Borrelia burgdorferi

Background

Microbiology

• Spirochete
• Lyme disease can also be caused by Borrelia mayonii

Epidemiology

• Most cases occur during June and July, when nymphal ticks are most active and people are outdoors
• Infection is possible year-round, though, with ticks being active any time temperatures are above freezing

North America

• Transmitted by Ixodes scapularis (deer or black-legged tick), or Ixodes pacificus in the Pacific US
• Reservoirs include deer and small mammals such as rodents
• Lyme species are different outside of North America

Europe

• Three main species of Borrelia exist in Europe: B. burgdorferi, B. afzelii, B. garinii
• The vectors are Ixodes ricinus (in Europe and the Near East, and Ixodes persulcatus in Asia
• The species have cross-reactivity with Lyme serology

Life Cycle

Pathophysiology

• Tick bites host
• Borrelia migrates from hindgut to mouth over ~36 hours, then gets regurgitated into the wound
  • May take as little as 24 hours
• Local multiplication followed by dissemination

Risk Factors

• Hiking or camping in Vermont or other endemic area, with known or possible tick exposure

Clinical Manifestations

• May not remember tick bite
• There can be overlap between the three stages (early localized, early disseminated, late)
• Requires minimum of 24 hours of tick attachment, but typically takes 36 hours or longer

Early Localized Disease (7 days)

• Presents within 1 month of exposure
• Erythema migrans in 80%; appears 7-14 days after tick bite (range 3 to 32 days)
  • Expanding red or bluish-red patch ≥5 cm, with or without central clearing
  • Spreads over days
  • Can present atypically, without target appearance, with ulceration, or with vesicles
  • If appears immediately and rapidly; need to consider local irritation and allergy, rather than Lyme
• Fever, fatigue, malaise, lethargy
• Mild headache and neck stiffness
• Myalgias and arthralgias
• May have mildly elevated liver enzymes

Early Disseminated Disease (14-21 days)

• Early disseminated (weeks to months), inflammatory phase
• Can be a non-specific febrile illness with headaches, arthralgias and fatigue, but can also cause a number of other symptoms
  • Bell palsy, unilateral or bilateral, or other cranial nerve palsies
  • Aseptic meningitis with lymphocytosis
  • Carditis with heart block
  • Secondary skin lesions
  • Conjunctivitis

Neuroborreliosis

• Refers specifically to the neurological manifestations of early disseminated Lyme disease
• More common with Borrelia garinii
• Meningo-radiculitis, meningitis, and peripheral facial nerve palsy
• Rarely, encephalitis or myelitis or cerebral vasculitis
• CSF shows lymphocytic pleocytosis, slightly elevated protein, and normal glucose

Cardiac Lyme

• AV conduction dysfunction, arrhythmia, and sometimes myocarditis or pericarditis, without other explanation
• Resolves with treatment, so only ever needs temporary pacemaker

Late Disease

• Late or chronic (months to years), less inflammatory, usually within a single body site
• Arthritis in 60% of untreated patients, now down to 15-20%
  • PCR of synovial fluid
• Encephalomyelitis/encephalopathy next-most common
  • LP fairly benign, with slightly elevated protein
  • Diagnose with simultaneous serum/CSF antibodies
• Peripheral neuropathy
• Affects heart, nervous system and joints; arrhythmias, heart block and sometimes myopericarditis; recurrent arthritis affecting large joints (i.e., knees); peripheral neuropathy; central nervous system manifestations – meningitis; encephalopathy (i.e., behavior changes, sleep disturbance, headaches); and fatigue

Lyme Arthritis

• Recurrent attacks or persisting arthritis involving one or more large joints, without other explanation
• Arthrocentesis shows 25,000 cells (range 500 to 110,000), mostly PMNs

Acrodermatitis Chronica Atrophicans

• Chronic red or bluish-red leions, usually on the extensor surgaces
• Initially doughy, eventually atrophic
• Can occur up to 8 years after infection

Late Neuroborreliosis

• Encephalopathy, encephalitis, and peripheral neuropathy

Complications

• Carditis in 5% of untreated patients
  • Heart block
  • Cardiomyopathy
• Neurologic involvement in 15% of untreated patients
  • Uni- or bilateral cranial nerve defects, especially CN VII
  • Meningitis and encephalitis
• Migratory arthralgias in 60% of untreated patients
• Conjunctivitis in 10% of untreated patients
• Regional or generalized lymphadenopathy

Borrelial Lymphocytoma

• Painless bluish-red nodule, usually on the ear, nipple, or scrotum
• More common in adults

Ocular Manifestations

• Conjunctivitis, uveitis, papillitis, episcleritis, keratitis

Coinfections

• Anaplasma or Babesia may be transmitted by the same ticks in areas of endemicity
• Can have thrombocytopenia, leukopenia, neutropenia, and anemia
  • Hemolytic anemia is highly suggestive of Babesia microti
• Other signs include fever lasting more than one day after start of antibiotics, especially for Babesia microti

Post-Lyme Disease Syndrome

• Subjective symptoms that persist following treatment, without objective clinical findings of infection

Differential Diagnosis

Erythema Migrans

• Tick or insect bite hypersensitivity reaction
• Cellulitis, erysipelas
• Erythema multiforme
• STARI
• Tinea
• Nummular eczema
• Granuloma annulare
• Contact dermatitis
• Urticaria
• Fixed drug eruption
• Pityriasis rosea
• Parvovirus B19 (in children)

Borrelial Lymphocytoma

• Breast cancer
• B-cell lymphoma
• Pseudolymphoma

Lyme Neuroborreliosis

• Other causes of facial nerve palsy
• Viral meningitis
• Mechanical radiculopathy
• First episode of relapsin-remitting multiple sclerosis
• Primary progressive multiple sclerosis

Lyme Carditis

• Other causes of heart block or myopericarditis

Lyme Arthritis

• Gout or pseudogout
• Septic arthritis
• Viral arthritis
• Psoriatic arthritis
• Juvenile oligoarthritis
• Reactive arthritis
• Sarcoidosis
• Early rheumatoid arthritis
• Seronegative spondyloarthropathies

Acrodermatitis Chronic Atrophicans

• Old age
• Chillblains
• Chronic venous insufficiency
• Superficial thrombophlebitis
• Hypostatic eczema
• Arterial obliterative disease
• Acrocyanosis
• Livedo reticularis
• Lymphoedema
• Erythromelalgia
• Scleroderma
• Rheumatoid nodules
• Gouty tophi
• Erythema nodosum

Diagnosis

• Treatment should be based on symptoms and compatible exposure history
  • If erythema migrans is present, further testing is unhelpful outside of unusual cases and is not routinely recommended
• The most commonly used test is serology from blood, with EIA followed by reflexive Western blot
• CSF antibodies is useful for neuroborreliosis, but persist years after treatment
• PCR may be helpful in cases where patients are from populations with high seroprevalence
  • Pretty good for joint, less sensitive for CSF

Lyme Serology

• Typically done as a screening EIA followed by reflexive Western blot
  • In Ontario, the screening test is Borrelia Vls1/pepC10 IgM/IgG ELISA
  • The Western blot is done for IgM and IgG
• EIA should be positive by 4 to 6 weeks; if negative, Lyme is unlikely
  • Usually positive around 2 weeks
  • False negatives common early in clinical course
  • False positives with HIV, hepatitis C, and syphilis
  • Cross-reacts with European Lyme
• Western blot split into IgM and IgG if positive or equivocal
  • IgM 4 weeks, IgG 8 weeks
  • IgM is prone to over-interpretation and false positives
    • False positives with spirochetes (syphilis), viruses (cytomegalovirus, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, and parvovirus B19), and bacteria
  • Does NOT cross-react with European Lyme (in Ontario)
• Serology is most helpful when the pretest probability is >20%
• Serology remains elevated to months to years and should not be used to monitor response to treatment

EIA	Western Blot	Interpretation	Action
+	+	Early disseminated or late disease Previous exposure, treated or not	Treat if compatible symptoms and history
+	–	Early disease Early disease, treated European Lyme False-positive	If <8 weeks from exposure, repeat If >8 weeks, look for other cause Rule out HIV, hepatitis C, and syphilis Assess for autoimmune diseases Consider European Lyme
–	–	Very early Lyme <2 weeks Negative	Treat if erythema migrans

• Health Canada now recommends a modified two-tier EIA with combined IgM/IgG, with the screening EIA done with whole-cell lysate and the confirmatory EIA done with a recombinant protein
  • This approach has increased sensitivity at all stages (50-60% for early Lyme, around 100% for late Lyme including Lyme arthritis), and maintains
  • If you get a negative result when there is high pre-test probability for early Lyme, then submit a follow-up serology 3 to 6 weeks later

EIA 1	EIA 2	Interpretation
–	N/A	Negative; consider alternative diagnosis or resubmit in 3-6 weeks if compatible with early Lyme
+/±	+/±	Positive; treat based on clinical syndrome, if appropriate
+/±	–	Negative; consider alternative diagnosis or resubmit in 3-6 weeks if compatible with early Lyme

Management

Erythema Migrans

• Doxycycline 100 mg PO bid for 10 days
• Second-line: amoxicillin 500 mg PO tid for 14 days, cefuroxime 500 mg PO bid for 14 days
• Third-line: azithromycin for 7 days

Neurological Lyme Disease

• Any of the following: ceftriaxone IV, cefotaxime IV, penicillin G IV, doxycycline PO
• Duration of 14 to 21 days
• If there is parenchymal involvement, which is rare and usually based on MRI
  • If present, prefer IV antibiotics and a 2 to 4 week course
• In cases of facial nerve palsy, they may also receive corticosteroids within 72 hours

Lyme Carditis

• See Lyme carditis

Lyme Arthritis

• Oral antibiotics for 28 days
• If no response to oral antibiotics, can consider a course of ceftriaxone IV for 2 to 4 weeks

Post-Antibiotic Lyme Arthritis

• Refer to rheumatologist for consideration of DMARDs, biologics, intraarticular steroid injections, or arthroscopic synovectomy

Borrelial Lymphocytoma

• Oral antibiotics for 14 days

Acrodermatitis Chronica Atrophicans

• Oral antibiotics for 21 to 28 days

Prevention

• Routine personal protective measures to reduce tick exposure
• DEET, picaridin, IR3535, oil of lemon eucalyptus, PMD, 2-undecanone, or permethrin
• Remove ticks with clean fine-tipped tweezer inserted between the tick body and the skin
  • Do not cover, spray, or burn the tick
  • See tick removal for more information

Prophylaxis

• Can be considered in children and adults within 72 hours of tick removal if all of the following criteria are met:
  • Ixodes tick is identified
    • Small, tear-drop shaped
    • Plain oval shield
    • Lack of festoons
  • Occurs in a highly endemic area
  • Tick was attached for ≥36 hours
    • You can get a sense by asking if the tick was flat or engorged
    • If definitely flat, almost certainly attached less than 36 hours
    • However, still looks flat at 24 hours
• Use a single oral dose of doxycycline 4.4 mg/kg (max 200 mg) for children or 200 mg for adults

Further Reading

• 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease. Clin Infect Dis. 2020. doi: 10.1093/cid/ciaa1215
• Health Quality Ontario (2018). Management of Tick Bites and Investigation of Early Localized Lyme Disease.