Lyme Disease - Borrelia burgdorferi

Diagnosis

Lyme Disease Evaluation

Indications for Testing

  • Patient at risk for Lyme disease with clinical symptoms
    • Tick bite
    • Endemic area
  • No testing necessary, if patient presents with tick bite and erythema migrans – proceed with treatment

Laboratory Testing

  • Current two-step testing CDC recommendations for serologic diagnosis of Lyme disease
  • Borrelia burgdorferi or C6 peptide antibodies total by ELISA
    • Positive or indeterminate (if neurological symptoms present, see Neurologic Disease Evaluation below)
      • <4 weeks after disease onset
        • B. burgdorferi IgG and IgM antibodies by Western blot
          • Positive IgG and negative IgM – Lyme disease confirmed
          • Negative IgG and positive IgM – Lyme disease or false-positive IgM
            • Follow-up IgG Western Blot (within 30 days) recommended to help confirm Lyme disease and rule out false-positive IgM Western Blot
          • Negative IgG and IgM – consider other causes of false-positive result (syphilis, rheumatoid arthritis, acute EBV, HIV, subacute bacterial endocarditis, systemic lupus erythematosus, periodontitis)
            • If Lyme disease still suspected or patient immunocompromised – order Borrelia spp DNA by PCR
      • >4 weeks after disease onset
        • B. burgdorferi IgG antibodies by Western blot
          • Positive – Lyme disease confirmed
          • Negative – see negative IgG and IgM above
      • Consider coinfection with Babesia microti, Anaplasma phagocytophilum (HGA), or Ehrlichia chaffeensis
    • Negative
      • Endemic regions – consider coinfection with Babesia microti, Anaplasma phagocytophilum, Ehrlichia chaffeensis
        • Negative – no further testing on initial specimen; test convalescent sample
      • Nonendemic regions – no further testing on initial specimen; test convalescent sample

Neurologic Disease Evaluation

Indications for Testing

  • Meningoradiculitis, meningitis, cranial nerve deficits

Criteria for Diagnosis

  • Suggested criteria for Lyme neuroborreliosis (European Federation of Neurological Societies, 2010)

    Criteria

    • Neurological symptoms suggestive of Lyme neuroborreliosis (LNB) without other obvious reason
    • CSF pleocytosis
    • Intrathecal B. burgdorferi antibody production

    Definite neuroborreliosis*

    • All three criteria fulfilled

    Possible neuroborreliosis**

    • Two criteria fulfilled

    *Applies to all subclasses of LNB except for late LNB with polyneuropathy where the following are required for diagnosis: peripheral neuropathy, acrodermatitis chronica atrophicans, B. burgdorferi-specific antibodies in serum

    ** If no intrathecal B. burgdorferi antibody production, B. burgdorferi-specific IgG antibodies in serum must be found after 6 weeks

Laboratory Testing

  • Acute neurological symptoms present
    • Full meningitis workup (CSF studies)
      • Lumbar fluid analysis; should also include testing for other bacterial and viral etiologies (eg, West Nile virus)
      • Cell count – lymphocytic pleocytosis is typical (>8 wbc/mm3)
      • Total protein, glucose, culture with gram stain
    • B. burgdorferi antibodies, total, by ELISA (CSF)
    • As an alternative, consider
      • B. burgdorferi total C6 peptide antibodies by ELISA (CSF)
      • B. burgdorferi IgG and IgM antibodies by Western blot (CSF)
      • Borrelia species DNA detection by PCR
    • If any of the Borrelia tests above are positive – CNS disease confirmed
  • Chronic neurological symptoms present
    • Full meningitis workup (CSF studies; see above)
    • B. burgdorferi IgG antibodies by Western blot (CSF)
    • Consider Borrelia spp by PCR
    • If either Borrelia test is positive – CNS disease confirmed
  • Immunohistochemistry
    • CXCL13 – markedly increased in the B-cell-rich cerebrospinal fluid (CSF) of patients with acute Lyme neuroborreliosis (LNB)

Differential Diagnosis

Clinical Background

Lyme disease is the most common vector-borne disease in the U.S.

Epidemiology

  • Incidence – 20-100/100,000 in U.S.
  • Age – bimodal peaks 
    • Pediatric – 5-14 years
    • Elderly – >60 years
  • Sex – M:F, equal
    • M<F with acrodermatitis chronica atrophicans
  • Transmission
    • Tick bite – Ixodes spp
      • Vector – Ixodes scapularis (formerly Ixodes dammini)
        • More commonly known as blacklegged or deer tick (in U.S.)

Organism

  • Borrelia burgdorferi is a member of the Spirochaetales family, which also includes Treponema and Leptospira

Risk Factors

  • Exposure during the spring or summer in regions where deer population is high
    • Infected Ixodes tick must feed on patient for 48-72 hours in order to transmit B. burgdorferi
  • Northeast or Midwest location

Clinical Presentation

  • Clinical case epidemiologic surveillance criteria for defining Lyme disease (see CDC 2011 case definition)
    • Erythema migrans ≥5 cm in diameter or laboratory confirmation of infection plus ≥1 of the following late manifestations
      • Musculoskeletal manifestation – recurrent, brief attacks of objective swelling in 1 or more joints
      • Neurological manifestations – all or some of the items listed below
        • Lymphocytic meningitis – cerebrospinal fluid (CSF) pleocytosis with higher number of monocytes
        • Cranial neuritis
        • Radiculoneuritis (Garin-Bujadoux-Bannwarth syndrome)
        • Encephalomyelitis – requires demonstration of CSF antibody production
      • Cardiovascular manifestations – acute second- or third-degree arteriovenous heart block
  • Presentation timeframe
    • Initial symptoms usually appear in late spring/early summer when ticks are active
    • Late manifestations may occur anytime
  • Lyme disease stages
    • Stage 1 – early localized
      • Occurs within hours to several weeks after infection
      • Characterized by erythema migrans (EM) or lymphocytoma
        • Lymphocytoma rare in U.S.
      • Manifestations
        • EM appears at site of tick bite in 3-30 days (typically 7-14 days)
          • Present in >90% of cases
        • Regional adenopathy, minor constitutional symptoms
    • Stage 2 – early disseminated
      • Occurs weeks to months following tick bite
      • Manifestations
      • Most frequent organs involved
        • Neurologic – 15%
        • Cardiac – 8%
    • Stage 3 – late disseminated
      • Occurs a few weeks to 2 years following infection
      • Symptoms are more severe than early disseminated-stage disease
      • Manifestations
        • Memory loss
        • Fatigue
        • Monoarticular (sometimes oligoarticular) arthritis – affects large joints (particularly the knee)
        • Neuropathy (often polyneuropathy)
          • Occurs in 60% of individuals not effectively treated early in infection
          • Tends to be intermittent, lasting from several days to weeks
      • Most frequent organs involved
        • Musculoskeletal – arthritis
        • Central nervous system

Prevention

  • Avoid tick exposure
    • If unavoidable, use protective clothing and tick repellant (DEET)
  • Check for and remove ticks

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Borrelia burgdorferi Antibodies, Total by ELISA with Reflex to IgG and IgM by Western Blot (Early Disease) 0050267
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Screen for Lyme disease <4 weeks after onset of disease

If known tick bite and erythema migrans present, proceed with treatment – no testing necessary 

Diagnosis of Lyme disease should not be made on the basis of positive IgM results alone in patients with symptoms <4 weeks' duration; antibodies are usually undetectable during early localized stage
 
Borrelia burgdorferi C6 Peptide Antibodies, Total by ELISA with Reflex to IgG & IgM by Western Blot 0051043
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Alternative screen for Lyme disease <4 weeks after onset of disease

If known tick bite and erythema migrans present, proceed with treatment – no testing necessary 

   
Borrelia burgdorferi Antibodies, IgG & IgM by Western Blot 0050254
Method: Qualitative Western Blot

Confirm an equivocal or positive ELISA screen performed <4 weeks after appearance of erythema migrans

If known tick bite and erythema migrans present, proceed with treatment – no testing necessary

 

Retesting in 10-14 days may be helpful when serology test results are equivocal

Borrelia burgdorferi Antibody, IgG by Western Blot 0050255
Method: Qualitative Western Blot

Confirm an equivocal or positive ELISA screen performed >4 weeks after appearance of erythema migrans

If known tick bite and erythema migrans present, proceed with treatment – no testing necessary

   
Borrelia Species by PCR (Lyme Disease) 0055570
Method: Qualitative Polymerase Chain Reaction

Use to diagnose Lyme disease in patient with negative serology and strong suspicion for disease or immunocompromised state

If known tick bite and erythema migrans present, proceed with treatment – no testing necessary

Negative result does not rule out presence of PCR inhibitors or B. burgdorferi DNA concentrations below detection level of assay  
Cell Count, CSF 0095018
Method: Cell Count/Differential

Aid in differentiating Lyme disease from other forms of meningitis

   
Protein, Total, CSF 0020514
Method: Reflectance Spectrophotometry

Aid in differentiating Lyme disease from other forms of meningitis

   
Glucose, CSF 0020515
Method: Enzymatic

Aid in differentiating Lyme disease from other forms of meningitis

   
Cerebrospinal Fluid (CSF) Culture and Gram Stain 0060106
Method: Stain/Culture/Identification

Aid in differentiating Lyme disease from other forms of meningitis

   
Borrelia burgdorferi (Lyme Disease) Reflexive Panel (CSF) 2007335
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Test of choice for diagnosis of neuroborreliosis

If B. burgdorferi total antibodies by ELISA are 1.00 LIV or greater, then B. burgdorferi IgG antibody by Western Blot and IgM antibody by Western blot will be added  

   
Borrelia burgdorferi C6 Peptide Antibodies, Total by ELISA (CSF) 0051046
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Adjunct test for diagnosis of acute neuroborreliosis in patient with neurologic symptoms <4 weeks from onset of disease

Blood contamination or transfer of serum antibodies across blood-brain barrier is possible

Detection of antibodies of B. burgdorferi in CSF may indicate CNS infection; follow up with additional CSF studies

Retesting in 10-14 days may be helpful when serology test results are equivocal

Borrelia burgdorferi Antibodies, IgG & IgM by Western Blot (CSF) 0055260
Method: Qualitative Western Blot
Confirm positive test for CSF antibodies Blood contamination or transfer of serum antibodies across blood-brain barrier is possible Detection of antibodies to B. burgdorferi in CSF may indicate CNS infection; follow up with additional CSF studies
Babesia microti Antibodies, IgG and IgM by IFA 0093048
Method: Semi-Quantitative Indirect Fluorescent Antibody

Consider testing symptomatic patients living in regions endemic for Lyme disease or patients testing negative for Lyme disease but with clinical symptoms

   
Anaplasma phagocytophilum (HGA) Antibodies, IgG and IgM 0097303
Method: Semi-Quantitative Indirect Fluorescent Antibody

Consider testing symptomatic patients living in regions endemic for Lyme disease or patients testing negative for Lyme disease but with clinical symptoms

   
Ehrlichia and Anaplasma Species by Real-Time PCR 2007862
Method: Qualitative Polymerase Chain Reaction

Diagnose infection from Ehrlichia or Anaplasma species infecting humans

Detects Anaplasma phagocytophilum; Ehrlichia chaffeensis; E. ewingii/E. canis; E. muris-like

E. ewingii and E. canis cannot be differentiated by this test

 
CXCL13 by Immunohistochemistry 2008622
Method: Immunohistochemistry

Identify increased CXCL13 levels to aid in histologic diagnosis of Lyme disease

Stained and returned to client pathologist for interpretation; consultation available if needed

   
CD57+ NK Cells, Peripheral Blood by Flow Cytometry 2008912
Method: Flow Cytometry

Identifies and quantifies CD57+/CD3-NK cells as an indirect measure of infection severity

Significance of low CD57+NK values in diagnosing and monitoring chronic Lyme disease is not well established; use only in conjunction with other diagnostic tests specified in CDC Lyme Disease case definition

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Borrelia burgdorferi C6 Peptide Antibodies, Total by ELISA 0051044
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Borrelia burgdorferi Antibody, IgM by Western Blot 0050253
Method: Qualitative Western Blot
Borrelia burgdorferi Total Antibodies, IgG and/or IgM by ELISA with Reflex to IgG by Western Blot (Late Disease) 0050268
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot
Borrelia burgdorferi Antibody, IgM by Western Blot (CSF) 0055258
Method: Qualitative Western Blot
Borrelia burgdorferi Antibodies, Total by ELISA, CSF 0099483
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Screening test for acute neuroborreliosis in patient with neurologic symptoms <4 weeks from onset of disease

Results should be confirmed by Western Blot antibody testing

Detection of antibodies to B. burgdorferi in CSF may indicate CNS infection; follow up with additional CSF studies

Retesting in 10-14 days may be helpful when serology test results are equivocal

Borrelia burgdorferi Antibody, IgG by Western Blot (CSF) 0055259
Method: Qualitative Western Blot

Adjunct test for diagnosis of neuroborreliosis in patient with neurological symptoms >4 weeks after onset of disease

Detection of antibodies to B. burgdorferi in CSF may indicate CNS infection; follow up with additional CSF studies

Borrelia hermsii Antibody Panel, IFA 0093170
Method: Semi-Quantitative Immunofluorescence Assay
(Indirect Fluorescent Antibody)
Borrelia burgdorferi Antibodies, Total by ELISA 0050216
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Borrelia burgdorferi C6 Peptide Antibodies, Total by ELISA with Reflex to IgG by Western Blot 0051045
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot
Ehrlichia chaffeensis Antibodies, IgG & IgM by IFA 0051002
Method: Semi-Quantitative Indirect Fluorescent Antibody