• Clinical science

Lyme disease


Lyme disease (or borreliosis) is a tick-borne infection caused by certain species of the Borrelia genus (B. burgdorferi in the US, predominantly B. afzelii and B. garinii in Asia and Europe), a genus of obligate intracellular bacteria. There are three stages of Lyme disease. Stage I (early localized disease) is characterized by erythema migrans (EM), an expanding circular red rash at the site of the tick bite, and may be associated with flu‑like symptoms. In stage II (early disseminated disease), patients may present with neurological symptoms (e.g., facial palsy), migratory arthralgia, and cardiac manifestations (e.g., myocarditis). Stage III (late disease) is characterized by chronic arthritis and CNS involvement (late neuroborreliosis) with possible progressive encephalomyelitis. In Asia and Europe, further skin manifestations may also occur in stage II (lymphadenitis cutis benigna) and stage III (acrodermatitis chronica atrophicans). Lyme disease is a clinical diagnosis in patients presenting with EM. Serological tests (e.g., Western blot; enzyme-linked immunosorbent assay) can help support the clinical diagnosis, especially if the presence of EM is not known or questionable. Lyme disease is treated with antibiotics; the drugs of choice are doxycycline for localized disease and ceftriaxone for disseminated disease.


  • Incidence: most commonly reported vector-borne disease in the US
  • Geographical distribution: primarily the Northeast and upper Midwest of the US


Epidemiological data refers to the US, unless otherwise specified.


  • Pathogen
    • In the US: Borrelia burgdorferi, an anaerobic, obligate intracellular spirochete bacteria
      • Atypical and cystic forms of B. burgdorferi can persist in the body for years.
    • In Europe and Asia: B. afzelii and B. garinii
      • Rarely B. valaisiana, B. lusitaniae, B. spielmanii, and B. bavariensis infect humans.
  • Vector
    • Various tick species: mainly Ixodes scapularis (deer or black-legged tick); in the northeastern and upper midwestern US
    • Typically found in forests or fields on tall brush or grass
    • The incidence of Lyme disease is highest between April and October (especially from June to August).
    • Peromyscus leucopus, the white‑footed mouse, is the primary reservoir of B. burgdorferi in the US.
    • Increased risk of disease for:
      • Outdoor workers (landscapers, farmers, etc.)
      • Outdoor enthusiasts (i.e., hikers, hunters, etc.)
  • Reservoir hosts: deer, cattle


Clinical features

Stage I (early localized Lyme disease)

Symptoms develop within 7–14 days after a tick bite.

  • Erythema chronicum migrans (EM)
    • Pathognomonic of early Lyme disease
    • Occurs in approx. 70–80% of infected individuals [3]
    • Usually a slowly expanding red ring around the bite site with central clearing (“bull's eye rash”)
    • Typically warm, painless
    • EM is often the only symptom.
    • Self-limiting (typically subsides within 3–4 weeks)
  • Flu‑like symptoms: fever, fatigue, malaise, lethargy, headache, myalgias, and arthralgias

Stage II (early disseminated Lyme disease)

Symptoms develop 3–10 weeks after a tick bite

Stage III (late Lyme disease)

Symptoms develop months to years after the initial infection

To remember important symptoms of Lyme disease, think of someone making a FACE (Facial nerve palsy, Arthritis, Carditis, Erythema migrans) when biting into a lime.



Two‑step serological testing

Other tests

Borrelia-specific intrathecal antibodies with normal protein and without pleocytosis indicate a past infection. Detection of elevated antibodies alone does not provide conclusive evidence of an active infection

  • Arthrocentesis
    • Commonly conducted if signs of arthritis are present, but results do not allow differentiation from septic arthritis without PCR
    • Synovial fluid findings
      • Appearance: yellow and cloudy
      • Leukocyte count: 3000–100,000/mm3 with > 50% neutrophils
      • PCR test: positive
      • Negative findings: Gram stain, culture, crystals
  • Rule of 7s: Children who meet all of the following criteria can be identified as at low risk for Lyme meningitis and may be treated accordingly in an outpatient setting until lab results become available.


Differential diagnoses


The differential diagnoses listed here are not exhaustive.

Differential diagnoses of tick bite

Tick-borne diseases (endemic to US) [10] Pathophysiology / Epidemiology

Clinical features

Diagnostics Treatment
Lyme disease
Tick paralysis
  • Locate and remove the tick!
  • Supportive therapy (e.g., ventilatory support in a patient with respiratory failure)
Rocky Mountain spotted fever (RMSF)
  • Incubation period: 2–14 days
  • Flu-like symptoms
  • Blanching maculopapular rash (90% of cases): begins on wrists and ankles 2–5 days after onset of fever spreads to trunk, palms, and soles → becomes petechial and/or hemorrhagic in 50% of cases
  • Ankle and/or wrist swelling
  • Gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain)
  • Meningitis, focal neurological deficits
  • Rapid clinical deterioration with shock and multi-organ dysfunction
  • Incubation period: 1–2 weeks
  • Flu-like symptoms
  • Gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain)
  • Rarely, symptoms of meningitis and/or encephalitis (e.g., headache, altered mental status, stiff neck, neurological deficits)
  • Typically no rash


  • Incubation period: 1–2 weeks
  • Flu-like symptoms
  • Gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain)
  • Cough
  • Typically no rash
Tularemia [11][12]
  • Incubation period: typically 3–5 days (range 1–21 days)
  • High fever
  • Skin ulcer at the site where F. tularensis enters the body
  • Tender regional lymphadenopathy
  • Localized signs if:
    • Oculoglandular
    • Oropharyngeal
    • Pneumonic
    • Typhoidal
Colorado tick fever (CTF) [13][14]
  • No specific treatment; supportive management only
Tick-borne relapsing fever [15]
  • Incubation period: 4–18 days
  • Recurring episodes of high fever lasting 3 days followed by an afebrile period of 7 days
  • Arthralgia
  • Gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain)
  • Less commonly
  • Macular rash or scattered petechiae in 15–20% of cases
Southern tick‑associated rash illness (STARI)
  • Incubation period: ∼ 7 days
  • Resembles early localized Lyme disease with erythema migrans lesion and possibly flu-like symptoms
  • Clinical features of early disseminated and late Lyme disease typically do not occur
  • Treatment for Lyme disease


Stages Presentation General therapy Therapy in pregnant/nursing patients
Localized Lyme disease
Disseminated Lyme disease

Doxycycline is relatively contraindicated in pregnant/nursing women due to its adverse effects on growing bones and teeth! Administer amoxicillin (or cefuroxime axetil) instead!

If infection is likely (e.g., EM is present), start antibiotic treatment!

Possible complications following successful antibiotic treatment

  • Post-Lyme disease syndrome (PLDS)
    • Description: a somewhat controversial syndrome (the medical community does not agree on its existence) following successful treatment of Lyme disease that is associated with pain, fatigue, and difficulty concentrating that lasts > 6 months [16]
    • Differential diagnosis: somatoform disorders, unsuccessfully treated chronic Lyme disease
    • Treatment: symptomatic treatment with general medical and psychosomatic support



  • There is no approved vaccine on the market for Lyme disease. There was a Lyme disease vaccine in the past that offered temporary protection, but it was discontinued in 2002 because of low demand.
  • Avoid prime habitats in areas known for Lyme disease.
  • Prevent and properly manage tick bites to avoid exposure.
    • Wear protective clothing: e.g., long-sleeved shirts, long pants, and light colors.
    • Use tick repellent and pesticides.
    • Check body for tick bites.
    • Remove ticks immediately!
      1. Grasp the tick with tweezers directly above the skin's surface.
      2. Carefully pull upward with even pressure.
      3. Do not use nail polish remover, adhesives, oils, or similar substances to remove the tick. The tick should be removed quickly rather than waiting for it to detach slowly.
      4. Disinfect the site of the bite and dispose of the tick
    • Observe the bite site for early detection of EM.

References: [18]

Post‑exposure prophylaxis (PEP) [19]

  • Although controversial, PEP may be considered for patients who meet all of the following criteria:
    • The attached tick can be identified as an adult or nymphal Ixodes scapularis tick.
    • The tick has been attached for ≥ 36 hours (based on degree of engorgement or amount of time since exposure).
    • Prophylaxis can be started within 72 hours of tick removal.
    • The local rate of tick infection with B. burgdorferi is ≥ 20% (known to occur in parts of New England, parts of the mid‑Atlantic states, and parts of Minnesota and Wisconsin).
    • The patient can take doxycycline (e.g., the person is neither pregnant nor breastfeeding, nor a child < 8 years of age).
  • If the patient meets all the above criteria, 200 mg of doxycycline can be given to adults and 4 mg/kg to children ≥ 8 years (maximum dose: 200 mg).