Multi-organ animal-borne disease, caused by spirochetes of Borrelia burgdorferi (Bb), which typically affect the skin, nervous system, musculoskeletal system and heart.
The black-legged tick can carry the bacterium that causes Lyme disease. | ISTOCK.COM/DIETERMEYRL
Contents
Multi-organ animal-borne disease, caused by spirochetes of Borrelia burgdorferi (Bb), which typically affect the skin, nervous system, musculoskeletal system and heart.
M/C tick-borne infectious disease in the west
Epidemiology
Distribution of Ixodes ticks that transmit Borrelia burgdorferi s.l. to humans: Borrelia burgdorferi s.l. are transmitted by ticks of the Ixodes ricinus complex. In Europe, the principal tick vector is I. ricinus (red), which transmits all three major pathogenic genospecies of B. burgdorferi s.l. The tick Ixodes persulcatus (yellow), is found in western Russia, the Baltic countries, parts of Finland, central regions of eastern Russia, northern Mongolia, China and Japan. I. persulcatus transmits Borrelia afzelii and Borrelia garinii, but is not known to transmit B. burgdorferi. In eastern Europe, I. ricinus and I. persulcatus overlap (orange). In North America, the main tick vectors are Ixodes scapularis in the eastern and mid-western United States (blue) and some areas in middle southern and southeastern Canada and Ixodes pacificus in the western United States (green); both of these ticks transmit B. burgdorferi. Within these broad areas, tick abundance and infection prevalence vary widely and are influenced by microclimate, vegetation and the abundance of reservoir vertebrate hosts. The regions of most intense transmission of B. burgdorferi s.l. are in the northeastern United States and in central Europe3, where the prevalence of B. burgdorferi s.l. infection among ticks can be as high as 40–50%. By contrast, infection prevalence in the southern United States is <1%. The life cycle of ticks is illustrated in the inset. Larvae, nymph and adult are the main life stages (illustrated as would be seen with magnification), but each stage of each of these species is nearly identical in appearance. The tiny nymphal stage, which feeds in the late spring and early summer, is primarily responsible for transmission of the disease. | Steere, A., Strle, F., Wormser, G. et al. Lyme borreliosis. Nat Rev Dis Primers 2, 16090 (2016). https://doi.org/10.1038/nrdp.2016.90
Deer tick (Ixodes sp.)
B burgdorferi sl spirochetes are transmitted through the bite of tick species belonging to the genus Ixodes, which are largely confined to temperate climate zones of the northern hemisphere. In North America, the Ixodes species that transmits the causative agent of Lyme borreliosis is primarily Ixodes scapularis; however, Ixodes pacificus also acts as a vector in the western coastal regions.In Europe, Ixodes ricinus is the tick species primarily responsible for transmitting B burgdorferi sl, whereas Ixodes persulcatus is predominant in large parts of Russia and Asia.
Infective stage: Nymph/adult phase
Natural reservoir: Mouse, lizards, birds, etc
Two-year lifecycle of Ixodid ticks: Larvae hatch in the summer when they may feed on a small mammal infected with B. burgdorferi. The larvae survive the winter and emerge the following spring as nymphs, when they are most likely to transmit infection. The nymphs molt to become adults in the fall, attach to large animals during the winter, and the females lay eggs the following spring. | CDC Open access photo
Microbiology
Borrelia:
Lyme borreliosis is caused by spirochetes belonging to the Borrelia burgdorferi sensu lato (sl) complex, which consists of ~20 genospecies with a complex genomic structure.1 Not all B burgdorferi sl species are pathogenic, and in North America, Borrelia burgdorferi ss is the dominant genospecies associated with Lyme borreliosis, although a novel genospecies, Borrelia mayonii, was recently identified.In Eurasia, B afzelii and B garinii are the most common B burgdorferi sl genospecies in ticks and humans.
Using darkfield microscopy technique, this photomicrograph, magnified 400x, reveals the presence of spirochete, or “corkscrew-shaped” bacteria known as Borrelia burgdorferi, which is the pathogen responsible for causing Lyme disease. Borrelia burgdorferi are helical shaped bacteria, and are about 10-25µm long. These bacteria are transmitted to humans by the bite of an infected deer tick, and caused more than 23,000 cases of Lyme disease in the United States during 2002. | CDC – #6631. Public Domain, https://commons.wikimedia.org/w/index.php?curid=4393667
USA: Borrelia burgdorferi
Asia, Europe: Borrelia garinii, Borrelia afzeilii
Morphology and cellular architecture of Borrelia burgdorferi: a | Borrelia burgdorferi has a flat-wave morphology, is ∼300 nm in diameter and 10–30 μm in length. b | A coloured model of one end of B. burgdorferi. The flagellar filaments are confined to the periplasmic space and are anchored to each cell pole by the flagellar motors, which are located next to methyl-accepting chemotaxis proteins (MCPs) that direct movement. c | The outer membrane of B. burgdorferi consists of a lipid bilayer that is heavily decorated with lipoproteins. Different sets of lipoproteins are expressed on the surface in the tick or mammalian environments. When a larval tick acquires B. burgdorferi from an infected mammalian host, the bacteria express tick-phase lipoproteins in the tick midgut. After larval ticks moult to nymphal-stage ticks and when these ticks feed, cues from tick engorgement block the expression of tick-phase lipoproteins and activate the expression of mammalian-phase lipoproteins through a complex regulatory network, including but not limited to Borrelia oxidative stress regulator (BosR) and the RNA polymerase alternative σ-factor RpoS. As the host mounts an adaptive immune response to B. burgdorferi, outer-surface protein C (OspC) is downregulated and VlsE, a lipoprotein that undergoes antigenic variation, is upregulated and expressed on the bacterial surface. The regulatory network for the adaptation of B. burgdorferi to different environments is much more complex than depicted in this figure; for example, the pathways leading to the activation of BosR and RpoS are still being determined, RpoS-dependent expression of lipoproteins could involve mechanisms other than the recruitment of RNA polymerase, the expression of some mammalian-phase-specific lipoproteins, such as VlsE and complement regulator-acquiring surface proteins (CRASPs), is not regulated through RpoS and not all tick-phase-specific lipoproteins are directly repressed by BosR. Lp6.6, 6.6-kDa lipoprotein; | ROS, reactive oxygen species. | Steere, A., Strle, F., Wormser, G. et al. Lyme borreliosis. Nat Rev Dis Primers 2, 16090 (2016). https://doi.org/10.1038/nrdp.2016.90
During infection, the bacteria migrate through the host tissues, adhere to certain cells and can evade immune clearance. Yet, these organisms are eventually killed by both innate and adaptive immune responses and most inflammatory manifestations of the infection resolve.
Clinical features
Without antibiotic therapy, the clinical manifestations of the disease typically occur in three stages, beginning with early localized infection of the skin and ending with late infection, most commonly Lyme arthritis in the United States or acrodermatitis chronica atrophicans in Europe.
The stages and most common clinical features of Lyme borreliosis: The natural history of the infection without antibiotic therapy begins with localized infection in the skin, then dissemination of the bacteria to numerous sites, but long-term survival in only one or a few localized niches. In patients who have not been treated with antibiotics, Lyme borreliosis typically occurs in stages, with different clinical manifestations at each stage. However, the stages can overlap and late manifestations can be the presenting feature. The infection typically begins as a localized infection of the skin, but, particularly in the United States, Borrelia burgdorferi often disseminates, which is commonly associated with systemic symptoms. However, as the disease progresses and as the immune response matures, the infection typically becomes more localized, such as to the knee joint, and is accompanied by minimal, if any, systemic symptoms. | Steere, A., Strle, F., Wormser, G. et al. Lyme borreliosis. Nat Rev Dis Primers 2, 16090 (2016). https://doi.org/10.1038/nrdp.2016.90
Stage 1 | Early localized stage:
Infection typically begins during summer with erythema migrans, which occurs at the site of the tick bite. Even without antibiotic therapy, erythema migrans typically improves or resolves within weeks.
Erythema migrans (typical “bulls-eye” configuration): Presenting manifestation in ∼80% cases
Nonspecific symptoms (∼18%)
Borrelial lymphocytoma (rare): Typically located on the earlobe in children or on the nipple in adults
2–3% present with a manifestation of early/late disseminated infection: Facial palsy, trigeminal neuropathy or Lyme arthritis
Dermatological manifestations of Lyme borreliosis: All pathogenic Borrelia burgdorferi s.l. genospecies typically cause an expanding skin lesion known as erythema migrans, which occurs at the site of the tick bite. a | Classic erythema migrans lesions, with a brighter red outer border, partial central clearing and a bull’s eye centre. Other erythema migrans lesions can have a more-intense inflammation and purplish discolouration in the centre. b | Borrelial lymphocytoma (arrows) is a subacute lesion that typically occurs on the nipple in adults or on the earlobe in children. c | Acrodermatitis chronica atrophicans is the most common late manifestation of Lyme borreliosis in Europe. These lesions have an inflammatory phase with a reddish or blue colour followed by an atrophic phase, in which the skin thins considerably, sometimes with fibrotic features. Borrelial lymphocytoma and acrodermatitis chronica atrophicans have been noted in Europe and Asia, but not in North America. | Steere, A., Strle, F., Wormser, G. et al. Lyme borreliosis. Nat Rev Dis Primers 2, 16090 (2016). https://doi.org/10.1038/nrdp.2016.90
Stage 2 | Early disseminated stage:
Within days to weeks, B. burgdorferi disseminate from the site of the tick bite to other regions of the body
Peripheral nervous system: Radiculoneuritis (inflammation of the spinal nerve root)
CNS (meningitis) abnormalities
Lyme neuroborreliosis (B. burgdorferi in US): Lymphocytic meningitis with episodic headaches and mild neck stiffness, cranial neuropathy (particularly facial palsy), or motor or sensory radiculoneuritis
Bannwarth syndrome or tick-borne meningopolyneuritis (B. garinii in Europe): Begins with painful radiculoneuritis that is associated with lymphocytic meningitis, often without headache, and can be followed by cranial neuropathy or pareses of the extremities
Other CNS features: Headache, dizziness, concentration and memory disturbances and paresthesia
Cardiac involvement: AV block > Myopericarditis/mild LV dysfunction/cardiomegaly/pancarditis
Prolonged PR interval from Lyme carditis. This EKG is was performed on a 9 yr old child from a Lyme endemic area with known tick exposures who presented with a history of fever, flu-like symptoms, and syncope. His PR interval (shown by the arrow) was 0.548 (nl 0.12-0.2) consistent with first degree heart block. He was admitted to the hospital and placed on ceftriaxone therapy. His symptoms improved after three days and he was discharged home on doxycycline to complete 21 days of antimicrobial therapy. | Murray, T. S., & Shapiro, E. D. (2010). Lyme disease. Clinics in laboratory medicine, 30(1), 311–328. https://doi.org/10.1016/j.cll.2010.01.003
Stage 3 | Late disseminated stage:
Lyme arthritis: Joint swelling and pain typically occurred in intermittent attacks primarily in large joints, especially the knee, over a period of several years
Acrodermatitis chronica atrophicans/acrodermatitis (ACA) (M/C late manifestation of Lyme borreliosis): Slowly progressive lesion located primarily on the extensor (acral) surfaces of the extremities
Chronic encephalomyelitis: Characterized by spastic paraparesis, cranial neuropathy or cognitive impairment
Diagnosis
WHO criteria:
Lyme borreliosis is diagnosed in a patient who has been previously exposed to ticks and who subsequently developed the typical signs and symptoms associated with Lyme borreliosis, affecting the skin, nervous system, musculoskeletal system and heart
Serodiagnosis:
Positive antibody response against Borrelia burgdorferi determined by a two-tiered approach of ELISA & western blooting
IgG immunoblot used to aid in the diagnosis of Lyme disease. Immunoblots are indicated after a positive ELISA from a patient with a clinical syndrome consistent with Lyme disease. The criteria for a positive IgG immunoblot are the presence of 5 bands. In patients with erythema migrans, the immunoblot can initially be negative prior to the development of antibodies against B.burgdorferi. | Murray, T. S., & Shapiro, E. D. (2010). Lyme disease. Clinics in laboratory medicine, 30(1), 311–328. https://doi.org/10.1016/j.cll.2010.01.003
Management
All manifestations of the infection can usually be treated with appropriate antibiotic regimens, but the disease can be followed by post-infectious sequelae in some patients. Prevention of Lyme borreliosis primarily involves the avoidance of tick bites by personal protective measures.
Antibiotic therapy:
EM or borrelial lymphocytoma: Doxycycline (DOC) or amoxicillin or cefuroxime axetil
Arthritis: Oral doxycycline, amoxicillin or cefuroxime axetil
Neuroborreliosis, recurrent arthritis and heart involvement: Ceftriaxone, cefotaxime or penicillin G
ACA: Amoxicillin, doxycycline, ceftriaxone, cefotaxime and penicillin G
Tick removal (if still present)
Removal of a tick using tweezers | cdc.gov – https://www.cdc.gov/lyme/removal/index.html, Public Domain, https://commons.wikimedia.org/w/index.php?curid=38679532
Post-Lyme syndrome:
Characterized by complaints and symptoms persisting more than 6 months after proper Lyme borreliosis treatment.
Musculoskeletal or radicular pain
Dysaesthesia
Neurocognitive symptoms
Sleep abnormalities and fatigue
Summary
Lyme borreliosis is a tick-borne disease, caused by three genospecies of Borrelia burgdorferi sensu lato, that can cause a distinctive skin lesion, and neurological and cardiovascular symptoms. | Lyme borreliosis. Nat Rev Dis Primers 2, 16091 (2016). https://doi.org/10.1038/nrdp.2016.91
