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). There are three stages of Lyme disease. Stage I (early localized disease) is characterized by erythema migrans, 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., AV block). Stage III (late disease) is characterized by chronic arthritis and neurological 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 with erythema migrans. For all other patients, Lyme serology is recommended. Antibiotic treatment varies depending on the stage of Lyme disease and presentation. Options include oral doxycycline, amoxicillin, or cefuroxime axetil, and, in severe cases, intravenous ceftriaxone. Postexposure prophylaxis (PEP) for Lyme disease after a tick bite may be required in selected cases.

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

References:^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Pathogen
  • In the US: Borrelia burgdorferi, a microaerophilic 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 northwestern US
    • Ixodes ricinus (castor bean tick) in Europe
  • 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).
  • Increased risk of disease for:
    • Outdoor workers (e.g., landscapers, farmers)
    • Outdoor enthusiasts (e.g., hikers, hunters)
• Reservoir hosts
  • Deer, cattle
  • Peromyscus leucopus, the white‑footed mouse, is the primary reservoir of B. burgdorferi in the US.

References:^[2]

Stage I (early localized Lyme disease) ^[2][3][4]

Symptom onset occurs 7–14 days after a tick bite.

• Erythema migrans
• Flu‑like symptoms
  • Fever
  • Headache
  • Fatigue, malaise, lethargy
  • Myalgias, arthralgias

Stage II (early disseminated Lyme disease) ^[2][3][4]

Symptom onset occurs 3–10 weeks after a tick bite. ^[5]

• Migratory arthralgia; can progress to Lyme arthritis if left untreated
• Early neuroborreliosis
• Lyme carditis
• Cutaneous manifestations
  • Multiple erythema migrans lesions
  • Borrelial lymphocytoma
• Ocular manifestations
  • Retinal vasculitis
  • Keratitis
  • Iridocyclitis
  • Uveitis

Consider coinfection with other tick-borne pathogens (e.g., babesiosis or anaplasmosis) in patients with severe systemic symptoms (e.g., high-grade fever), clinical features of anemia, or persistent systemic symptoms after rash resolution.

Stage III (late disseminated Lyme disease) ^[2][3][4]

Symptom onset occurs months to years after the initial infection. ^[5]

• Lyme arthritis
• Late neuroborreliosis
• Acrodermatitis chronica atrophicans

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.

Approach ^[5][6]

• Asymptomatic patients with tick bite
  • No testing necessary
  • Check if the patient fulfills criteria for PEP for Lyme disease.
• Patients with typically-appearing erythema migrans
  • Lyme disease diagnosed clinically
  • No further testing required; see “Erythema migrans” for treatment.
• All other symptomatic patients
  • Perform Lyme serology if indicated
  • Consider further testing (e.g., laboratory studies, ECG, arthrocentesis, lumbar puncture) depending on clinical manifestations.
  • Consider testing (e.g., neuroimaging) to exclude differential diagnoses.

Lyme serology ^[5][6]

• Preferred testing protocol for new infections. ^[6]
• Detects IgM and IgG antibodies against Borrelia burgdorferi. ^[5][6]

Indications

Possible tick exposure in Lyme-endemic regions, PLUS any of the following: ^[6][7]

• Atypically-appearing erythema migrans
• Clinical features suggestive of neuroborreliosis, Lyme carditis, or Lyme arthritis
• Other manifestations of Lyme disease (in consultation with an ID specialist)

Lyme serology can be deferred for patients with typically appearing erythema migrans and asymptomatic patients with a recent tick bite. ^[6]

Protocol ^[6][8]

• Initial test: enzyme‑linked immunosorbent assay (ELISA) or indirect fluorescent antibody test
• Positive or equivocal initial test: confirmatory testing with a western blot or second-tier immunoassay

Interpretation

Correlate results with clinical features and time from onset.

• Negative result: no laboratory evidence of Lyme disease
  • False-negative results can occur.
  • Consider repeat testing after 2–4 weeks. ^[9]
• Positive result ^[5][8]
  • IgM positive, IgG negative: consistent with acute or recent infection
  • IgG positive: consistent with recent or remote infection

Both IgM and IgG antibodies against B. burgdorferi can persist for years after a remote infection, even if it was treated. ^[6]

False-positive results can occur due to cross-reactivity, e.g., with syphilis, Rocky Mountain spotted fever, systemic lupus erythematosus, or rheumatoid arthritis. ^[5]

Further testing

Further testing may be considered depending on the clinical presentation.

• ECG: See “Lyme carditis.”
• Lumbar puncture (LP): See “Neuroborreliosis.”
• Arthrocentesis: See “Lyme arthritis.”
• Laboratory studies
  • CBC: mild anemia, normal total WBC count with lymphopenia
  • Inflammatory markers: ↑ ESR
  • Liver enzymes: mildly elevated
  • Troponin: may be elevated in Lyme carditis ^[6]

Leukopenia, thrombocytopenia, significant anemia, and laboratory evidence of hemolysis are not typically seen in Lyme disease and should raise concern for coinfection with A. phagocytophilum and/or B. microti. ^[6]

• See “Differential diagnosis” in “Erythema migrans,” “Lyme carditis,” “Neuroborreliosis,” and “Lyme arthritis.”
• See “Overview of tick-borne diseases” including:
  • Tick paralysis
  • Rocky Mountain spotted fever (RMSF)
  • Babesiosis
  • Ehrlichiosis
  • Anaplasmosis
  • Tularemia
  • Colorado tick fever (CTF)
  • Tick-borne relapsing fever
  • Southern tick‑associated rash illness (STARI)

The differential diagnoses listed here are not exhaustive.

Asymptomatic patients with tick bite

• Remove the tick, if present.
• Provide PEP for Lyme disease if indicated.

Tick removal ^[5][6][10]

• Perform as soon as possible. ^[5]
• Grasp the tick with forceps at the closest point of attachment to the skin. ^[6][10]
• Gently pull the tick out and submit it for species identification. ^[6]
• If parts of the tick remain attached: Apply local anesthesia and perform local excision. ^[10]

Do not use nail polish remover, adhesives, oils, or other similar substances to remove ticks.

Antibiotics ^[5][6]

• Indications for oral therapy
  • Erythema migrans
  • Neuroborreliosis without parenchymal CNS involvement (e.g., isolated cranial nerve palsy, radiculoneuropathy, mild meningitis)
  • Mild Lyme carditis
  • Lyme arthritis
  • Borrelial lymphocytoma
  • Acrodermatitis chronica atrophicans
• Indications for IV therapy
  • Neuroborreliosis with severe meningitis or parenchymal CNS involvement (i.e., encephalitis, myelitis)
  • Neuroborreliosis in patients with impaired tolerance or adherence to oral therapy ^[6]
  • Severe Lyme carditis
  • Treatment-resistant Lyme arthritis
• Preferred oral agents: doxycycline, amoxicillin, or cefuroxime axetil
• Preferred IV agent: : ceftriaxone
• Dosages: based on patient presentation
  • See “Erythema migrans.”
  • See “Neuroborreliosis.”
  • See “Lyme carditis.”
  • See “Lyme arthritis.”
  • See “Borrelial lymphocytoma.”
  • See “Acrodermatitis chronica atrophicans.”

Weigh the risks and benefits of doxycycline in pregnant, lactating, and young (< 8 years old) individuals under specialist guidance. Many experts consider short courses (e.g., < 14–21 days) safe for children, irrespective of age. ^[6][11][12]

Disposition ^[5][6]

• Patients with indications for IV antibiotics: inpatient therapy with specialist consultation
• Uncomplicated disease requiring oral antibiotics only: outpatient therapy with infectious disease follow-up
• See “Disposition” in “Lyme carditis” and “Neuroborreliosis” for additional considerations.

Overview

Description ^[2][3][4]

• A rash that occurs in 70–80% of affected individuals
• Pathognomonic of early localized (stage I) Lyme disease ^[13]

Clinical features ^[2][3][4]

• Onset: 7–14 days after a tick bite
• Usually a slowly expanding red ring around the tick bite site with central clearing (“bull's eye rash”)
• Typically warm, painless; possibly pruritic
• Often occurs in isolation
• Self-limiting (typically subsides within 3–4 weeks)

Diagnosis ^[6]

• Typical appearance: Make a clinical diagnosis.
• Atypical appearance: Perform Lyme serology on acute and convalescent serum.

Diagnostic testing is not required before treating typically-appearing erythema migrans. ^[6]

Differential diagnosis

See also “Overview of annular skin lesions.”

• Cellulitis
• Contact dermatitis (discoid eczema)
• Erythema marginatum (rheumatic fever)
• Erythema multiforme
• Granuloma annulare
• Annular erythema
• Southern tick‑associated rash illness (STARI)

Treatment ^[6]

• Preferred (one of the following)
  • Oral cefuroxime axetil (off-label in children < 13 years) for 14 days ^[6][11][14]
  • Oral doxycycline (off-label) for 10 days ^[6][11][14]
  • Oral amoxicillin (off-label) for 14 days ^[6][11][14]
• Alternative: oral azithromycin (off-label) for 7 days ^[6][11][14]

A small number of patients may experience Jarisch-Herxheimer reaction after starting treatment for early Lyme disease. ^[5][6]

Courses of oral doxycycline for ≤ 14 days are generally considered safe in all children; however, some specialists prefer amoxicillin or cefuroxime in children < 8 years of age. ^[6][14]

Description ^[6][15]

• A manifestation of disseminated Lyme disease
• Can cause PNS or CNS dysfunction

Clinical features

• Onset
  • Early neuroborreliosis: within the first few months after a tick bite; typically has an acute onset
  • Late neuroborreliosis: months to years after the initial infection; typically has an indolent onset
• Peripheral neuropathy: weakness, pain, paresthesia
  • Cranial neuropathy: most commonly facial nerve palsy (often bilateral)
  • Radiculitis, plexopathy, mononeuropathy, or mononeuritis multiplex
• Lyme meningitis: can cause benign intracranial hypertension
• Encephalitis, myelitis, or encephalomyelitis

There is no proven association between Lyme disease and specific neurodegenerative diseases (e.g., multiple sclerosis, Alzheimer disease, Parkinson disease) or psychiatric conditions (e.g., depression, anxiety, bipolar disorder). ^[6][15]

Diagnosis ^[6]

• Lyme serology
• Exclusion of other causes (see “Differential diagnosis”)

Lumbar puncture ^[5][6]

• Indications: not routinely recommended; can be considered in certain cases of suspected CNS neuroborreliosis ^[6]
  • Suspected meningitis: to rule out bacterial and viral causes
  • When required for management or treatment decisions ^[6]
• Opening pressure: ICP may be elevated.
• CSF analysis: signs of lymphocytic meningitis, including lymphocytic and/or monocytic pleocytosis and elevated protein levels ^[6]
• Intrathecal IgG or IgM antibodies with simultaneous serum antibody test: elevated CSF/serum antibody index ^[6]

An elevated CSF/serum antibody index with normal protein levels and no pleocytosis may indicate a past infection; it does not confirm an ongoing infection. ^[6]

PCR and cultures have low sensitivity for detecting B. burgdorferi in CSF and are not recommended. ^[6]

Differential diagnosis

• Other etiologies of meningitis, encephalitis, and CNS lesions
• Other etiologies of cranial nerve palsies (e.g., Bell palsy) and other peripheral neuropathies.

Treatment ^[6]

• Meningitis, radiculopathy, cranial neuropathy, and/or other peripheral neuropathy : either oral or IV antibiotics for 14–21 days
  • Preferred (one of the following)
    • Oral doxycycline (off-label) ^[6][11][14]
    • IV ceftriaxone (off-label) ^[6][14][16]
  • Alternatives
    • IV cefotaxime (off-label) ^[6][11]
    • IV penicillin G (off-label) ^{[6] [11][14]}
• Encephalitis and/or myelitis : IV antibiotics with good CNS penetration for 14–28 days
  • Preferred: IV ceftriaxone (off-label) ^[6][11][14]
  • Alternative: Contact infectious diseases.

For Lyme-induced facial nerve palsy, oral doxycycline is the preferred treatment; consult a specialist regarding glucocorticoid use as the risk-benefit profile is unclear. ^[6][16]

Courses of oral doxycycline > 14 days should be used with caution in children < 8 years of age. ^[6]

Disposition ^[5][6]

• Admit patients with severe symptoms and those requiring hospitalization for concurrent Lyme carditis for IV antibiotics. ^[6]
• Children with signs of meningitis can be managed as outpatients until test results are available if they fulfill the “Rule of 7s”. ^[17]
  • Headache for < 7 days
  • CSF < 70% mononuclear cells
  • Absence of seventh or other cranial nerve palsy

Description ^[5][6]

• A manifestation of early disseminated Lyme disease
• Inflammation and dysfunction involving any part of the heart, e.g., atrial or ventricular arrhythmias, pericarditis, myocarditis.

Clinical features ^[5][6]

• Onset: within days to weeks (typically 3–5 weeks) after a tick bite
• Tachycardia, bradycardia, presyncope or syncope
• Clinical features of heart failure
• Clinical features of pericarditis
• Clinical features of myocarditis

Diagnosis ^[5][6]

• Lyme serology
• ECG
  • Conduction system abnormalities: e.g., AV block with rapidly fluctuating complete heart block (most common), bundle branch blocks, sinus node dysfunction. ^[6]
  • Other arrhythmias, e.g., ECG findings in atrial fibrillation
  • ECG features of pericarditis
• Echocardiography: pericardial effusion, left ventricular dysfunction
• Elevated troponin

Differential diagnoses

• See “Etiology of atrioventricular blocks.”
• See “Bradyarrhythmias” and “Tachyarrhythmias.”
• See “Etiology of myocarditis” and “Etiology of pericarditis.”

Treatment ^[6]

The choice of IV or oral antibiotics depends on symptoms; patients with severe manifestations (e.g., PR prolongation > 300 ms, high-degree AV block, arrhythmias, or features of perimyocarditis) require IV antibiotics.

• Mild symptoms: oral antibiotics for 14–21 days
  • Preferred (one of the following)
    • Oral doxycycline (off-label) ^[6][11][14]
    • Oral amoxicillin (off-label) ^[6][11][14]
    • Oral cefuroxime axetil (off-label) ^[6][11][14]
  • Alternative: azithromycin (off-label) (efficacy unclear) ^[6][11][14]
• Significant cardiac involvement : IV antibiotics for 14–21 days. ^[6]
  • Preferred: IV ceftriaxone (off-label) ^[6][11][14]
  • Alternatives
    • IV cefotaxime (off-label) ^[6]
    • IV penicillin G (off-label) ^[6][14]

Courses of oral doxycycline > 14 days should be used with caution in children < 8 years of age. ^[6]

Lyme-induced symptomatic bradycardia usually resolves within 3–7 days of initiating antibiotic therapy. ^[6]

Disposition ^[5][6]

• Consider outpatient therapy for patients with mild symptoms.
• Admit patients with any of the following for IV antibiotics and cardiac monitoring:
  • PR interval > 300 ms or high-degree AV block
  • Arrhythmias
  • Clinically apparent pericarditis or myocarditis

Description ^[18]

• Inflammation of the joint tissue due to Borrelia infection
• Can be permanently disabling if untreated

Clinical features ^[18]

• Onset: weeks to years after the initial infection
• Prodrome of migratory arthralgia: can occur in early disseminated Lyme disease
  • Affects joints at different times; typically involves the bursae and tendons at onset
  • Can progress to Lyme arthritis if left untreated
• Lyme arthritis: typically occurs in late disseminated Lyme disease
  • Monoarthritis or asymmetric oligoarthritis
  • Typically affects the large joints (especially the knee or elbow)
  • May be intermittent or persistent

Diagnosis ^[6]

• Lyme serology
• Exclusion of other causes (see “Differential diagnosis”)

Arthrocentesis ^[5][6]

• Indications
  • Patients with acute arthritis: to exclude septic arthritis
  • Uncertain diagnosis: to obtain synovial fluid or tissue for PCR detection of B. burgdorferi
• Synovial fluid analysis: typically nonspecific (see “Interpretation of synovial fluid analysis” for other etiologies) ^[5]
  • Appearance: yellow and cloudy
  • Leukocyte count: mean of 25,000/mm³ with > 50% neutrophils
  • Glucose: usually normal
  • Other: culture negative for growth, microscopy negative for crystals, negative Gram stain ^[6]
• Synovial fluid or tissue PCR
  • Positive result: consistent with acute or recent Lyme arthritis ^[6]
  • Negative result: does not exclude Lyme arthritis, as PCR has low sensitivity

Arthrocentesis is usually conducted to rule out septic arthritis. Lyme arthritis is typically diagnosed based on clinical presentation and positive serology; PCR is not obligatory. ^[6]

Differential diagnosis

• See “Differential diagnoses of infection-associated arthritis.”
• See “Differential diagnoses of inflammatory arthritis.”

Treatment ^[6]

• Initial treatment: one of the following oral antibiotics for 28 days
  • Oral doxycycline (off-label) ^[6][11][14]
  • Oral amoxicillin (off-label) ^[6][11][14]
  • Oral cefuroxime axetil (off-label) ^[6][11][14]
• Further management
  • Partial response : Either observe or give another course of oral antibiotics for 28 days. ^[6][11]
  • No or minimal response : IV ceftriaxone (off-label) for 14–28 days ^[6][14]
  • For persistent symptoms despite two courses of antibiotics, refer to rheumatology for additional management. ^[6][11][14]

Courses of oral doxycycline > 14 days should be used with caution in children < 8 years of age. ^[6][14]

It may take weeks to months for patients with Lyme arthritis to respond to antibiotic therapy; most patients respond within 1–3 months. ^[5][6]

Borrelial lymphocytoma ^[6]

• Description
  • A rare, cutaneous manifestation of European Lyme disease (endemic for Ixodes ricinus)
  • Occurs in early disseminated Lyme disease
  • Manifests as a bluish-red nodular swelling typically located on the earlobe, face, mamillae, and/or near a previous or concurrent lesion of erythema migrans
  • Localized lymphadenopathy is common.
  • Resolves spontaneously
• Treatment: oral antibiotics for 14 days ^[6]
  • Oral doxycycline (off-label) ^[6]
  • OR oral amoxicillin (off-label) ^[6]
  • OR oral cefuroxime axetil (off-label) ^[6]

Acrodermatitis chronica atrophicans (Herxheimer disease) ^[6]

• Description
  • Chronic progressive dermatological disease due to infection with Borrelia afzelii
  • Occurs only in Europe and Asia
  • Most commonly affects women > 40 years old
  • Occurs in late disseminated Lyme disease
  • Typically involves the extensor surface of the extremities
• Treatment: oral antibiotics for 21–28 days ^[6]
  • Oral doxycycline (off-label) ^[6]
  • OR oral amoxicillin (off-label) ^[6]
  • OR oral cefuroxime axetil (off-label) ^[6]

Post-treatment Lyme disease syndrome (PTLDS)

• Definition: nonspecific symptoms (e.g., pain, fatigue, cognitive impairment) lasting > 6 months after successful treatment for Lyme disease ^[3][19][20]
• Pathophysiology: unknown ^[20]
• Diagnostics ^[19]
  • Clinical diagnosis based on new or residual symptoms following antibiotic treatment for serologically confirmed Lyme disease
  • Rule out treatment failure and reinfection.
  • Inflammatory markers are typically normal. ^[3]
• Differential diagnosis: somatoform disorders, fibromyalgia, chronic fatigue syndrome
• Treatment: There are no established effective therapies. ^[20]
  • Provide reassurance, education, and patient-centered counseling.
  • Long-term antibiotic therapy has no proven benefit. ^[6][21]

After treatment for Lyme disease, avoid additional antibiotic therapy in patients with new or residual nonspecific symptoms if there is no evidence of treatment failure or reinfection. ^[6]

Many patients with PTLDS are ultimately diagnosed with fibromyalgia, chronic fatigue syndrome, or medically unexplained symptoms. ^[22]

We list the most important complications. The selection is not exhaustive.

General prevention

• There is no approved vaccine on the market for Lyme disease.
• Avoid prime habitats in areas known for Lyme disease.
• Tick bite prevention: 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; see “Tick removal.”
  • Observe the bite site for early detection of erythema migrans.

Postexposure prophylaxis for Lyme disease ^[6]

• Consider prophylaxis for patients who fulfill all of the following criteria: ^[6]
  • The bite was from an identified Ixodes spp. tick.
  • The tick bite occurred in a highly endemic area. ^[23]
  • The tick was attached for ≥ 36 hours. ^[5]
  • Prophylaxis can be started within 72 hours of tick removal.
• Prophylactic regimen: single dose of oral doxycycline (off-label) ^[6]

Consult infectious diseases about prophylaxis for pregnant or breastfeeding patients. ^[6]

Advise patients to monitor children < 12 years of age, even with postexposure prophylaxis, because of the limited data on doxycycline efficacy in this age group. ^[6]