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Lyme Disease

Infectious MONDO:0019632 Bacterial Infection Tick-Borne Disease

Lyme disease is a tick-borne infectious disease caused by Borrelia burgdorferi and related Borrelia species. It is the most common vector-borne disease in North America and Europe. The disease progresses through stages: early localized (erythema migrans), early disseminated (multiple erythema migrans, neurological, cardiac involvement), and late disseminated (arthritis, chronic neurological). Early antibiotic treatment is highly effective, while delayed treatment may lead to persistent symptoms.

0
Mappings
0
Definitions
0
Inheritance
3
Pathophysiology
0
Histopathology
9
Phenotypes
1
Genes
3
Treatments
4
Subtypes
7
Differentials
0
Datasets
3
Trials
◆

Subtypes

4
Early Localized Lyme Disease
Initial stage within weeks of tick bite, characterized by erythema migrans and flu-like symptoms.
Early Disseminated Lyme Disease
Hematogenous spread within weeks to months, with multiple erythema migrans, neurological, or cardiac involvement.
Late Disseminated Lyme Disease
Months to years after infection, characterized by Lyme arthritis or chronic neurological manifestations.
Post-Treatment Lyme Disease Syndrome
Persistent symptoms after appropriate antibiotic therapy, occurring in 10-20% of treated patients.
⚙

Pathophysiology

3
Spirochete Invasion and Dissemination
Borrelia burgdorferi is transmitted through Ixodes tick bites. The spirochete disseminates from the skin through the bloodstream to multiple organ systems including joints, heart, and nervous system. Surface adhesins like BBK32 and decorin-binding proteins (DbpA/DbpB) facilitate tissue colonization.
endothelial cell link
cell adhesion link
Show evidence (1 reference)
PMID:33669940 SUPPORT
"The clinical manifestations of Lyme disease range from a localized infection, for example, erythema migrans (EM) to a disseminated neurological or rheumatological infection, cardiac involvement, or even chronic disease."
Epidemiologic series shows Borrelia disseminates beyond skin to neurologic, rheumatologic, and cardiac sites.
Autoimmune Activation after Persistent Infection
Prolonged exposure of the host immune system to Borrelia antigens can drive post-infectious autoimmunity, with reported triggers of systemic autoimmune disease after Lyme borreliosis.
T cell link
immune system process link
Show evidence (1 reference)
PMID:34786243 SUPPORT
"long-term exposure of the host's immune system to spirochetes can contribute to the development of chronic autoimmune disease de novo."
Case review links persistent Borrelia exposure to downstream autoimmune disease.
Inflammatory Response and Tissue Damage
The host immune response to Borrelia antigens contributes to tissue damage. Spirochetal lipoproteins and peptidoglycan trigger robust innate immune activation with production of IL-6, IL-8, TNF, and chemokines (CCL3/CCL4). Persistent inflammation in joints may continue even after spirochete clearance.
neutrophil link macrophage link T cell link
inflammatory response link
Show evidence (1 reference)
PMID:37407232 SUPPORT
"Aspiration of the left knee joint revealed a white cell count of 21.0×109/L (83% neutrophils) with negative Gram stain and culture. However, Lyme PCR was positive and accompanied by serologies consistent with Lyme arthritis."
Lyme arthritis joint fluid shows marked neutrophilic inflammation despite negative cultures, consistent with immune-driven damage.
●

Phenotypes

9
Cardiovascular(2) Head and Neck(1) Immune(1) Integument(1) Musculoskeletal(1) Nervous System(1) Constitutional(2)
Cardiovascular 2
Erythema Migrans VERY_FREQUENT Erythema migrans (HP:0031180)
Show evidence (1 reference)
PMID:33669940 SUPPORT
"Results: In total, 1005 patients were enrolled with the following prevalence of clinical syndromes: erythema migrans (EM), 945 (94.02%); Lyme arthritis, 32 (3.18%); neuroborreliosis, 23 (2.28%); Lyme carditis, 4 (0.39%); and acrodermatitis, 1 (0.09%)."
Large Lithuanian cohort confirms erythema migrans as the dominant presentation.
Atrioventricular Block OCCASIONAL Atrioventricular block (HP:0001678)
Show evidence (1 reference)
PMID:37234726 SUPPORT
"the most common clinical manifestation is AV block, which can be acute in onset and can rapidly progress to complete heart block."
Case report and review emphasize AV block as the hallmark of Lyme carditis.
Head and Neck 1
Facial Palsy OCCASIONAL Facial palsy (HP:0010628)
Show evidence (1 reference)
PMID:33669940 SUPPORT
"The main symptoms were the following: nervus facialis neuropathy (47.8%), myalgia (39%), head pain (26%), and radiculitis (21%)."
Neuroborreliosis cases frequently manifested facial nerve palsy.
Immune 1
Myelitis RARE Myelitis (HP:0012486)
Show evidence (1 reference)
PMID:33082765 SUPPORT
"We report a case of acute neuroborreliosis that manifested as extended isolated cervical myelitis."
Case report confirms Lyme-associated cervical myelitis with CSF pleocytosis and intrathecal Borrelia antibodies.
Integument 1
Bullous Skin Lesions RARE Subepidermal blistering (HP:0033804)
Show evidence (1 reference)
PMID:41133080 SUPPORT
"developed acquired epidermolysis bullosa (EBA) following an LD diagnosis. Initially, the patient presented with atypical erythema migrans, which later evolved into multiple bullous lesions"
Case report documents bullous lesions evolving after Lyme disease.
Musculoskeletal 1
Arthritis FREQUENT Arthritis (HP:0001369)
Show evidence (1 reference)
PMID:33669940 SUPPORT
"Lyme arthritis mainly manifested among middle-aged women as an oligoarthritis, mostly affecting the knee joint."
Cohort study documents oligoarticular knee-predominant Lyme arthritis.
Nervous System 1
Dementia (Reversible Neuroborreliosis) RARE Dementia (HP:0000726)
Show evidence (2 references)
PMID:30046879 SUPPORT
"Dementia-like syndromes are rare manifestations of Lyme neuroborreliosis... The response to 2-4 weeks of antibiotic treatment with ceftriaxone was excellent."
Review of definite neuroborreliosis cases shows dementia syndromes resolving after ceftriaxone.
PMID:36740841 SUPPORT
"Lyme disease is an uncommon cause of reversible dementia... the brilliant clinical improvement after the appropriate antimicrobial therapy is strongly suggestive for a diagnosis of neuroborreliosis."
Geriatric case of reversible dementia with marked improvement after antimicrobial therapy.
Constitutional 2
Fatigue VERY_FREQUENT Fatigue (HP:0012378)
Show evidence (1 reference)
PMID:33669940 SUPPORT
"Clinical symptoms were as follows: arthralgia (33.2%), general weakness (19%), head pain (13.1%), myalgia (11.2%), fever (6.2%), joint swelling (5.9%), head dizziness (5.1%), nervus facialis neuropathy (2.4%), and radiculitis (2.0%)."
Population data list general weakness among frequent symptoms of Lyme disease.
Arthralgia FREQUENT Arthralgia (HP:0002829)
Show evidence (1 reference)
PMID:33669940 SUPPORT
"Clinical symptoms were as follows: arthralgia (33.2%), general weakness (19%), head pain (13.1%), myalgia (11.2%), fever (6.2%), joint swelling (5.9%), head dizziness (5.1%), nervus facialis neuropathy (2.4%), and radiculitis (2.0%)."
Arthralgia was reported in one-third of patients in a large endemic cohort.
🧬

Genetic Associations

1
HLA-DR4 (Susceptibility)
💊

Treatments

3
Oral Doxycycline MAXO:0000058
Drug: doxycycline ↗
First-line treatment for early localized and early disseminated Lyme disease in adults. Typical dose is 100mg twice daily for 10-21 days. Also provides prophylaxis for tick bites in endemic areas.
Show evidence (1 reference)
PMID:17029130 SUPPORT
"Tables list the doses and durations of antimicrobial therapy recommended for treatment and prevention of Lyme disease"
IDSA guidelines provide evidence-based antibiotic treatment recommendations for Lyme disease.
Oral Amoxicillin MAXO:0000058
Drug: amoxicillin ↗
Alternative first-line agent for early Lyme disease, preferred in children under 8 years and pregnant women. Typical dose is 500mg three times daily.
Show evidence (1 reference)
PMID:17176487 SUPPORT
"We describe a favorable outcome in a 42-year-old woman who developed Lyme disease in the third trimester and was treated with a full course of oral amoxicillin."
Case report in pregnancy shows successful treatment with amoxicillin.
Intravenous Ceftriaxone MAXO:0000058
Drug: ceftriaxone ↗
Recommended for neurological Lyme disease (neuroborreliosis), Lyme carditis with high-degree AV block, and some cases of Lyme arthritis. Duration typically 14-28 days.
Show evidence (1 reference)
PMID:37692616 SUPPORT
"The patient's symptoms resolved quickly with a four-day inpatient course of IV ceftriaxone followed by 10 days of oral doxycycline."
Neuroborreliosis case improved with intravenous ceftriaxone then doxycycline.
🌍

Environmental Factors

5
Tick Exposure
Ixodes scapularis (deer tick) in eastern North America, I. pacificus in western North America, I. ricinus in Europe
Geographic Location
Endemic areas include northeastern and upper midwestern United States, and parts of Europe and Asia
Seasonal Exposure
Peak transmission during late spring and summer months (May-August) when nymphal ticks are active
Outdoor Activities
Risk factors include hiking, camping, gardening, and activities in wooded or grassy areas
Non-Ixodes Tick Exposure
Rare reports of dog tick (Rhipicephalus) transmission in India; underscores need to consider atypical vectors in endemic settings
Show evidence (1 reference)
PMID:36352974 SUPPORT
"we present the case of Lyme's disease in an adult male with dog tick, Rhipecephalus as a vector."
Case report documents Lyme transmission by Rhipicephalus dog tick, highlighting atypical vector risk.
🔬

Biochemical Markers

3
Anti-Borrelia Antibodies (IgM/IgG) (Detected)
Context: Two-tier testing with ELISA screening and Western blot confirmation; antibodies may take 2-4 weeks to develop
Elevated ESR/CRP (Elevated)
Context: Markers of systemic inflammation, especially in disseminated disease
CSF Pleocytosis (Elevated)
Context: In neuroborreliosis, lymphocytic pleocytosis with elevated protein and intrathecal antibody production
🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Lyme Disease:

Southern Tick-Associated Rash Illness (STARI) Not Yet Curated MONDO:0025294
Overlapping Features Lone star tick-associated erythema migrans–like rash without Borrelia burgdorferi infection.
Distinguishing Features
  • Occurs after Amblyomma americanum bite in southeastern/south-central US; Borrelia testing negative.
  • Typically lacks systemic neurologic or cardiac involvement seen in disseminated Lyme.
Show evidence (1 reference)
PMID:40788480 SUPPORT
"Southern tick-associated rash illness (STARI)"
Highlights STARI as a distinct erythema migrans–like illness linked to lone star tick bites.
Cellulitis Not Yet Curated MONDO:0005230
Overlapping Features Bacterial skin infection that can mimic early erythema migrans.
Distinguishing Features
  • Painful, warm, expanding erythema often with fever.
  • No central clearing.
  • Responds rapidly to anti-staphylococcal/streptococcal therapy.
Show evidence (1 reference)
PMID:26437159 SUPPORT
"atypical vesicular features... resulted in multiple misdiagnoses and delayed treatment"
Atypical erythema migrans presentations can be misdiagnosed as bacterial cellulitis.
Septic Arthritis Not Yet Curated MONDO:0042485
Overlapping Features Acute bacterial arthritis of large joints.
Distinguishing Features
  • Very high synovial WBC with positive Gram stain/culture.
  • Lacks migratory arthralgias and Borrelia serology.
  • Requires urgent drainage.
Show evidence (1 reference)
PMID:24028811 SUPPORT
"clinical and biological picture often resembles that of septic arthritis"
Pediatric Lyme arthritis cases can initially be confused with septic arthritis.
Rheumatoid Arthritis MONDO:0008383
Overlapping Features Chronic symmetric inflammatory polyarthritis.
Distinguishing Features
  • Small-joint symmetric involvement with RF/anti-CCP positivity.
  • No tick exposure history or erythema migrans.
  • Nodules and erosions on imaging.
Show evidence (1 reference)
PMID:24028811 SUPPORT
"clinical and biological picture often resembles that of septic arthritis and juvenile rheumatoid arthritis"
Lyme arthritis may mimic rheumatoid patterns, prompting serologic differentiation.
Viral Encephalitis Not Yet Curated MONDO:0006009
Overlapping Features CNS infection causing encephalopathy that can overlap with neuroborreliosis symptoms.
Distinguishing Features
  • CSF PCR panels for HSV/VZV/arboviruses.
  • Absent Borrelia intrathecal antibodies.
  • Often acute febrile onset.
Show evidence (1 reference)
PMID:29848409 SUPPORT
"Two serum samples from one patient showed neutralizing antibodies against TBE virus."
Tick-borne encephalitis virus infection was found in a patient initially suspected of Lyme, illustrating viral encephalitis as a key differential.
Multiple Sclerosis and Other Demyelinating Myelopathies MONDO:0005301
Overlapping Features Demyelinating CNS disease that can mimic neuroborreliosis with cord lesions.
Distinguishing Features
  • Oligoclonal bands without intrathecal Borrelia antibodies.
  • Typical MS lesion distribution.
  • Relapsing course without tick exposure.
Show evidence (1 reference)
PMID:34861197 SUPPORT
"examples... newly diagnosed included multiple sclerosis"
Cohort of presumed Lyme referrals identified multiple sclerosis as a frequent alternate diagnosis.
Viral Myocarditis/Other Causes of AV Block Not Yet Curated MONDO:0004496
Overlapping Features Cardiac conduction disease from viral myocarditis or idiopathic fibrosis.
Distinguishing Features
  • Elevated cardiac biomarkers and viral serologies.
  • Absence of erythema migrans or Lyme serology.
  • Persistent AV block without rapid reversal on antibiotics.
Show evidence (1 reference)
PMID:40385752 SUPPORT
"Comprehensive investigations excluded other bradyarrhythmia causes, such as Lyme disease, sarcoidosis, and myocarditis"
Case of dengue-related complete heart block underscores non-Lyme infectious causes of advanced AV block.
🔬

Clinical Trials

3
NCT03769194 PHASE_II COMPLETED
Randomized, controlled, observer-blind Phase 2 study evaluating immunogenicity and safety of VLA15, a multivalent recombinant OspA-based Lyme borreliosis vaccine candidate in healthy adults aged 18-65 years. Participants received 3 immunizations at monthly intervals.
Target Phenotypes: Erythema migrans ↗
Show evidence (1 reference)
clinicaltrials:NCT03769194 SUPPORT
"The study was investigated 3 doses of a multivalent OspA (Outer Surface Protein A) based Lyme vaccine (VLA15) in healthy adults aged 18 to 65 years of age. Study participants received 3 immunizations of the vaccine at a monthly interval."
This Phase 2 trial evaluates VLA15, a preventive vaccine targeting OspA surface protein, offering evidence for active immunization against Lyme borreliosis.
NCT06785402 PHASE_II RECRUITING
Randomized, double-blind, placebo-controlled Phase 1/2 trial evaluating pulse-dosed intravenous ceftriaxone for Post-Treatment Lyme Disease Syndrome (PTLDS). Investigates whether periodic high-dose antibiotic therapy can eliminate persistent Borrelia burgdorferi in patients with persistent symptoms.
Target Phenotypes: Fatigue ↗ Arthralgia ↗
Show evidence (1 reference)
clinicaltrials:NCT06785402 SUPPORT
"Lyme disease is a public health crisis in the US. It is estimated that over 400,000 cases occur every year with 10-20% of those infected going on to develop Post-Treatment Lyme disease Syndrome (PTLDS). The goal of this study is to investigate if giving Ceftriaxone every 5 days for about 6 weeks..."
This Phase 1/2 trial directly addresses post-treatment Lyme disease syndrome with a novel pulse-dosing regimen, providing clinical evidence for managing antibiotic-refractory cases.
NCT03584919 NOT_APPLICABLE COMPLETED
European prospective clinical trial comparing doxycycline and cefuroxime axetil for treatment of erythema migrans in adult patients. Participants were evaluated at baseline, 14 days, and 2, 6, and 12 months post-enrollment to assess treatment efficacy and long-term outcomes.
Target Phenotypes: Erythema migrans ↗
Show evidence (1 reference)
clinicaltrials:NCT03584919 SUPPORT
"A European, prospective clinical trial in which doxycycline and cefuroxime axetil were compared in the treatment of adult patients with erythema migrans included a control group to address this question. Evaluations of patients were conducted at baseline, 14 days and 2, 6, and 12 months after enrollment."
This comparative trial evaluates two oral antibiotics for early Lyme disease, providing evidence for treatment options and long-term symptom outcomes in erythema migrans patients.
{ }

Source YAML

click to show 
name: Lyme Disease
creation_date: '2026-01-09T05:55:26Z'
updated_date: '2026-02-27T21:53:00Z'
category: Infectious
description: >
  Lyme disease is a tick-borne infectious disease caused by Borrelia burgdorferi
  and related Borrelia species. It is the most common vector-borne disease in
  North America and Europe. The disease progresses through stages: early localized
  (erythema migrans), early disseminated (multiple erythema migrans, neurological,
  cardiac involvement), and late disseminated (arthritis, chronic neurological).
  Early antibiotic treatment is highly effective, while delayed treatment may lead
  to persistent symptoms.
disease_term:
  preferred_term: Lyme disease
  term:
    id: MONDO:0019632
    label: Lyme disease
parents:
- Bacterial Infection
- Tick-Borne Disease
has_subtypes:
- name: Early Localized Lyme Disease
  description: Initial stage within weeks of tick bite, characterized by erythema migrans and flu-like symptoms.
- name: Early Disseminated Lyme Disease
  description: Hematogenous spread within weeks to months, with multiple erythema migrans, neurological, or cardiac involvement.
- name: Late Disseminated Lyme Disease
  description: Months to years after infection, characterized by Lyme arthritis or chronic neurological manifestations.
- name: Post-Treatment Lyme Disease Syndrome
  description: Persistent symptoms after appropriate antibiotic therapy, occurring in 10-20% of treated patients.
pathophysiology:
- name: Spirochete Invasion and Dissemination
  description: >
    Borrelia burgdorferi is transmitted through Ixodes tick bites. The spirochete
    disseminates from the skin through the bloodstream to multiple organ systems
    including joints, heart, and nervous system. Surface adhesins like BBK32 and
    decorin-binding proteins (DbpA/DbpB) facilitate tissue colonization.
  evidence:
  - reference: PMID:33669940
    supports: SUPPORT
    snippet: "The clinical manifestations of Lyme disease range from a localized infection, for example, erythema migrans (EM) to a disseminated neurological or rheumatological infection, cardiac involvement, or even chronic disease."
    explanation: Epidemiologic series shows Borrelia disseminates beyond skin to neurologic, rheumatologic, and cardiac sites.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: cell adhesion
    term:
      id: GO:0007155
      label: cell adhesion
- name: Autoimmune Activation after Persistent Infection
  description: >
    Prolonged exposure of the host immune system to Borrelia antigens can drive
    post-infectious autoimmunity, with reported triggers of systemic autoimmune
    disease after Lyme borreliosis.
  evidence:
  - reference: PMID:34786243
    supports: SUPPORT
    snippet: "long-term exposure of the host's immune system to spirochetes can contribute to the development of chronic autoimmune disease de novo."
    explanation: Case review links persistent Borrelia exposure to downstream autoimmune disease.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: immune system process
    term:
      id: GO:0002376
      label: immune system process
- name: Inflammatory Response and Tissue Damage
  description: >
    The host immune response to Borrelia antigens contributes to tissue damage.
    Spirochetal lipoproteins and peptidoglycan trigger robust innate immune
    activation with production of IL-6, IL-8, TNF, and chemokines (CCL3/CCL4).
    Persistent inflammation in joints may continue even after spirochete clearance.
  evidence:
  - reference: PMID:37407232
    supports: SUPPORT
    snippet: "Aspiration of the left knee joint revealed a white cell count of 21.0×109/L (83% neutrophils) with negative Gram stain and culture. However, Lyme PCR was positive and accompanied by serologies consistent with Lyme arthritis."
    explanation: Lyme arthritis joint fluid shows marked neutrophilic inflammation despite negative cultures, consistent with immune-driven damage.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
phenotypes:
- name: Erythema Migrans
  category: Dermatologic
  frequency: VERY_FREQUENT
  description: Characteristic expanding circular rash at the site of tick bite, often with central clearing (bull's-eye appearance). Present in 70-80% of cases.
  phenotype_term:
    preferred_term: Erythema migrans
    term:
      id: HP:0031180
      label: Erythema migrans
  evidence:
  - reference: PMID:33669940
    supports: SUPPORT
    snippet: "Results: In total, 1005 patients were enrolled with the following prevalence of clinical syndromes: erythema migrans (EM), 945 (94.02%); Lyme arthritis, 32 (3.18%); neuroborreliosis, 23 (2.28%); Lyme carditis, 4 (0.39%); and acrodermatitis, 1 (0.09%)."
    explanation: Large Lithuanian cohort confirms erythema migrans as the dominant presentation.
- name: Fatigue
  category: Constitutional
  frequency: VERY_FREQUENT
  description: Profound fatigue is common in all stages of Lyme disease and may persist in post-treatment Lyme disease syndrome.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:33669940
    supports: SUPPORT
    snippet: "Clinical symptoms were as follows: arthralgia (33.2%), general weakness (19%), head pain (13.1%), myalgia (11.2%), fever (6.2%), joint swelling (5.9%), head dizziness (5.1%), nervus facialis neuropathy (2.4%), and radiculitis (2.0%)."
    explanation: Population data list general weakness among frequent symptoms of Lyme disease.
- name: Arthralgia
  category: Musculoskeletal
  frequency: FREQUENT
  description: Joint pain, particularly affecting large joints such as the knee, commonly precedes frank arthritis.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:33669940
    supports: SUPPORT
    snippet: "Clinical symptoms were as follows: arthralgia (33.2%), general weakness (19%), head pain (13.1%), myalgia (11.2%), fever (6.2%), joint swelling (5.9%), head dizziness (5.1%), nervus facialis neuropathy (2.4%), and radiculitis (2.0%)."
    explanation: Arthralgia was reported in one-third of patients in a large endemic cohort.
- name: Facial Palsy
  category: Neurological
  frequency: OCCASIONAL
  description: Unilateral or bilateral facial nerve palsy (Bell's palsy) in early disseminated disease, occurring in approximately 5% of untreated patients.
  phenotype_term:
    preferred_term: Facial palsy
    term:
      id: HP:0010628
      label: Facial palsy
  evidence:
  - reference: PMID:33669940
    supports: SUPPORT
    snippet: "The main symptoms were the following: nervus facialis neuropathy (47.8%), myalgia (39%), head pain (26%), and radiculitis (21%)."
    explanation: Neuroborreliosis cases frequently manifested facial nerve palsy.
- name: Arthritis
  category: Musculoskeletal
  frequency: FREQUENT
  description: Inflammatory arthritis, typically monoarticular or oligoarticular, affecting large joints especially the knee. Occurs in approximately 60% of untreated patients.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
  evidence:
  - reference: PMID:33669940
    supports: SUPPORT
    snippet: "Lyme arthritis mainly manifested among middle-aged women as an oligoarthritis, mostly affecting the knee joint."
    explanation: Cohort study documents oligoarticular knee-predominant Lyme arthritis.
- name: Atrioventricular Block
  category: Cardiac
  frequency: OCCASIONAL
  description: Cardiac involvement including AV block (first, second, or third degree) and myocarditis. Lyme carditis occurs in 1-5% of untreated patients.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  evidence:
  - reference: PMID:37234726
    supports: SUPPORT
    snippet: "the most common clinical manifestation is AV block, which can be acute in onset and can rapidly progress to complete heart block."
    explanation: Case report and review emphasize AV block as the hallmark of Lyme carditis.
- name: Dementia (Reversible Neuroborreliosis)
  category: Neurological
  frequency: RARE
  description: Subcortical or reversible dementia presentations of neuroborreliosis that improve with antibiotic therapy.
  phenotype_term:
    preferred_term: Dementia
    term:
      id: HP:0000726
      label: Dementia
  evidence:
  - reference: PMID:30046879
    supports: SUPPORT
    snippet: "Dementia-like syndromes are rare manifestations of Lyme neuroborreliosis... The response to 2-4 weeks of antibiotic treatment with ceftriaxone was excellent."
    explanation: Review of definite neuroborreliosis cases shows dementia syndromes resolving after ceftriaxone.
  - reference: PMID:36740841
    supports: SUPPORT
    snippet: "Lyme disease is an uncommon cause of reversible dementia... the brilliant clinical improvement after the appropriate antimicrobial therapy is strongly suggestive for a diagnosis of neuroborreliosis."
    explanation: Geriatric case of reversible dementia with marked improvement after antimicrobial therapy.
- name: Myelitis
  category: Neurological
  frequency: RARE
  description: Inflammatory spinal cord involvement as a rare manifestation of acute neuroborreliosis, sometimes with mild clinical symptoms despite marked MRI edema.
  phenotype_term:
    preferred_term: Myelitis
    term:
      id: HP:0012486
      label: Myelitis
  evidence:
  - reference: PMID:33082765
    supports: SUPPORT
    snippet: "We report a case of acute neuroborreliosis that manifested as extended isolated cervical myelitis."
    explanation: Case report confirms Lyme-associated cervical myelitis with CSF pleocytosis and intrathecal Borrelia antibodies.
- name: Bullous Skin Lesions
  category: Dermatologic
  frequency: RARE
  description: Autoimmune blistering lesions (epidermolysis bullosa acquisita-like) following Lyme infection; reported after atypical erythema migrans.
  phenotype_term:
    preferred_term: Subepidermal blistering
    term:
      id: HP:0033804
      label: Subepidermal blistering
  evidence:
  - reference: PMID:41133080
    supports: SUPPORT
    snippet: "developed acquired epidermolysis bullosa (EBA) following an LD diagnosis. Initially, the patient presented with atypical erythema migrans, which later evolved into multiple bullous lesions"
    explanation: Case report documents bullous lesions evolving after Lyme disease.
biochemical:
- name: Anti-Borrelia Antibodies (IgM/IgG)
  presence: Detected
  context: Two-tier testing with ELISA screening and Western blot confirmation; antibodies may take 2-4 weeks to develop
- name: Elevated ESR/CRP
  presence: Elevated
  context: Markers of systemic inflammation, especially in disseminated disease
- name: CSF Pleocytosis
  presence: Elevated
  context: In neuroborreliosis, lymphocytic pleocytosis with elevated protein and intrathecal antibody production
genetic:
- name: HLA-DR4
  association: Susceptibility
  notes: HLA-DRB1*04 alleles associated with antibiotic-refractory Lyme arthritis and autoimmune mechanisms
environmental:
- name: Tick Exposure
  notes: Ixodes scapularis (deer tick) in eastern North America, I. pacificus in western North America, I. ricinus in Europe
- name: Geographic Location
  notes: Endemic areas include northeastern and upper midwestern United States, and parts of Europe and Asia
- name: Seasonal Exposure
  notes: Peak transmission during late spring and summer months (May-August) when nymphal ticks are active
- name: Outdoor Activities
  notes: Risk factors include hiking, camping, gardening, and activities in wooded or grassy areas
- name: Non-Ixodes Tick Exposure
  notes: Rare reports of dog tick (Rhipicephalus) transmission in India; underscores need to consider atypical vectors in endemic settings
  evidence:
  - reference: PMID:36352974
    supports: SUPPORT
    snippet: "we present the case of Lyme's disease in an adult male with dog tick, Rhipecephalus as a vector."
    explanation: Case report documents Lyme transmission by Rhipicephalus dog tick, highlighting atypical vector risk.
treatments:
- name: Oral Doxycycline
  description: >
    First-line treatment for early localized and early disseminated Lyme disease
    in adults. Typical dose is 100mg twice daily for 10-21 days. Also provides
    prophylaxis for tick bites in endemic areas.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
  evidence:
  - reference: PMID:17029130
    supports: SUPPORT
    snippet: "Tables list the doses and durations of antimicrobial therapy recommended for treatment and prevention of Lyme disease"
    explanation: IDSA guidelines provide evidence-based antibiotic treatment recommendations for Lyme disease.
- name: Oral Amoxicillin
  description: >
    Alternative first-line agent for early Lyme disease, preferred in children
    under 8 years and pregnant women. Typical dose is 500mg three times daily.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: amoxicillin
      term:
        id: CHEBI:2676
        label: amoxicillin
  evidence:
  - reference: PMID:17176487
    supports: SUPPORT
    snippet: "We describe a favorable outcome in a 42-year-old woman who developed Lyme disease in the third trimester and was treated with a full course of oral amoxicillin."
    explanation: Case report in pregnancy shows successful treatment with amoxicillin.
- name: Intravenous Ceftriaxone
  description: >
    Recommended for neurological Lyme disease (neuroborreliosis), Lyme carditis
    with high-degree AV block, and some cases of Lyme arthritis. Duration
    typically 14-28 days.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: ceftriaxone
      term:
        id: CHEBI:29007
        label: ceftriaxone
  evidence:
  - reference: PMID:37692616
    supports: SUPPORT
    snippet: "The patient's symptoms resolved quickly with a four-day inpatient course of IV ceftriaxone followed by 10 days of oral doxycycline."
    explanation: Neuroborreliosis case improved with intravenous ceftriaxone then doxycycline.
differential_diagnoses:
- name: Southern Tick-Associated Rash Illness (STARI)
  disease_term:
    preferred_term: Southern Tick-Associated Rash Illness
    term:
      id: MONDO:0025294
      label: tick-borne infectious disease
  description: Lone star tick-associated erythema migrans–like rash without Borrelia burgdorferi infection.
  distinguishing_features:
  - Occurs after Amblyomma americanum bite in southeastern/south-central US; Borrelia testing negative.
  - Typically lacks systemic neurologic or cardiac involvement seen in disseminated Lyme.
  evidence:
  - reference: PMID:40788480
    supports: SUPPORT
    snippet: "Southern tick-associated rash illness (STARI)"
    explanation: Highlights STARI as a distinct erythema migrans–like illness linked to lone star tick bites.
- name: Cellulitis
  disease_term:
    preferred_term: cellulitis
    term:
      id: MONDO:0005230
      label: cellulitis
  description: Bacterial skin infection that can mimic early erythema migrans.
  distinguishing_features:
  - Painful, warm, expanding erythema often with fever.
  - No central clearing.
  - Responds rapidly to anti-staphylococcal/streptococcal therapy.
  evidence:
  - reference: PMID:26437159
    supports: SUPPORT
    snippet: "atypical vesicular features... resulted in multiple misdiagnoses and delayed treatment"
    explanation: Atypical erythema migrans presentations can be misdiagnosed as bacterial cellulitis.
- name: Septic Arthritis
  disease_term:
    preferred_term: infective arthritis
    term:
      id: MONDO:0042485
      label: infective arthritis
  description: Acute bacterial arthritis of large joints.
  distinguishing_features:
  - Very high synovial WBC with positive Gram stain/culture.
  - Lacks migratory arthralgias and Borrelia serology.
  - Requires urgent drainage.
  evidence:
  - reference: PMID:24028811
    supports: SUPPORT
    snippet: "clinical and biological picture often resembles that of septic arthritis"
    explanation: Pediatric Lyme arthritis cases can initially be confused with septic arthritis.
- name: Rheumatoid Arthritis
  disease_term:
    preferred_term: rheumatoid arthritis
    term:
      id: MONDO:0008383
      label: rheumatoid arthritis
  description: Chronic symmetric inflammatory polyarthritis.
  distinguishing_features:
  - Small-joint symmetric involvement with RF/anti-CCP positivity.
  - No tick exposure history or erythema migrans.
  - Nodules and erosions on imaging.
  evidence:
  - reference: PMID:24028811
    supports: SUPPORT
    snippet: "clinical and biological picture often resembles that of septic arthritis and juvenile rheumatoid arthritis"
    explanation: Lyme arthritis may mimic rheumatoid patterns, prompting serologic differentiation.
- name: Viral Encephalitis
  disease_term:
    preferred_term: viral encephalitis
    term:
      id: MONDO:0006009
      label: viral encephalitis
  description: CNS infection causing encephalopathy that can overlap with neuroborreliosis symptoms.
  distinguishing_features:
  - CSF PCR panels for HSV/VZV/arboviruses.
  - Absent Borrelia intrathecal antibodies.
  - Often acute febrile onset.
  evidence:
  - reference: PMID:29848409
    supports: SUPPORT
    snippet: "Two serum samples from one patient showed neutralizing antibodies against TBE virus."
    explanation: Tick-borne encephalitis virus infection was found in a patient initially suspected of Lyme, illustrating viral encephalitis as a key differential.
- name: Multiple Sclerosis and Other Demyelinating Myelopathies
  disease_term:
    preferred_term: multiple sclerosis
    term:
      id: MONDO:0005301
      label: multiple sclerosis
  description: Demyelinating CNS disease that can mimic neuroborreliosis with cord lesions.
  distinguishing_features:
  - Oligoclonal bands without intrathecal Borrelia antibodies.
  - Typical MS lesion distribution.
  - Relapsing course without tick exposure.
  evidence:
  - reference: PMID:34861197
    supports: SUPPORT
    snippet: "examples... newly diagnosed included multiple sclerosis"
    explanation: Cohort of presumed Lyme referrals identified multiple sclerosis as a frequent alternate diagnosis.
- name: Viral Myocarditis/Other Causes of AV Block
  disease_term:
    preferred_term: myocarditis
    term:
      id: MONDO:0004496
      label: myocarditis
  description: Cardiac conduction disease from viral myocarditis or idiopathic fibrosis.
  distinguishing_features:
  - Elevated cardiac biomarkers and viral serologies.
  - Absence of erythema migrans or Lyme serology.
  - Persistent AV block without rapid reversal on antibiotics.
  evidence:
  - reference: PMID:40385752
    supports: SUPPORT
    snippet: "Comprehensive investigations excluded other bradyarrhythmia causes, such as Lyme disease, sarcoidosis, and myocarditis"
    explanation: Case of dengue-related complete heart block underscores non-Lyme infectious causes of advanced AV block.
clinical_trials:
- name: NCT03769194
  phase: PHASE_II
  status: COMPLETED
  description: Randomized, controlled, observer-blind Phase 2 study evaluating immunogenicity and safety of VLA15, a multivalent recombinant OspA-based Lyme borreliosis vaccine candidate in healthy adults aged 18-65 years. Participants received 3 immunizations at monthly intervals.
  target_phenotypes:
  - preferred_term: Erythema migrans
    term:
      id: HP:0031180
      label: Erythema migrans
  evidence:
  - reference: clinicaltrials:NCT03769194
    supports: SUPPORT
    snippet: "The study was investigated 3 doses of a multivalent OspA (Outer Surface Protein A) based Lyme vaccine (VLA15) in healthy adults aged 18 to 65 years of age. Study participants received 3 immunizations of the vaccine at a monthly interval."
    explanation: This Phase 2 trial evaluates VLA15, a preventive vaccine targeting OspA surface protein, offering evidence for active immunization against Lyme borreliosis.
- name: NCT06785402
  phase: PHASE_II
  status: RECRUITING
  description: Randomized, double-blind, placebo-controlled Phase 1/2 trial evaluating pulse-dosed intravenous ceftriaxone for Post-Treatment Lyme Disease Syndrome (PTLDS). Investigates whether periodic high-dose antibiotic therapy can eliminate persistent Borrelia burgdorferi in patients with persistent symptoms.
  target_phenotypes:
  - preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  - preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: clinicaltrials:NCT06785402
    supports: SUPPORT
    snippet: "Lyme disease is a public health crisis in the US. It is estimated that over 400,000 cases occur every year with 10-20% of those infected going on to develop Post-Treatment Lyme disease Syndrome (PTLDS). The goal of this study is to investigate if giving Ceftriaxone every 5 days for about 6 weeks kills the organism that produces persistent Lyme infection."
    explanation: This Phase 1/2 trial directly addresses post-treatment Lyme disease syndrome with a novel pulse-dosing regimen, providing clinical evidence for managing antibiotic-refractory cases.
- name: NCT03584919
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: European prospective clinical trial comparing doxycycline and cefuroxime axetil for treatment of erythema migrans in adult patients. Participants were evaluated at baseline, 14 days, and 2, 6, and 12 months post-enrollment to assess treatment efficacy and long-term outcomes.
  target_phenotypes:
  - preferred_term: Erythema migrans
    term:
      id: HP:0031180
      label: Erythema migrans
  evidence:
  - reference: clinicaltrials:NCT03584919
    supports: SUPPORT
    snippet: "A European, prospective clinical trial in which doxycycline and cefuroxime axetil were compared in the treatment of adult patients with erythema migrans included a control group to address this question. Evaluations of patients were conducted at baseline, 14 days and 2, 6, and 12 months after enrollment."
    explanation: This comparative trial evaluates two oral antibiotics for early Lyme disease, providing evidence for treatment options and long-term symptom outcomes in erythema migrans patients.
datasets: