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
        • Negative IgG and positive IgM – Lyme disease confirmed
        • 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

Differential Diagnosis

• Neurologic
  • HIV
  • Acute meningitis
  • Acute encephalitis
  • Multiple sclerosis
  • Demyelinating disorder
  • Guillain-Barré syndrome
  • Treponema pallidum
  • Arbovirus
  • EBV
• Musculoskeletal
  • Neisseria gonorrheae
  • 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

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
  • 12 U.S. states account for 94% of reported cases (see 2011 CDC statistics)

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 Fever Myalgias Meningitis Bell palsy Guillain-Barré-like syndrome Cardiac conduction abnormalities (generally PR interval prolongation or complete heart block) Arthritis 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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

Diagnostic Algorithm

  Lyme Disease Testing Algorithm