Lyme Disease

Lyme disease is a tick-borne infection caused by the gram-negative spirochete Borrelia burgdorferi. Lyme disease is transmitted by the black-legged Ixodes tick (commonly known as a deer tick), which is only found in specific geographic regions. Patient presentation can vary depending on the stage of the disease and may include a characteristic erythema migrans rash. Neurologic, cardiac, ocular, and joint manifestations are also common in later stages. Diagnosis relies on clinical findings and tick exposure, and is supported by serological testing. Antibiotics are used for treatment. Avoidance of tick exposure is key to prevention in endemic areas.

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Overview

Epidemiology

  • First recognized in 1977 as “Lyme arthritis” in Connecticut
  • Most common tick-borne infection in North America and Europe
    • United States endemic areas: Northeast and Midwest regions
    • European endemic areas: central and eastern European countries
    • Geographic distribution appears to be increasing and may be related to:
      • Climate change
      • Land-use practices
      • Increasing virulent strains
  • > 30,000 cases reported in the United States each year
  • 5%–35% of Ixodes ticks are infected with Borrelia.
  • Infection can occur from March to October and peaks around June–July.

Etiology

  • Causative organism: 
    • Spirochete (gram-negative bacterium)
    • Most common species in North America: Borrelia burgdorferi 
    • Most common species in Europe:
      • B. afzelii
      • B. garinii
  • Reservoir hosts:
    • Small mammals (white-footed mouse)
    • White-tailed deer 
  • Vector for transmission: Ixodes tick
    • Transmission occurs through saliva injection during feeding
    • Longer attachment is associated with a higher risk of transmission (typically 36–72 hours)
  • At-risk groups:
    • Hikers
    • Woodworkers
Life cycle and reservoirs of b. burgdorferi

Lifecycle, reservoirs, and vector transmission of B. burgdorferi

Image by Lecturio.

Pathophysiology

  • Tick attachment and feeding → Borrelia (found in saliva) is injected into the skin:
    • May be eliminated by the immune system
    • Otherwise, will produce an erythema migrans skin lesion
  • Spirochetes then spread to the blood and regional lymph nodes within days to weeks.
  • Eventual spread to multiple organs (e.g., heart, joints, central nervous system, eyes)
  • Manifestations are secondary to the host’s immune response:
    • Induction of autoantibodies against neuronal and glial antigens
    • Cross-reactivity of Borrelia antibodies with neural and connective tissue
    • T-cell–mediated immune response
  • There may be some weak endotoxin-like activity.
Pathophysiology of lyme disease

Progression of Lyme disease after a tick bite

Image by Lecturio.

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Clinical Presentation

The incubation period for Lyme disease is 3–30 days (mean of 7 days). The clinical manifestations of Lyme disease are broken down into 3 stages: early localized disease, early disseminated disease, and late disease.

Early localized disease

Symptoms appear in 1–5 weeks and resolve in approximately 30 days.

  • Erythema chronicum migrans (EM)
    • Occurs in approximately 80% of patients
    • Classic “bull’s-eye” rash with slowly expanding red ring and central clearing
    • Appears at the site of the tick bite
  • Fever
  • Myalgia
  • Arthralgia
  • Fatigue
  • Lymphadenopathy

Early disseminated disease

Symptoms develop in weeks to months in untreated patients.

  • Musculoskeletal:
    • Migratory arthralgias
    • Myalgias
  • Cardiac (approximately 8% of patients): 
    • Myocarditis
      • Inflammation to the myocardium, which affects the muscle and electrical system of the heart
      • Manifests as chest pain and shortness of breath
      • Can lead to congestive heart failure
    • Pericarditis
      • Inflammation of the pericardium
      • Manifests as sudden onset of sharp chest pain
    • Atrioventricular (AV) block 
      • Secondary to myocarditis
      • Most common cardiac manifestation
  • Neurologic (approximately 15% of patients):
    • Facial nerve palsy (Bell’s palsy)
      • Typically bilateral
      • Most common neurologic manifestation
    • Meningoradiculitis (Bannwarth syndrome):
      • Radiculopathy and paresthesia
      • Follows a dermatome distribution
    • Polyneuropathy
    • Lymphocytic meningitis
    • Encephalitis
  • Cutaneous:
    • Multiple secondary EM lesions
      • Due to spirochetemia (presence of Borrelia in the blood)
      • Not from multiple tick bites
    • Lymphadenosis cutis benigna (also known as pseudolymphoma or borrelial lymphocytoma)
      • Rare, more often seen in Europe
      • Blue-red swelling, usually of the earlobe or near the nipple
  • Ocular:
    • Conjunctivitis (10% of patients)
    • Rare manifestations:
      • Keratitis (inflammation of the cornea)
      • Retinal vasculitis
      • Optic neuropathy
      • Uveitis (inflammation of the uvea)

Late disease

Symptoms develop in months to years in untreated patients.

  • Migratory polyarthritis (60% of patients)
    • Large joints, particularly the knee
    • Intermittent joint swelling and pain
    • Baker cysts can form.
  • Neurologic symptoms:
    • Lyme encephalopathy: subtle cognitive, mood, and sleep disturbances
    • Chronic axonal polyneuropathy
      • Spinal radicular pain
      • Distal paresthesias
    • Chronic encephalomyelitis
      • Spastic paraparesis
      • Cranial neuropathy
      • Cognitive impairment
  • Acrodermatitis chronica atrophicans 
    • More common in Europe due to B. afzelii
    • Starts with unilateral bluish-red discoloration and swelling
    • Atrophy eventually develops and vasculature appears more prominent.

Mnemonic

Common symptoms of Lyme disease can be remembered by the mnemonic phrase “a key Lyme pie to the FACE.”

  • Facial nerve palsy
  • Arthritis
  • Cardiac block
  • Erythema migrans

Diagnosis

Diagnostic algorithm

Lyme disease diagnosis

Diagnostic algorithm for Lyme disease

ELISA: enzyme-linked immunosorbent assay

Image by Lecturio.
  • A Lyme disease diagnosis is based on the clinical picture and supported by serologic testing.
  • Blinical symptoms largely depend on the stage of disease.
  • Lyme testing is not warranted for:
    • Screening asymptomatic patients
    • Patients with only nonspecific symptoms (fatigue, myalgia)

Laboratory testing

Laboratory tests are only significant in conjunction with the clinical history due to a high false-positive and false-negative rate.

  • Antibody testing
    • Enzyme-linked immunosorbent assay (ELISA)
      • Initial test
      • Detects antibodies through a coupled enzyme-antibody complex, which produces a color change
      • False-positives can occur due to other infections (e.g., syphilis) or autoimmune disease.
      • False-negatives can occur in the early stage; thus, ELISA is not done if the characteristic EM rash is seen.
    • Western blot
      • Confirmation test if the ELISA is positive
      • Detects antibodies to individual protein components of B. burgdorferi using electrophoresis
  • Polymerase chain reaction (PCR)
    • May be performed on cerebrospinal fluid and synovial fluid for those who present with meningitis or arthritis.
    • High false-negative rate
    • Can remain positive for years after treatment
Western blotting of B. burgdorferi

Western blotting of B. burgdorferi.
A, B, and C: positive controls for specific monoclonal antibodies
D and E: seropositive patients for IgM
F: positive control
G: negative control
H: white control
MW: molecular weight

Image: “Western blotting of B. burgdorferi” by Department of Biomedicine and Biotecnology, Alcalá University, 28871 Alcalá de Henares, Spain. License: CC BY 3.0

Management

Treatment

Oral antibiotics:

  • Doxycycline
  • Amoxicillin
  • Cefuroxime
  • Used in all stages of Lyme disease

Intravenous (IV) antibiotics:

  • Ceftriaxone
  • Used for:
    • Those who cannot tolerate oral antibiotics
    • Early disseminated disease with meningitis, encephalomyelitis, or severe cardiac manifestations (3rd-degree AV block)
    • Late disease with neurologic manifestations
    • Recurrent arthritis despite oral therapy

Additional considerations:

  • 3rd-degree AV block
    • May require temporary pacing
    • AV block is usually short-lived with treatment.
  • Jarisch-Herxheimer reaction
    • Seen in 15% of patients with early Lyme disease
    • Transient worsening of symptoms during the initial 24 hours of treatment
    • Due to an immune response to the antigens released by dying spirochetes
Table: Summary of the management of the different clinical manifestations of Lyme disease
Clinical manifestationsManagement
Asymptomatic patient with a tick bite requires no prophylactic treatment unless:
  • Known Ixodes scapularis bite
  • Tick attached for ≥ 36 hours
  • In an endemic area
If meets criteria, then must receive prophylactic doxycycline within 72 hours of bite
Early disseminated disease:
  • Erythema migrans lesions
  • Risk of exposure
  • Doxycycline
  • Amoxicillin or cefuroxime
Facial nerve palsy or joint involvement
  • Doxycycline
  • Amoxicillin or cefuroxime
Cardiac and neurologic manifestationsIntravenous ceftriaxone
ReinfectionSame antibiotic as recommended for a primary infection

Post-Lyme disease syndrome (PLDS) and chronic Lyme disease

  • Controversial syndromes
  • Persistent or recurrent symptoms despite treatment
  • Chronic subjective symptoms are not thought to be due to persistent infection.
  • Patients should be reevaluated since this may be due to:
    • Incorrect Lyme diagnosis
    • Coinfection with another tick-borne disease (Babesia, Anaplasma)
    • Another concurrent condition (fibromyalgia, depression)
    • Permanent tissue damage (particularly from neurologic involvement)
  • No proven benefit to additional antibiotics

Prevention and Prophylaxis

  • If the tick is removed within the first 12 hours, the infection risk is very low.
  • Do not assume immunity is developed after a previous infection.
  • For persons from non-endemic areas, there is no need for prophylactic antibiotics, but the tick site should be observed.

Precautions against ticks

  • Protective clothing
  • Repellents
  • Scanning the body for ticks after being outside
  • Removing ticks from bite sites as soon as possible with a tweezer

Doxycycline prophylaxis

Doxycycline prophylaxis is indicated if all the following criteria are met:

  • Tick is identified as Ixodes scapularis.
  • Tick has been attached for ≥ 36 hours.
  • Prophylaxis will start within 72 hours of tick removal.
  • Rate of B. burgdorferi infection of ticks in the area is ≥ 20%.
  • Doxycycline is not contraindicated.

Differential Diagnosis

  • Babesiosis: a tick-borne infection caused by Babesia. Patients can be asymptomatic or develop fever, fatigue, malaise, and arthralgias. Asplenic, immunocompromised, and elderly patients are at risk for severe disease, causing hemolytic anemia, thrombocytopenia, hepatosplenomegaly, renal failure, and death. Diagnosis is confirmed with a peripheral blood smear, serologic testing, and PCR. Treatment includes antibiotics, such as atovaquone plus azithromycin.
  • Ehrlichiosis and anaplasmosis: tick-borne infections caused by Ehrlichia chaffeensis and Anaplasmosis phagocytophilum, respectively. Symptoms include fever, headache, and malaise. A rash is uncommon, but can appear petechial or maculopapular. The diagnosis is made with a PCR test. Treatment of both diseases is with doxycycline.
  • Rocky Mountain spotted fever: a disease caused by Rickettsia rickettsii that presents with fever, fatigue, headache, and a rash following a tick bite. However, this disease is associated with the Dermacentor tick, and the rash begins on the distal extremities and spreads centrally. Diagnosis is made based on the clinical features, biopsy of the rash, and serologic testing. Treatment involves antibiotics, including doxycycline.
  • Epidemic typhus: a disease caused by Rickettsia prowazeki that presents with myalgia, arthralgia, rash, and encephalitis. A rash starts on the trunk and spreads outward to the extremities. Epidemic typhus is transmitted to humans by lice. Diagnosis is based on the clinical picture, biopsy of the rash, and serologic testing. Treatment involves antibiotics, including doxycycline. 
  • Infectious mononucleosis: a disease caused by the Epstein-Barr virus that is characterized by fever, fatigue, lymphadenopathy, and pharyngitis. Diagnosis is based on clinical features and testing, such as a heterophile antibody test or serology. Treatment is supportive. The use of amoxicillin can cause a characteristic maculopapular rash. 
  • Juvenile idiopathic arthritis: a group of rheumatic diseases that cause arthritis, fever, rash, adenopathy, splenomegaly, and iridocyclitis in children under 16 years of age. The rash may vary, but can appear macular with a central clearing. Diagnosis is based on the clinical picture and an autoimmune workup, including rheumatoid factor (RF), antinuclear antibodies (ANA), anticyclic citrullinated peptide antibodies (anti-CCP), and human leukocyte antigen (HLA)-B27. Treatment includes corticosteroids and disease-modifying antirheumatic drugs (DMARDs).
  • Rheumatoid arthritis: an autoimmune disease of the joints, causing an inflammatory and destructive arthritis. Patients typically have swelling and pain of the peripheral joints (e.g., hands, wrists, knees, ankles). Associated extra-articular manifestations include pericarditis, lymphadenopathy, episcleritis, or mononeuritis multiplex. Diagnosis is based on the clinical picture, inflammatory markers, RF, and anti-CCP. Treatment usually starts with glucocorticoids, DMARDs, and nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Reactive arthritis: a spondyloarthropathy that is often precipitated by a gastrointestinal or genitourinary infection. Patients may present with an asymmetric arthritis, typically of the lower extremities. This arthritis can be associated with fever, tendinitis, enthesitis, mucocutaneous ulcers, and conjunctivitis. Diagnosis is clinical. Treatment includes NSAIDs, DMARDs, and treatment of the infection.

References

  1. Bush, L.M., and Vazquez-Pertejo, M.T. (2020). Lyme disease. [online] MSD Manual Professional Version. Retrieved December 5, 2020, from https://www.msdmanuals.com/professional/infectious-diseases/spirochetes/lyme-disease
  2. Mead, P., and Schwartz, A. (2020). Epidemiology of Lyme disease. In Mitty, J. (Ed.), UpToDate. Retrieved December 5, 2020, from https://www.uptodate.com/contents/epidemiology-of-lyme-disease
  3. Hu, L. (2020). Clinical manifestations of Lyme disease in adults. In Mitty, J. (Ed.), UpToDate. Retrieved December 5, 2020, from https://www.uptodate.com/contents/clinical-manifestations-of-lyme-disease-in-adults
  4. Hu, L. (2019). Diagnosis of Lyme disease. In Mitty, J. (Ed.), update. Retrieved December 5, 2020, from https://www.uptodate.com/contents/diagnosis-of-lyme-disease
  5. Hu, L. (2020). Treatment of Lyme disease. In Mitty, J. (Ed.), Uptodate. Retrieved December 5, 2020, from https://www.uptodate.com/contents/treatment-of-lyme-disease
  6. Meyerhoff, J.O., Steele, R.W., and Zaidman, G.W. (2019). Lyme disease. In Diamond, H.S. (Ed.), Medscape. Retrieved December 5, 2020, from https://emedicine.medscape.com/article/330178-overview

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