99.5%) 2

Direct Detection Methods

1. Culture:

   • Limited utility due to low sensitivity and technical difficulty
   • Reserved for reference laboratories and specific clinical scenarios
   • Highest yield from skin biopsy of EM lesions (50-70% sensitivity) 1, 2

2. PCR:

   • Useful for synovial fluid in suspected Lyme arthritis (50-70% sensitivity)
   • Low sensitivity in CSF (10-30%) 1
   • Not routinely recommended for blood samples

3. Microscopy for TBRF:

   • Direct visualization of spirochetes in peripheral blood during febrile episodes
   • Sensitivity approximately 70% using dark-field microscopy or Giemsa/Wright stain 1

Special Considerations and Pitfalls

• Timing of Antibody Response:

  • IgM antibodies develop ~3 weeks post-infection
  • IgG antibodies develop ~6 weeks post-infection
  • Early antibiotic treatment may blunt or prevent antibody response 2

• False Negatives:

  • Early infection (seronegative window)
  • Immunosuppressed patients
  • Prior antibiotic treatment

• False Positives:

  • Cross-reactivity with other spirochetes (especially syphilis)
  • Autoimmune diseases
  • Other infections

• Neuroborreliosis:

  • Intrathecal antibody production (comparison of CSF and serum antibodies) is helpful
  • PCR of CSF has low sensitivity (10-30%) 1

• Post-Treatment Serology:

  • Antibodies may persist for months to years after successful treatment
  • Not useful for monitoring treatment response

Diagnostic Algorithm

1. Patient with EM rash in endemic area:

   • Clinical diagnosis is sufficient
   • Treat empirically without waiting for serological confirmation

2. Patient with suspected early disseminated or late Lyme disease:

   • Two-tier serological testing (ELISA/IFA followed by Western blot)
   • All patients should be seropositive by IgG immunoblot in late disease

3. Patient with suspected Lyme arthritis:

   • Two-tier serological testing
   • Consider PCR of synovial fluid if diagnosis uncertain

4. Patient with suspected neuroborreliosis:

   • Two-tier serological testing of serum
   • CSF analysis for intrathecal antibody production
   • PCR of CSF (limited sensitivity)

5. Patient with suspected TBRF:

   • Blood smear examination during febrile episodes
   • PCR targeting 16S rRNA or flagellin genes may be helpful

Remember that routine testing is not recommended for patients with nonspecific symptoms without objective findings or for patients with typical amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, dementia, new-onset seizures, or psychiatric illness 2.