Animedix

Lyme disease (A69.20)

Lyme disease is a multisystem infectious disease caused primarily by the spirochete bacterium Borrelia burgdorferi, which is transmitted to humans through the bite of infected Ixodes ticks, commonly known as deer ticks or black-legged ticks. It is the most common vector-borne illness in North America and Europe and typically begins with early localized infection characterized by the classic erythema migrans “bull’s-eye” rash, fatigue, fever, headache, and myalgias. If untreated, the infection can disseminate to involve the nervous system, joints, heart, and other tissues, leading to manifestations such as facial nerve palsy, meningitis, carditis, migratory arthritis, and chronic musculoskeletal symptoms. The organism’s ability to evade immune detection, disseminate through connective tissues, and trigger inflammatory responses contributes to its diverse clinical presentation. Diagnosis is based on clinical findings, exposure history, and serologic testing, while treatment generally involves antibiotics such as doxycycline, amoxicillin, or ceftriaxone depending on disease stage and organ involvement.

Causes

The etiology of Lyme disease involves infection with the spirochete bacterium Borrelia burgdorferi in North America, and related Borrelia species such as Borrelia afzelii and Borrelia garinii in Europe and Asia. The organism is transmitted to humans primarily through the bite of infected Ixodes ticks, including the black-legged tick (Ixodes scapularis) and western black-legged tick (Ixodes pacificus). Ticks acquire the bacteria by feeding on infected reservoir hosts, particularly small mammals such as white-footed mice, and later transmit the pathogen during subsequent blood meals. Human infection risk is greatest in wooded, grassy, and humid environments where tick populations thrive. Transmission generally requires prolonged tick attachment, allowing the spirochete to migrate from the tick’s midgut into the host. Environmental factors, expanding tick habitats, wildlife ecology, and climate-related changes in vector distribution have all contributed to the increasing incidence of Lyme disease in endemic regions.

Pathophysiology

The pathophysiology of Lyme disease begins when Borrelia burgdorferi is introduced into the skin through the bite of an infected Ixodes tick. The spirochete initially replicates locally, producing inflammation that often manifests as the characteristic erythema migrans rash. Through its corkscrew-like motility and expression of specialized surface proteins, the organism can penetrate connective tissues, evade immune detection, and disseminate hematogenously to joints, the nervous system, heart, and other organs. Borrelia alters expression of outer surface proteins during different stages of infection, helping it adapt to both tick and human hosts while reducing immune clearance. The host immune response, including activation of inflammatory cytokines and both innate and adaptive immune pathways, contributes substantially to tissue injury and clinical symptoms. In later stages, persistent inflammation within synovial tissue, neural structures, or cardiac tissue may lead to arthritis, neuropathy, meningitis, or carditis. Many manifestations of Lyme disease therefore result from a combination of direct spirochetal invasion and dysregulated inflammatory responses.

Clinical features

The clinical features of Lyme disease vary according to the stage of infection and the organs involved. Early localized disease typically presents with erythema migrans, an expanding erythematous rash often accompanied by fever, fatigue, headache, myalgias, arthralgias, and regional lymphadenopathy. As the infection disseminates, neurologic manifestations such as facial nerve palsy, meningitis, radiculopathy, and peripheral neuropathy may develop, along with cardiac involvement including atrioventricular conduction abnormalities and Lyme carditis. Musculoskeletal symptoms are common and may progress to intermittent or persistent migratory arthritis, particularly involving large joints such as the knee. Some patients experience cognitive difficulties, sleep disturbance, paresthesias, or chronic fatigue-like symptoms during later stages of disease. Because Lyme disease can affect multiple organ systems and mimic numerous inflammatory or neurologic conditions, its presentation may be highly variable depending on the timing of diagnosis and extent of dissemination.

Diagnosis

The diagnosis of Lyme disease is based on a combination of clinical presentation, exposure history, and laboratory testing. In patients with characteristic erythema migrans and compatible tick exposure in an endemic region, the diagnosis is often made clinically without requiring confirmatory testing, since early serologic studies may initially be negative. For disseminated or later-stage disease, the standard diagnostic approach involves two-tier serologic testing using an enzyme immunoassay (EIA or ELISA) followed by confirmatory immunoblot testing or modified two-step testing protocols. Additional evaluation may include cerebrospinal fluid analysis in suspected neuroborreliosis, electrocardiography for Lyme carditis, or synovial fluid studies in Lyme arthritis. Polymerase chain reaction (PCR) testing may occasionally assist in detecting Borrelia DNA in selected tissues or fluids, although its sensitivity varies by disease stage. Because antibodies may persist long after infection has resolved and symptoms can overlap with many other inflammatory or neurologic disorders, diagnostic interpretation must always be correlated with clinical findings and epidemiologic risk factors.

Mechanism of action videos

Biological pathways

  • Signaling by Interleukins
  • Interleukin-4 and Interleukin-13 signaling
  • Interleukin-10 signaling
  • Chemokine receptors bind chemokines
  • CD163 mediating an anti-inflammatory response
  • Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)
  • CLEC7A/inflammasome pathway
  • Parasitic Infection Pathways
  • Leishmania infection
  • Calcitonin-like ligand receptors
  • ATF4 activates genes in response to endoplasmic reticulum stress
  • Activation of Matrix Metalloproteinases
  • Interleukin-1 processing
  • Peptide ligand-binding receptors
  • PERK regulates gene expression
  • Senescence-Associated Secretory Phenotype (SASP)
  • Diseases associated with the TLR signaling cascade
  • GPCR ligand binding
  • Diseases of Immune System
  • MyD88 deficiency (TLR2/4)
  • CASP4-mediated substrate cleavage
  • Leishmania parasite growth and survival
  • Anti-inflammatory response favouring Leishmania parasite infection
  • IRAK4 deficiency (TLR2/4)
  • Collagen degradation
  • Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation
  • NFE2L2 regulating inflammation associated genes
  • Pyroptosis
  • Degradation of the extracellular matrix
  • Class A/1 (Rhodopsin-like receptors)
  • TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation
  • Regulation of TLR by endogenous ligand
  • Interleukin-12 family signaling
  • Differentiation of T cells
  • RUNX1 regulates transcription of genes involved in differentiation of myeloid cells
  • RUNX2 regulates genes involved in cell migration
  • Purinergic signaling in leishmaniasis infection
  • Cell recruitment (pro-inflammatory response)
  • Signaling by GPCR
  • Cellular Senescence

Clinical trials

  • A Phase 2, Randomized, Observer-blind, Dose-finding, Placebo-controlled Study to Evaluate the Safety, Reactogenicity, and Immunogenicity of mRNA-1982, an mRNA Vaccine to Prevent Lyme Disease in Healthy Adult Participants (18 to 70 Years of Age)
  • A PHASE 3, RANDOMIZED, PLACEBO-CONTROLLED, OBSERVER-BLINDED TRIAL TO EVALUATE THE SAFETY OF A 6-VALENT OspA-BASED LYME DISEASE VACCINE (VLA15) IN HEALTHY CHILDREN 5 THROUGH 17 YEARS OF AGE
  • A PHASE 3, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLINDED STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF A FIFTH DOSE OF 6-VALENT OSPA-BASED LYME DISEASE VACCINE, VLA15, IN HEALTHY PARTICIPANTS ≥7 YEARS OF AGE
  • Investigating the Human Immune Response to Ixodes Scapularis Tick Bites
  • A PHASE 3, PLACEBO-CONTROLLED, DOUBLE-BLINDED, RANDOMIZED STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF DIFFERENT VACCINATION SCHEDULES OF 6-VALENT OSPA-BASED LYME DISEASE VACCINE, VLA15, IN HEALTHY ADULT PARTICIPANTS
  • A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of TP-05 in Healthy Participants at High Risk of Tick Exposure
  • Searching for Persistence of Infection in Lyme Disease
  • Phase 1/2, Randomized, Double-Blind, Placebo-Controlled Trial of Pulse Dosed Ceftriaxone for Post-Treatment Lyme Disease
  • Effects of Psilocybin in Post-Treatment Lyme Disease
  • Phase 1, Randomized, Double-Blind, Placebo-Controlled Trial of Pulse Dosed Ceftriaxone for Post-Treatment Lyme Disease
  • T4 - Tetracycline Treatment Tolerability Trial A Pilot Study Examining the Feasibility and Tolerability of Tetracycline Therapy in Post-Treatment Lyme Disease (PTLD)
  • A Monocenter, Randomized, Double Blind Pilot Study Comparing Doxycycline in Combination With Hydroxychloroquine Treatment Versus Doxycycline Monotherapy in Patients With Long-Term Complaints Attributed to Lyme Borreliosis.
  • SAFETY AND IMMUNOGENICITY STUDY OF VLA15, A MULTIVALENT RECOMBINANT OSPA BASED VACCINE CANDIDATE AGAINST LYME BORRELIOSIS: A RANDOMIZED, CONTROLLED, OBSERVER-BLIND PHASE 2 STUDY IN A HEALTHY PEDIATRIC AND ADULT STUDY POPULATION
  • A Phase 3, Multicenter, Placebo-Controlled, Randomized, Observer-Blinded Trial to Evaluate the Efficacy, Safety, Tolerability, Immunogenicity, and Lot Consistency of a 6-Valent OspA-Based Lyme Disease Vaccine in Healthy Participants ≥5 Years of Age
  • Effect of Saccharomyces Boulardii CNCM I-745 on Gut Microbiota in Patients Undergoing Antibiotic Therapy (in the Context of Erythema Migrans (Early Skin Form of Lyme Borreliosis))
  • A Phase 1/2, Randomized, Observer-blind, Placebo-controlled, Dose-ranging Study to Evaluate the Safety and Immunogenicity of Heptavalent mRNA-1975 (SR1-7) and Monovalent mRNA-1982 (SR1) in Parallel Against Lyme Disease in Healthy Participants 18 Through 70 Years of Age
  • Disulfiram ("Antabuse"): A Test of Symptom Reduction Among Patients With Previously Treated Lyme Disease
  • A Phase 2a, Randomized, Double-Blind, Placebo Controlled, Single-Center, Human Tick Kill Proof-of-Concept Study Evaluating the Safety, Tolerability, and Whole Blood Concentration of TP-05 (lotilaner) in Healthy Volunteers
  • Six Versus Two Weeks Treatment With Doxycycline in Lyme Neuroborreliosis; a Multicenter, Non-inferiority, Penta-blind, Randomized Trial
  • Effect of Intravenous Ceftriaxone and Oral Doxycycline for Lyme Neuroborreliosis. A Randomized Double-blind Comparison
  • ALTERNATIVE SCHEDULE STUDY FOR VLA15, A MULTIVALENT RECOMBINANT OSPA BASED VACCINE CANDIDATE AGAINST LYME BORRELIOSIS, IN HEALTHY ADULTS AGED 18 TO 65 YEARS - A RANDOMIZED, CONTROLLED, OBSERVER-BLIND PHASE 2 STUDY.
  • Study Assessing the Safety, Immunogenicity and Dose Response of VLA15, A New Multivalent Recombinant OspA Vaccine Candidate Against Lyme Borreliosis, In Healthy Adults Aged Below 40 Years
  • Immunogenicity and Safety Study of VLA15, A Multivalent Recombinant OspA (Outer Surface Protein A) Based Vaccine Candidate Against Lyme Borreliosis, in Healthy Adults Aged 18 to 65 Years. A Randomized, Controlled, Observer-blind Phase 2 Study.
  • A Phase 1 Study in Healthy Subjects to Evaluate the Safety and Pharmacokinetics of a Human Monoclonal Antibody (2217LS) Against Borrelia Burgdorferi (B. Burgdorferi) Outer Surface Protein A (OspA)
  • Randomized, Double-Blind, Phase 1/2 Clinical Study to Investigate the Safety and Immunogenicity of a Multivalent Recombinant OspA Lyme Borreliosis Vaccine (mv rOspA LB Vaccine) in Healthy Subjects Aged 18 to 70 Years
  • Study of Lyme Neuroborreliosis: Epidemiology, Manifestations, Diagnostics and Treatment
  • Persistent Lyme Empiric Antibiotic Study Europe. A Prospective, Randomised Study Comparing Two Prolonged Oral Antibiotic Strategies After Initial Intravenous Ceftriaxone Therapy for Patients With Symptoms of Proven or Possible Persistent Lyme Disease
  • Tick Borne Diseases in Norwegian General Practice. A Randomized, Controlled Trial for Treatment of Erythema Migrans in Norwegian General Practice. A Comparison of Phenoxymethylpenicillin, Amoxicillin and Doxycycline.
  • A Controlled Trial of a Primary and Secondary Program for Lyme Disease
  • Risk Factors for Failure of Erythema Migrans Treatment - Comparison of Doxycycline and Cefuroxime Axetil for Treatment of Adult Patients With Erythema Migrans: Clinical and Microbiological Outcome.
  • A Single Centre, Randomized, Investigator Blinded, Placebo-controlled Ascending Dose Study to Assess the Local Safety, the Skin and Plasma Concentration of Azithromycin Dermal Formulation During Repeated Applications on the Skin of Healthy Volunteers
  • A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of the Safety and Efficacy of Ceftriaxone and Doxycycline in the Treatment of Patients With Seropositive Chronic Lyme Disease
  • A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of the Safety and Efficacy of Ceftriaxone and Doxycycline in the Treatment of Patients With Seronegative Chronic Lyme Disease
  • Study and Treatment of Post Lyme Disease (STOP-LD)
  • PET and MRI Imaging of Persistent Lyme Encephalopathy

Therapeutic area: Infectious Disease

Lyme Disease (A69.20)