Borrelia Species - Lyme Disease and Borrelia hermsii

Borrelia species cause tickborne diseases that may be difficult to diagnose because initial symptoms are similar to other more common illnesses (eg, influenza). Most laboratory testing is retrospective and used as confirmation that an individual was infected with a tickborne organism. Lyme disease, caused by B. burgdorferi, is the most common vectorborne disease in the U.S.

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Diagnosis

Lyme Disease Evaluation

Indications for Testing

  • Borrelia burgdorferi (Lyme disease)
    • Patient at risk for Lyme disease with clinical symptoms
      • Tick bite
      • Presence in area endemic for Lyme disease
    • No testing necessary if patient presents with tick bite and erythema migrans – proceed with treatment
  • Borrelia hermsii (tickborne relapsing fever [TBRF])
    • Patient at risk for TBRF with recurring fevers
      • Tick bite
      • Presence in area endemic for TBRF

Laboratory Testing

  • B. burgdorferi
    • Current two-step testing recommendations for serologic diagnosis of Lyme disease (CDC, 2015)
    • B. burgdorferi or C6 peptide antibodies total by enzyme-linked immunosorbent assay (ELISA)
      • Positive or indeterminate (if neurological symptoms present, see Neurologic Disease Evaluation)
        • <4 weeks after disease onset
          • B. burgdorferi IgG and IgM antibodies by immunoblot
            • Positive IgG and negative IgM – Lyme disease confirmed
            • Negative IgG and positive IgM – Lyme disease or false-positive IgM
              • Follow-up IgG immunoblot (within 30 days) recommended to help confirm Lyme disease and rule out false-positive IgM immunoblot
            • Negative IgG and IgM – consider other causes of false-positive ELISA result (syphilisrheumatoid arthritis, acute Epstein-Barr virus [EBV], HIV, subacute bacterial endocarditissystemic lupus erythematosus [SLE], periodontitis)
              • If Lyme disease still suspected or patient immunocompromised – order Borrelia spp by polymerase chain reaction (PCR)
        • ≥4 weeks after disease onset
          • B. burgdorferi IgG antibodies by immunoblot
            • Positive – Lyme disease confirmed
            • Negative – see negative IgG and IgM above
        • Even if testing is positive for Lyme disease, consider coinfection with Borrelia miyamotoi, Babesia microti, Anaplasma phagocytophilum, or Ehrlichia chaffeensis
      • Negative
        • No further testing on initial specimen; test convalescent specimen if suspicion for tickborne disease exists
        • Endemic regions – consider coinfection with Borrelia miyamotoiB. microti, A. phagocytophilum, E. chaffeensis
    • ​​Lyme arthritis
      • Use Lyme disease serologies to establish diagnosis
        • Patients need positive serologies for B. burgdorferi to consider evaluation for arthritis because arthritis is a late manifestation
      • PCR – B. burgdorferi DNA is detectable in synovial fluid or synovium in most untreated patients
  • B. hermsii
    • Blood smear during acute episode – observation of spirochetes confirms diagnosis
    • Serology for antibodies – retrospective confirmation requires acute and convalescent specimens
  • B. miyamotoi
    • Serology – retrospective confirmation

Neurologic Disease Evaluation

Indications for Testing

Meningoradiculitis, meningitis, cranial nerve deficits

Criteria for Diagnosis

Suggested Criteria for Lyme Neuroborreliosis

Criteria

  • Neurological symptoms suggestive of Lyme neuroborreliosis (LNB) without other obvious reason
  • Cerebrospinal fluid (CSF) pleocytosis
  • Intrathecal Borrelia burgdorferi antibody productiona

Definite neuroborreliosisb

  • All 3 criteria fulfilled

Possible neuroborreliosisa

  • 2 criteria fulfilled

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

bApplies 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

Source: Mygland, European Federation of Neurological Societies, 2010

Laboratory Testing

  • Acute neurological symptoms present
    • Full meningitis workup (cerebrospinal fluid [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 one of the following Borrelia tests instead of the total antibodies test
      • B. burgdorferi total C6 peptide antibodies by ELISA (CSF)
      • B. burgdorferi IgG and IgM antibodies by immunoblot (CSF)
      • Consider Borrelia spp by PCR
    • If any of the Borrelia tests above are positive – central nervous system (CNS) Lyme disease suggested
      • Full CSF antibody index must be performed to get more conclusive evidence of neurological disease
  • Chronic neurological symptoms present
    • Full meningitis workup (CSF studies; see above)
    • One of the following Borrelia tests
      • B. burgdorferi IgG antibodies by immunoblot (CSF)
      • Borrelia spp by PCR
      • If either Borrelia test is positive – CNS Lyme disease suggested

Differential Diagnosis

Background

Organisms, Risk Factors, and Epidemiology (CDC, 2016)
Species B. burgdorferi (Lyme disease) B. hermsii (tickborne relapsing fever [TBRF]) B. miyomotoi
Vector ticks

Ixodes scapularis (black-legged tick)

Ornithodoros hermsi (soft tick)

I. scapularis (black-legged tick) or I. pacificus (western black-legged tick)

Reservoir species

White-footed mouse

Squirrels and chipmunks

White-footed mouse

Incidence

~300,000 cases in U.S. per year

504 reported cases in U.S. from 1990-2011

~100 cases in U.S. identified to date

Season

Spring-early fall

Spring-early fall

July-early fall

Endemic area

Northeastern and upper midwestern states

Mountainous regions of the western states

Northeastern, upper midwestern, and western states

Risk factors

Exposure in endemic area

Hard tick bite – must feed for 48-72 hrs

Exposure in endemic area

Soft tick bite – <30 min

Exposure in endemic area

Hard tick bite – must feed for 48-72 hrs

Age

Bimodal peaks

  • Pediatric – 4-14 yrs
  • Elderly – >60 yrs

Bimodal peaks

  • Pediatric – 10-14 yrs
  • Adult – 40-44 yrs

Median age for adults – 38 yrs

Similar to B. burgdorferi

Sex

M:F, equal

M<F with acrodermatitis chronica atrophicans

M>F

M:F, equal

Coinfection

Babesia

Bartonella

Ehrlichia

Anaplasma

 

Babesia

Bartonella

Ehrlichia

Anaplasma

New species – Borrelia mayonii

  • Currently located only in upper Midwest; six reported cases (CDC, 2016)
  • Tick vector – same as Lyme disease, Ixodes scapularis (black-legged tick)
  • Clinical presentation – same as Lyme disease

Clinical Presentation

  • Lyme disease
    • Clinical case epidemiologic surveillance criteria for defining Lyme disease (see CDC 2017 case definition)
      • Erythema migrans (EM) ≥5 cm in diameter or laboratory confirmation of infection plus one or more of the following late manifestations
        • Musculoskeletal manifestations – Lyme arthritis
          • Recurrent, brief attacks of objective swelling in one or more joints
        • Neurological manifestations – all or some of the following
          • 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 or summer when ticks are most 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 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
        • Stage 3 – late disseminated
          • Occurs a few weeks to 2 years following infection
          • Symptoms are more severe than early disseminated 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 (CNS)
  • Tickborne relapsing fever (TBRF)
    • Nonspecific symptoms
      • Recurring fever
      • Constitutional symptoms
        • Myalgias
        • Pain in joints, neck, and eyes
        • Light sensitivity
      • Headache, confusion, dizziness
      • Nausea, vomiting, anorexia, diarrhea
      • Dry cough
      • Rash
    • Presentation time frame
      • Usually in spring and summer
        • Occurs in winter as rodent-infested cabins are heated
    • TBRF stages
      • Incubation period – ~7 days
      • First symptomatic period – ~3-5 days
      • Afebrile period – ~5-7 days after apparent recovery
      • If untreated, process can repeat itself up to four times
    • Pregnant females
      • Pregnant females often have higher spirochete loads and more severe symptoms
        • Higher spirochete loads have not been found to correlate with fetal outcome
      • Maternal/fetal transmission thought to occur either transplacentally or while traversing the birth canal
      • Complications – spontaneous abortion, premature birth, and neonatal death
  • B. miyamotoi
    • Rash uncommon
    • Influenza-like presentation – fever, chills, headache, arthralgias
    • No chronic sequelae observed in small populations identified to date (Molloy, 2015)

ARUP Laboratory Tests

Primary Tests

Preferred reflex test to detect Lyme disease in individuals with ≤4 weeks of clinical symptoms or exposure to tick

Positive/equivocal screen confirmed by immunoblot

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

Both IgM and IgG immunoblots should be performed on specimens obtained less than 4 weeks after appearance of erythema migrans

Only IgG immunoblot is to be performed on specimens greater than 4 weeks after disease onset

IgM immunoblot in the chronic stage is not recommended and does not aid in the diagnosis of neuroborreliosis or chronic Lyme disease

Preferred reflex test to detect Lyme disease in individuals with ≤4 weeks of clinical symptoms or exposure to tick

Positive/equivocal screen confirmed by immunoblot

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

Do not order in the absence of a positive/equivocal ELISA screening test

IgM immunoblot is not useful after the first 4 weeks of clinical symptoms

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

Do not order in the absence of a positive/equivocal ELISA screening test

During first 4 weeks of clinical symptoms, order concurrent IgM immunoblot test

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

Not a first-line test for Lyme disease

May be useful if strong suspicion of Lyme disease persists in spite of persistent negative serologic testing

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

Diagnose relapsing fever caused by various Borrelia species during the symptomatic phase of infection

Detects but does not differentiate the nucleic acid from B. hermsii, B. miyamotoi, B. parkeri, and B. turicatae; additional less-frequently encountered relapsing fever Borrelia species may also be detected, including B. recurrentisB. coriaceae, B. theileri, B. lonestari, and B. anserina​

Preferred panel for diagnosing possible tickborne disease (ie, anaplasmosis, ehrlichiosis, or babesiosis) during acute phase of disease

Preferred panel for diagnosing possible tick-borne disease (ie, anaplasmosis or ehrlichiosis) during acute phase of disease

Detect and speciate Anaplasma phagocytophilumEhrlichia chaffeensisE. ewingii/, E. canisE. muris-like​

Aid in differentiating Lyme disease from other forms of meningitis

Aid in differentiating Lyme disease from other forms of meningitis

Aid in differentiating Lyme disease from other forms of meningitis

Identify bacteria in CSF

Important informationLimited to the University of Utah Health Sciences Center only

Preferred CSF reflex panel for workup of suspected neuroborreliosis

Use in conjunction with positive serologic testing for the workup of suspected acute Lyme neuroborreliosis in patient with neurologic symptoms <4 weeks from onset of disease

Do not order in the absence of clinical symptoms

The detection of antibodies of B. burgdorferi in CSF may indicate central nervous system (CNS) infection; however, consideration must be given to possible contamination by blood or transfer of serum antibodies across the blood-brain barrier

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

Use in conjunction with positive serologic testing for the workup of suspected acute Lyme neuroborreliosis

Do not order in the absence of clinical symptoms

The detection of antibodies to B. burgdorferi in CSF may indicate CNS infection; however, consideration must be given to possible contamination by blood or transfer of serum antibodies across the blood-brain barrier

Useful if Giemsa stain is negative but high suspicion of babesiosis exists

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

Will not detect B. duncani or strain MO-1

Acceptable test for acute or convalescent phase of infection from A. phagocytophilium

May be useful when PCR testing is not an option (eg, outside the 2 week window for acute phase)

PCR testing is generally preferred; refer to tickborne disease panel by PCR, blood or Ehrlichia and Anaplasma species by real-time PCR

Identify and quantify 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

Related Tests

First-line serologic screening test for suspected Lyme disease

Positive or equivocal results must be confirmed by immunoblot

Do not order in the absence of a positive/equivocal ELISA screening test

Useful only when ordered during first 4 weeks of clinical symptoms and concurrently with IgG immunoblot test

Preferred reflex test to detect Lyme disease in individuals with >4 weeks of clinical symptoms or exposure to tick

Positive/equivocal screen confirmed by immunoblot

Use in conjunction with serologic testing for the workup of suspected acute Lyme neuroborreliosis

Do not order in the absence of clinical symptoms

Use in conjunction with positive serologic testing for the workup of suspected acute Lyme neuroborreliosis with neurologic symptoms <4 weeks from onset of disease

Do not order in the absence of clinical symptoms

Results should be confirmed by immunoblot antibody testing

The detection of antibodies to B. burgdorferi in CSF may indicate central nervous system (CNS) infection; however, consideration must be given to possible contamination by blood or transfer of serum antibodies across the blood-brain barrier

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

Use in conjunction with positive serologic testing for the workup of suspected acute Lyme neuroborreliosis with neurological symptoms >4 weeks after onset of disease

Do not order in the absence of clinical symptoms

The detection of antibodies to B. burgdorferi in CSF may indicate CNS infection; however, consideration must be given to possible contamination by blood or transfer of serum antibodies across the blood-brain barrier

First-line serologic screening test for suspected Lyme disease

Positive or equivocal results must be confirmed by immunoblot

Preferred reflex test to detect Lyme disease in individuals with >4 weeks of clinical symptoms or exposure to tick

Positive/equivocal screen confirmed by immunoblot

Diagnose infection from E. chaffeensis

Medical Experts

Contributor

Couturier

Marc Roger Couturier, PhD, D(ABMM)
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Parasitology/Fecal Testing, Infectious Disease Antigen Testing, Bacteriology, and Molecular Amplified Detection, ARUP Laboratories
Contributor
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References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®