Lyme Disease Test

Aka: Lyme Disease Test, Lyme Titer, Lyme Disease Antibody, Lyme Borreliosis Antibody, Lyme ELISA, Lyme Western Blot, Lyme Immunoblot Test, Lyme Culture, Lyme PCR, Two Tiered Lyme Test Protocol, Borrelia Burgdorferi Antibody Test

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II. Indications

  1. Endemic area with classic lyme symptoms and signs
  2. Endemic area with non-specific symptoms >2 weeks
  3. No test needed if highly endemic area and classic signs
    1. Treat empirically if high pretest probablity
    2. Erythema Migrans in endemic area is diagnostic
    3. Titers are insensitive for Lyme Disease in <2 weeks

III. Precautions

  1. Information based on IDSA and CDC guidelines
    1. IDSA: Infectious Disease Society of America
    2. IDSA is considered standard of care recommendations
    3. Tertiary centers (e.g. Mayo) follow these guidelines
  2. Other guidelines (e.g. ILADS) are not reviewed here
    1. ILADS: International Lyme and Associated Diseases
    2. ILADS guidelines are considered controversial
  3. Avoid using labs that do not follow IDSA and CDC guidelines
  4. Avoid starting with Tier 2 confirmatory testing (EIA or Western Blot)
    1. High False Positive Rate
    2. Faint positive bands in uninfected person is common

IV. Mechanism

  1. Most testing for Borrelia Burgdorferi is to detect Antibody (EIA/ELISA, IF, Western Blot)
    1. Antigen tests (PCR) have specific indications (e.g. synovial PCR), but is otherwise not recommended
    2. Lyme Culture is rarely indicated
  2. Lyme IgM
    1. Present within 1-3 weeks after disease onset
    2. Peaks between 3 and 6 weeks
    3. Presence represents
      1. Early Lyme Disease
      2. Persists in prolonged Lyme Disease
      3. Reappears in Late Lyme Disease exacerbation
  3. Lyme Specific IgG
    1. Requires more than 3 weeks to develop
    2. Peaks months after disease onset

V. Labs: Modified Two Tiered Lyme Test Protocol (modified 2019)

  1. Tier 1: Initial Lyme Titer
    1. Obtain polyvalent enzyme immunoassay (EIA such as ELISA), or immunofluorescence assay (IF)
    2. Not needed if Erythema Migrans in endemic areas
    3. False Positive Rate is high
    4. Positive results are reflexed to confirmation testing
  2. Tier 2: Lyme confirmatory testing (if tier 1 test equivocal or positive)
    1. Option 1: Lyme Serology Second Generation Tests (approved by FDA, 2019, preferred)
      1. New pathway established for tests with better Test Sensitivity, Test Specificity and precision than the first test
      2. Since 2019, modified 2 tier confirmation is with another enzyme immunoassay (EIA), and recommended by CDC
    2. Option 2: Lyme Western Blot (conventional, older protocol, replaced by option 1)
      1. Western Blot for Lyme IgM and IgG has been historically used for confirmation before 2019
      2. Higher False Negatives than EIA testing in acute and early disseminated Lyme Disease
        1. False Negative in 60-75% of patients without disseminated disease (decreases to 10% in later stages)
      3. With Lyme Serology, Test Specificity: 99-100%
      4. IgG must be positive for symptoms >4 weeks
  3. References
    1. Mead (2019) MMWR Morb Mortal Wkly Rep 68(32): 703 +PMID:31415492 [PubMed]

VI. Labs: Available Tests

  1. Borrelia Burgdorferi IgG and IgM
    1. Testing available by enzyme immunoassay (EIA such as ELISA), immunofluorescence assay, and Western Blot
    2. Persists for years following effective Antibiotic treatment
    3. Positive test after treatment does not indicate failed Antibiotics or chronic infection
  2. Cerebrospinal fluid (CSF) for Intrathecal Lyme Antibody production (by Antibody index assay)
    1. Indicated for neurologic symptoms
  3. Synovial Fluid Lyme PCR
    1. Joint Aspiration in cases of suspected Lyme Arthritis
  4. Skin Biopsy of Erythema Migrans for Quantitative PCR
    1. Most sensitive test in early Erythema Migrans
    2. May be indicated in atypical rash presentations
    3. Sensitivity: 81%
    4. Nowakowski (2001) Clin Infect Dis 33:2023-7 [PubMed]
  5. Skin Culture of Erythema Migrans (uncommonly performed)
    1. Sensitivity: 60-80% for organisms
    2. Sample types
      1. Saline-lavage needle aspirate
      2. Punch Biopsy (2 mm) of leading edge
  6. C6 Peptide assay (IgG Enzyme Linked Immunosorbent Assay)
    1. Under study as of 2012 for replacement of the two tiered protocol
  7. Lyme urine Antigen (not recommended)
    1. High False Positive Rate and not recommended
  8. Borrelia Burgdorferi serum PCR
    1. Not recommended (some protocols use in atypical dermatitis)

VII. Efficacy

  1. Every available Lymes test is imperfect with False Positives and False Negatives (see causes below)
    1. Acute Lyme Disease diagnosis (esp. Erythema Migrans) should be clinical regardless of test results
  2. Modified Two Tiered Lyme Test Protocol
    1. Acute Erythema Migrans Rash present
      1. Test Sensitivity: 35 to 54% (compared with 25% via conventional Western Blot control group)
      2. Test Specificity: 99%
    2. References
      1. Branda (2017) Clin Infect Dis 64(8):1074-80 [PubMed]
  3. Two Tiered Lyme Test Protocol (original/conventionaL, with Western Blot confirmation, pre-2019)
    1. Timing in relation to Erythema Migrans rash
      1. Acute Erythema Migrans rash: 25-40% seropositive
      2. Two to four weeks after Erythema Migrans: 60-70% seropositive
      3. Six weeks after Erythema Migrans: 90% seropositive
    2. Timing in relation to Lyme phase
      1. Stage 1: Early localized
        1. Acute phase: 17% seropositive
        2. Convalescent: 53% seropositive
      2. Stage 2: Early disseminated
        1. Multiple Erythema Migrans lesions: 43% seropositive
        2. Cardiac or neurologic findings: 100% seropositive
      3. Stage 3: Late
        1. Arthritis or neurologic findings: 100% seropositive
    3. References
      1. Steere (2008) Clin Infect Dis 47(2): 188-95 [PubMed]

VIII. Causes: Lyme Serology False Positives

  1. Infectious Mononucleosis (esp. Lyme IgM)
  2. Rheumatologic Conditions (esp. Lyme IgM)
  3. Prior Lyme Vaccine (LYMErix)
    1. Test Western Blot and ignore OspA band
  4. Cross reactivity with Treponema infection
    1. Syphilis
    2. Yaws
    3. Relapsing Fever
  5. Late stage Lyme Disease
    1. Serology (e.g. ELISA for IgG and IgM) Test Specificity falls with time
    2. Early-Stage: 93% (as high as 98% when pretest probability >50%)
    3. Late-Stage: 81%

IX. Causes: Lyme Serology False Negatives

  1. Testing within first 2 weeks of symptoms (acute and early disseminated Lyme Disease)
  2. Antibiotics early in course of lyme infection
    1. Inadequate Antibiotic course can blunt seroconversion

X. Reference

  1. Steere in Mandell (2000) Infectious Disease, p. 2504-14
  2. (1995) MMWR Morb Mortal Wkly Rep 44:590 [PubMed]
  3. Klempner (2001) Am J Med 110:217-9 [PubMed]
  4. Samar (2024) Am Fam Physician 110(1):85-6 [PubMed]

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