Borrelia burgdorferi - Lyme Disease

Lyme Disease

Indications for Testing

Patient at risk for Lyme disease with clinical symptoms
- No testing necessary if patient presents with tick bite and EM
- Diagnosis may be difficult in the absence of characteristic rash

Laboratory Testing

Current CDC recommendations for serologic diagnosis of Lyme disease (two-step procedure)
- Screen with a polyvalent ELISA test or C6 peptide antibodies (highly sensitive and specific)
- Confirm equivocal and positive results with Western Blot (highly specific)
  - <4 weeks after onset of disease – IgG-, IgM+
  - >4 weeks after onset of disease – IgG+
- If testing is initially negative, consider other diseases; test convalescent sample
Serological testing
- False-positive results from serologic tests may result from
  - Periodontitis
  - Other spirochetal disease (syphilis)
  - Autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis)
  - Other infections (subacute bacterial endocarditis, HIV, acute Epstein-Barr virus [EBV])
    - IgG and IgM persist for years, even after successful treatment
Co- and triple-infections by parasites that cause babesiosis and granulocytic anaplasmosis (formerly known as human granulocytic ehrlichiosis) may occur, particularly in endemic areas
- Serologic testing specific for these agents is recommended
  - Babesia microti IgG, IgM antibodies
  - Anaplasma phagocytophilum IgG, IgM antibodies
  - Ehrlichia chaffeensis IgG, IgM antibodies

Neurologic Disease Evaluation

Indications for Testing

Meningoradiculitis, meningitis, cranial nerve deficits

Criteria for Diagnosis

Possible neuroborreliosis
- Typical clinical features (eg, meningitis, meningoradiculitis, cranial nerve deficits)
- B. burgdorferi-specific IgG and/or IgM serum antibodies
- CSF findings not available (lumbar puncture not performed)
Probable neuroborreliosis
- Criteria of possible neuroborreliosis, plus
  - Inflammatory CSF changes (lymphocytic pleocytosis, elevated protein content, intrathecal IgG antibody production)
  - Exclusion of other causes
Proven (definite) neuroborreliosis
- Criteria of probable neuroborreliosis, plus
  - Intrathecal B. Burgdorferi-specific antibody production (positive culture or PCR)

Laboratory Testing

Lumbar fluid analysis; should also include testing for other bacterial and viral etiologies (eg, WNV)
Cell count – lymphocytic pleocytosis is typical (>8 wbc/mm³)
Total protein, glucose, culture with gram stain (all CSF)
IgG and IgM antibody testing
- Acute disease
  - B. burgdorferi C6 peptide antibodies
  - B. burgdorferi total antibodies
  - B. burgdorferi IgG, IgM antibodies
  - B. species DNA detection
- Chronic disease
  - B. burgdorferi IgG antibody
  - Borrelia species DNA detection

Differential Diagnosis

Neurologic
- HIV
- Acute meningitis
- Acute encephalitis
- Multiple sclerosis
- Demyelinating disorder
- Guillain-Barré syndrome
- Treponema pallidum
- Arbovirus
- EBV
Musculoskeletal
- Neisseria gonorrhea
- Parvovirus
- Septic arthritis
- Connective tissue diseases (eg, SLE)
- Rheumatoid arthritis
- Fibromyalgia
- Rheumatic fever
- Reactive arthritis trachomatis
- Crystalline arthritis
Acute febrile illness
- Ehrlichia chaffeensis
- Rickettsia rickettsii
- Babesia microti
- Francisella tularensis
- Plasmodium spp
- Colorado tick fever
- Arbovirus
- EBV
Heart block
- Endocarditis
- Sick sinus syndrome
- Connective tissue disease
- Anaplasma phagocytophilum

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 – infected Ixodes tick bite

Organism

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

Risk Factors

Exposure in regions where deer population is high during the spring or summer
Northeast or Midwest geographic location
- 12 U.S. states account for 95% of reported cases ( 2009 CDC statistics )
- Infected Ixodes tick must feed on patient for 48-72 hours in order to infect human host

Clinical Presentation

Clinical case epidemiologic surveillance criteria for defining Lyme disease ( CDC 2011 case definition)
- Erythema migrans (EM) ≥5 cm in diameter or laboratory confirmation of infection plus ≥1 late manifestation
  - Musculoskeletal manifestation – recurrent, brief attacks of objective swelling in 1 or more joints
  - Neurological manifestations (all or part of a triad)
    - 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 EM or lymphocytoma (lymphocytoma rare in U.S.)
  - Manifestations
    - EM appears at the 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
  - Characterized by neurologic (15% of patients) and cardiac (8% of patients) involvement
  - Manifestations
    - Fever
    - Myalgias
    - Multiple EM lesions (3-5 weeks after tick bite)
    - Meningitis
    - Bell palsy
    - Guillain-Barré-like syndrome
    - Cardiac conduction abnormalities (generally PR interval prolongation or complete heart block)
    - Arthritis
- Stage 3 – late disseminated; occurs a few weeks to 2 years following infection
  - Symptoms are more severe than early disseminated-stage disease
  - Characterized by arthritis or central nervous system involvement
    - Monoarticular (sometimes oligoarticular) arthritis – affects large joints (particularly the knee)
    - Occurs in 60% of individuals not effectively treated early in infection
    - Tends to be intermittent, lasting from several days to weeks
  - Manifestations
    - Memory loss
    - Fatigue
    - Neuropathy (often polyneuropathy)

Treatment

Lyme disease is easily treated if diagnosed early
- Oral antibiotics for early localized and early disseminated disease
- NSAIDs and IV antimicrobials required for more severe cases
- Treatment prevents progression to chronic stage (stages 2 or 3)
- Severe, long-term effects occur in <10% of untreated patients
If known tick bite and EM present, proceed with treatment; testing is not necessary
Prophylactic antibiotic therapy for tick bites not recommended, even in endemic regions

Prevention

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

Tests generally appear in the order most useful for common clinical situations

Test name: Borrelia burgdorferi Antibodies, Total by ELISA with Reflex to IgG & IgM by Western Blot (Early Disease)

ARUP #: 0050267

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Use:

Screen for Lyme disease <4 weeks after onset of disease

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

Limitations:

No objective tests for Lyme borreliosis are 100% sensitive and 100% specific

Diagnosis depends on clinical features, combined with available laboratory tests

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

Test name: Borrelia burgdorferi C6 Peptide Antibodies, Total by ELISA with Reflex to IgG & IgM by Western Blot

ARUP #: 0051043

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Use:

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

Limitations:

No objective tests for Lyme borreliosis are 100% sensitive and 100% specific

Diagnosis depends on clinical features combined with available laboratory tests

Test name: Borrelia burgdorferi Antibodies, IgG & IgM by Western Blot

ARUP #: 0050254

Methodology: Qualitative Western Blot

Use:

Confirm an equivocal or positive antibody test performed <4 weeks after appearance of erythema migrans

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

For IgG, positive result reported when greater than or equal to 5 bands are present: 18, 23, 28, 30, 39, 41, 45, 58, 66, or 93kDA; all other bandings reported as negative

For IgM, positive result reported when greater than or equal to 2 bands are present: 23, 39, or 41kDa; all others reported as negative

Limitations:

No objective tests for Lyme borreliosis are 100% sensitive and 100% specific

Diagnosis depends on clinical features combined with available laboratory tests

Follow-up:

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

Test name: Borrelia burgdorferi Antibody, IgG by Western Blot

ARUP #: 0050255

Methodology: Qualitative Western Blot

Use:

Confirm an equivocal or positive antibody test performed >4 weeks after appearance of erythema migrans

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

Positive result reported when greater than or equal to 5 bands are present: 18, 23, 28, 30, 39, 41, 45, 58, 66, or 93kDA; all other bandings reported as negative

Limitations:

No objective tests for Lyme borreliosis are 100% sensitive and 100% specific

Diagnosis depends on clinical features combined with available laboratory tests

Test name: Borrelia Species DNA Detection by PCR (Lyme Disease)

ARUP #: 0055570

Methodology: Qualitative Polymerase Chain Reaction

Use:

Diagnose Lyme disease in patient with negative serologic results but disease still strongly suspected or with immune deficiency

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

Limitations:

Negative result does not rule out presence of PCR inhibitors or B. burgdorferi DNA concentrations below detection level of assay

No objective tests for Lyme borreliosis are 100% sensitive and 100% specific

Diagnosis depends on clinical features, combined with available laboratory tests

Test name: Cell Count, CSF

ARUP #: 0095018

Methodology: Cell Count/Differential

Use:

Aids in differentiating Lyme disease from other forms of meningitis

Test name: Protein, Total, CSF

ARUP #: 0020514

Methodology: Reflectance Spectrophotometry

Use:

Aids in differentiating Lyme disease from other forms of meningitis

Test name: Glucose, CSF

ARUP #: 0020515

Methodology: Enzymatic

Use:

Aids in differentiating Lyme disease from other forms of meningitis

Test name: CSF Bacterial Culture (Includes Gram Stain 0060101)

ARUP #: 0060106

Methodology: Standard reference procedures for bacterial stain, aerobic culture, and identification

Use:

Aids in differentiating Lyme disease from other forms of meningitis

Test name: Borrelia burgdorferi Antibody, IgG by Western Blot (CSF)

ARUP #: 0055259

Methodology: Qualitative Western Blot

Use:

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

Positive result reported when greater than or equal to 5 bands are present: 18, 23, 28, 30, 39, 41, 45, 58, 66, or 93kDA; all other bandings reported as negative

Limitations:

No objective tests for Lyme borreliosis are 100% sensitive and 100% specific

Diagnosis depends on clinical features combined with available laboratory tests

Follow-up:

Detection of antibodies to B. burgdorferi in CSF may indicate CNS infection

Consider possible contamination by blood or transfer of serum antibodies across blood-brain barrier

Test name: Borrelia burgdorferi C6 Peptide Antibodies, Total by ELISA (CSF)

ARUP #: 0051046

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use:

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

Limitations:

No objective tests for Lyme borreliosis are 100% sensitive and 100% specific

Diagnosis depends on clinical features combined with available laboratory tests

Follow-up:

Detection of antibodies of B. burgdorferi in CSF may indicate CNS infection

Consider possible contamination by blood or transfer of serum antibodies across blood-brain barrier

For equivocal results, repeat testing in 10-14 days may be helpful

Test name: Borrelia burgdorferi Antibodies, Total by ELISA (CSF)

ARUP #: 0099483

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use:

Screening test (confirmed by Western Blot) for neuroborreliosis in patient with neurologic symptoms <4 weeks from onset of disease

Limitations:

No objective tests for Lyme borreliosis are 100% sensitive and 100% specific

Diagnosis depends on clinical features combined with available laboratory tests

Follow-up:

Detection of antibodies to B. burgdorferi in CSF may indicate CNS infection

Consider possible contamination by blood or transfer of serum antibodies across blood-brain barrier

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

Test name: Borrelia burgdorferi Antibodies, IgG & IgM by Western Blot (CSF)

ARUP #: 0055260

Methodology: Qualitative Western Blot

Use: Confirm positive test for CSF antibodies

Limitations:

No objective tests for Lyme borreliosis are 100% sensitive and 100% specific

Diagnosis depends on clinical features combined with available laboratory tests

For IgG, positive result reported when greater than or equal to 5 bands are present: 18, 23, 28, 30, 39, 41, 45, 58, 66, or 93kDA; all other bandings reported as negative

For IgM, positive result reported when greater than or equal to 2 bands are present: 23, 39, or 41kDa; all others reported as negative

Follow-up:

Detection of antibodies to B. burgdorferi in CSF may indicate CNS infection

Consider possible contamination by blood or transfer of serum antibodies across the blood-brain barrier

Test name: Babesia microti Antibodies, IgG & IgM by IFA

ARUP #: 0093048

Methodology: Semi-Quantitative Indirect Fluorescent Antibody

Use:

Consider for patients testing negative for Lyme disease antibodies but who live in endemic areas and have compatible symptoms

Test name: Anaplasma phagocytophilum (HGA) Antibodies, IgG & IgM

ARUP #: 0097303

Methodology: Semi-Quantitative Indirect Fluorescent Antibody

Use:

Consider for patients testing negative for Lyme disease antibodies but who live in endemic areas and have compatible symptoms

Test name: Ehrlichia and Anaplasma Species by Real-Time PCR

ARUP #: 2003078

Methodology: Real-Time Polymerase Chain Reaction/DNA Probe Hybridization

Use:

Consider for patients testing negative for Lyme disease antibodies but who live in endemic areas and have compatible symptoms

Additional Tests Available

Test name: Borrelia burgdorferi C6 Peptide Antibodies, Total by ELISA

ARUP #: 0051044

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Borrelia burgdorferi Antibody, IgM by Western Blot

ARUP #: 0050253

Methodology: Qualitative Western Blot

Comments:

Positive result reported when greater than or equal to 2 bands are present: 23, 39, or 41kDa; all others reported as negative

Test name: Borrelia burgdorferi Total Antibodies, IgG and/or IgM by ELISA with Reflex to IgG by Western Blot (Late Disease)

ARUP #: 0050268

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Comments:

Test name: Borrelia burgdorferi Antibody, IgM by Western Blot (CSF)

ARUP #: 0055258

Methodology: Qualitative Western Blot

Comments:

Positive result reported when greater than or equal to 2 bands are present: 23, 39, or 41kDa; all others reported as negative

Test name: Borrelia hermsii Antibody Panel, IFA

ARUP #: 0093170

Methodology: Semi Quantitative Immunofluorescence Assay

Comments:

Test name: Borrelia burgdorferi Antibodies, Total by ELISA

ARUP #: 0050216

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Borrelia burgdorferi C6 Peptide Antibodies, Total by ELISA with Reflex to IgG by Western Blot

ARUP #: 0051045

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Comments:

Test name: Ehrlichia chaffeensis Antibodies, IgG & IgM by IFA

ARUP #: 0051002

Methodology: Semi-Quantitative Indirect Fluorescent Antibody

Comments:

Consider for those who test negative for Lyme disease antibodies but who live in endemic areas and have compatible symptoms

Guidelines

General

Comprehensive Review: June 2011
Last Update: June 2011

Arboviruses

Babesia microti

Dengue Fever Virus

Ehrlichiosis and Colorado Tick Fever

Encephalitis, Infectious

Francisella tularensis

Meningitis, Acute

Rickettsia rickettsii

Rickettsia typhi

Sarcoidosis

Treponema pallidum