• 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 facultative 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), skin manifestations forming livid nodules along with lymphadenopathy (lymphadenitis cutis benigna; only in Europe and Asia), migratory arthralgia, and cardiac manifestations (e.g., myocarditis). Stage III (late disease) is characterized by chronic‑progressive skin atrophy (acrodermatitis chronica atrophicans; only in Europe), chronic arthritis and CNS involvement (late neuroborreliosis) with possible progressive encephalomyelitis. 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


Epidemiological data refers to the US, unless otherwise specified.


  • Pathogen
    • In the US: Borrelia burgdorferi, an anaerobic, facultative 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
      • Ixodes pacificus (western black-legged tick) in the northeastern US
      • Ixodes ricinus (castor bean tick) in Europe
    • Ticks populate many different areas, but require humid environments in order to survive.
    • 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.)


Clinical features

Stage I (early localized Lyme disease)

  • Symptoms develop within 7–14 days after a tick bite.
  • Erythema chronicum migrans (EM)
    • Occurs in 80% of infected individuals
    • Usually a circular, slowly expanding red ring around the bite site with central clearing
    • Typically warm, painless
    • EM is often the only symptom.
    • Self-limiting (typically subsides within 3–4 weeks)
  • Flu‑like symptoms

Stage II (early disseminated Lyme disease)

Stage III (late Lyme disease)




  • After a tick bite, observe for erythema chronicum migrans. Suspicious rashes may be monitored over several days.
  • If the patient history and clinical presentation indicate Stage I Lyme disease, empiric antibiotics may be started without further testing.
  • If symptoms of Lyme disease arise in a patient with possible exposure (especially if a history of recent travel to an area with high vector density) → conduct two-step serological testing
  • If signs of neuroborreliosis are present and other tests are inconclusive, consider additional procedures, such as a lumbar puncture for cerebrospinal fluid testing.

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!

  • Rule of 7s – Children who meet all of the following criteria can be identified as at low risk for Lyme meningitis and may accordingly be treated in an outpatient setting until lab results become available:
  • 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


Differential diagnoses


The differential diagnoses listed here are not exhaustive.

Differential diagnoses of tick bite

Tick-borne diseases (endemic to US) [8] Pathophysiology / Epidemiology

Clinical features

Diagnostics Treatment
Lyme disease
  • Pathogen: Borrelia burgdorferi
  • Vector
    • Ixodes scapularis
    • Ixodes pacificus
  • Distribution: upper midwestern, northeastern US, and West Coast
Tick paralysis
  • Tick neurotoxin
  • Locate and remove the tick!
  • Supportive therapy (e.g., ventilatory support in a patient with respiratory failure)
Rocky Mountain spotted fever (RMSF)
  • Pathogen: Rickettsia rickettsii
  • Vector
    • Dermacentor variabilis
    • Dermacentor andersoni
    • Rhipicephalus sanguineus
  • Distribution: northeast and south US
  • 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
  • Pathogen: Babesia species (typically Babesia microti)
  • Vector: Ixodes scapularis
  • Distribution: midwest and northeast US
  • Incubation period: 1–6 weeks
  • Flu-like symptoms
  • Hemolytic anemia → dark urine and/or icterus
  • Mild splenomegaly and/or hepatomegaly
  • Gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain)
  • Typically no rash
  • Pathogen: Ehrlichia chaffeensis, Ehrlichia ewingii
  • Vector: Amblyomma americanum
  • Distribution: southeastern and south-central US
  • 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


(Human granulocytic ehrlichiosis)

  • Pathogen: Anaplasma phagocytophilum
  • Vector
    • Ixodes scapularis
    • Ixodes pacificus
  • Distribution: upper midwest and northeastern US
  • Incubation period: 1–2 weeks
  • Flu-like symptoms
  • Gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain)
  • Cough
  • Typically no rash
Tularemia [9] [10]
  • Pathogen: Francisella tularensis
  • Vector
    • Dermacentor variabilis
    • Dermacentor andersoni
    • Amblyomma americanum
    • Deer flies (Chrysops species)
  • Transmission without a vector:
    • Inhalation of dust or aerosols contaminated with F. tularensis
    • Ingestion of contaminated food or water
  • Distribution: all states except Hawaii
Colorado tick fever (CTF) [11][12]
  • Pathogen: Colorado tick fever virus (CTFV)
  • Vector: Dermacentor andersoni
  • Distribution: western US
  • Incubation period: 1–14 days
  • Flu-like symptoms
    • 50% of patients develop a biphasic illness, in which fever remits after 2–4 days only to recur 1–3 days later.
  • Possibly, conjunctival injection, pharyngeal erythema, and cervical lymphadenopathy
  • Petechial or maculopapular rash in 5–15% of cases
  • No specific treatment; supportive management only
Tick-borne relapsing fever [13]
  • Pathogen: Borrelia hermsii
  • Vector: Ornithodoros species
  • Distribution: western US
  • Incubation period: 4–18 days
  • Recurring episodes of high fever (up to 106.7°F or 41.5°C) lasting 3 days followed by an afebrile period of 7 days
  • Arthralgia (∼ 70%)
  • Gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain)
    • Nausea, vomiting (∼ 70%)
    • Abdominal pain (40–50%)
    • Diarrhea (∼ 25%)
  • Jaundice (∼ 10%)
  • Hepatosplenomegaly (5–10%)
  • Less commonly, symptoms of meningitis
    • Confusion (∼ 40%)
    • Photophobia (∼ 25%)
    • Neck pain (∼ 25%)
    • Nuchal rigidity (∼ 2%)
  • Macular rash or scattered petechiae in 15–20% of cases
Southern tick‑associated rash illness (STARI)
  • Vector: Amblyomma americanum
  • Pathogen: unknown
  • Distribution: southeastern and eastern US
  • 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!

  • Complications following successful antibiotic treatment
    • Post‑treatment Lyme disease syndrome (post‑Lyme disease syndrome, PLDS)
      • Description: a controversial syndrome (the medical community does not agree on its existence) following successful treatment of Lyme disease that is associated with loss of performance, fatigue, and difficulty concentrating that may last up to 6 months
      • Differential diagnosis: somatoform disorders
      • Treatment: symptomatic treatment with general medical and psychosomatic support



  • There is no approved vaccine on the market.
  • Avoid 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.

Post‑exposure prophylaxis (PEP)

  • 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).