Borrelia burgdorferi - Lyme Disease

Diagnostic Algorithm

  Lyme Disease Testing Algorithm

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 – 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

Clinical Presentation

• Clinical case epidemiologic surveillance criteria for defining Lyme disease (Centers for Disease Control)
  • 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 (termed Garin-Bujadoux-Bannwarth syndrome)
      • Encephalomyelitis – requires demonstration of CSF antibody production
    • Cardiovascular manifestations – acute second- or third-degree arteriovenous heart block
• Lyme disease stages
  • Stage 1 – early localized
    • Occurs within hours to several weeks after infection
    • Characterized by EM or lymphocytoma (rare in U.S.)
    • Manifestations
      • Regional adenopathy, minor constitutional symptoms
  • Stage 2 – early disseminated
    • Occurs weeks to months following the tick bite
    • Characterized by neurologic (15% of patients) and cardiac (8% of patients) involvement
    • Manifestations
      • Fever
      • Myalgias
      • Multiple EM lesions
      • Meningitis
      • Bells palsy
      • Guillain-Barré-like syndrome
      • Cardiac conduction abnormalities
      • Arthritis
  • Stage 3 – late disseminated
    • Occurs within a few weeks to 2 years following infection
    • Symptoms are more severe than early disseminated-stage disease
    • Characterized by arthritis or central nervous system (CNS) involvement
      • 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)
• Initial symptoms usually appear in late spring/early summer, when ticks are active
• Late manifestations occur anytime

Treatment

• Lyme disease is easily treated if diagnosed early
  • 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

Diagnosis

Lyme Disease

Indications for Testing

• Patient at risk for Lyme disease with clinical symptoms
  • No testing necessary if patient presents with tick bite and erythema migrans

Laboratory Testing

• Current CDC recommendations for serologic diagnosis of Lyme disease
  • Screen with a polyvalent ELISA test or C6 peptide antibodies
  • Confirm equivocal and positive results with Western Blot
    • <8 weeks after onset of disease – IgG-, IgM+
    • >8 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
    • Other spirochetal disease (syphilis, periodontitis)
    • Autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis)
    • Other infections (subacute bacterial endocarditis, HIV, acute Epstein-Barr virus [EBV])
• 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
• 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
    • Borrelia burgdorferi C6 peptide antibodies
    • Borrelia burgdorferi total antibodies
    • Borrelia burgdorferi IgG, IgM antibodies
    • Borrelia species DNA detection
  • Chronic disease
    • Borrelia burgdorferi IgG antibody
    • Borrelia species DNA detection

Differential Diagnosis

• Neurologic
  • HIV
  • Acute meningitis
  • Acute encephalitis
  • Multiple sclerosis
  • Demyelinating disorder
  • Guillain-Barré syndrome
  • Treponema pallidum (syphilis)
  • Arboviral disease
  • 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
  • Malaria
  • Colorado tick fever
  • Arbovirus
  • EBV
• Heart block
  • Endocarditis
  • Sick sinus syndrome
  • Connective tissue disease
  • Anaplasma phagocytophilum

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: Enzyme-Linked Immunosorbent Assay
Borrelia burgdorferi Antibody, IgM by Western Blot 0050253 Method: Western Blot
Borrelia burgdorferi Total Antibodies, IgG and/or IgM by ELISA with Reflex to IgG by Western Blot (Late Disease) 0050268 Method: Enzyme-Linked Immunosorbent Assay/Western Blot
Borrelia burgdorferi Antibody, IgM by Western Blot (CSF) 0055258 Method: Western Blot
Borrelia hermsii Antibody Panel, IFA 0093170 Method: Immunofluorescence Assay
Lyme Antigen, Urine 0050219 Method: Lyme Dot-Blot Assay
Borrelia burgdorferi Antibodies, Total by ELISA 0050216 Method: Enzyme-Linked Immunosorbent Assay	Alternative first-line screening test for Lyme disease If known tick bite and erythema migrans present, proceed with treatment – no testing necessary Up to 40% of patients with early disease are seronegative by ELISA at time they present with erythema migrans Serologic diagnosis often not established until advanced stage of disease No objective tests for Lyme borreliosis are 100% sensitive and 100% specific Diagnosis depends on clinical features combined with available laboratory tests Retesting in 10-14 days may be helpful when serology test results are equivocal
Borrelia burgdorferi C6 Peptide Antibodies, Total by ELISA with Reflex to IgG by Western Blot 0051045 Method: Enzyme-Linked Immunosorbent Assay/Western Blot	Screen for Lyme disease >8 weeks after onset of disease If known tick bite and erythema migrans present, proceed with treatment – no testing necessary No objective tests for Lyme borreliosis are 100% sensitive and 100% specific Diagnosis depends on clinical features combined with available laboratory tests
Ehrlichia chaffeensis Antibodies, IgG & IgM by IFA 0051002 Method: Indirect Fluorescent Antibody	Consider for those who test negative for Lyme disease antibodies but who live in endemic areas and have compatible symptoms