Lyme disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Ilan Dock, B.S.

In 1883, Alfred Buchwald was the first to describe a condition associated with Lyme disease which is now known as acrodermatitis chronica atrophicans. Arvid Afzelius first observed ring-like lesions, now known as Erythema migrans, and associated the rash with tick bites. In the United States, Lyme disease was not recognized until 1975, when a cluster of cases was identified in three towns in Southeastern Connecticut (including towns Lyme and Old Lyme), which gave Lyme disease its popular name. In 1981, the infectious agent (a spirochete) was isolated by Willy Burgdorfer, a researcher at the National Institutes of Health, from the midgut of Ixodes ticks. The spirochete was named Borrelia burgdorferi in honor of Willy Burgdorfer.

In 1883 in Breslau (formerly in Germany, now known as Wrocław, Portland), Alfred Buchwald, a German physician, was the first to describe a condition associated with Lyme disease. He described the condition as diffuse idiopathic skin atrophy. The condition is a degenerative skin disorder now known as acrodermatitis chronica atrophicans.[1] In 1909, Arvid Afzelius, a Swedish physician, presented research about an expanding, ring-like lesion he had observed. In 1921, Arvid Afzelius published his work and stated that the rash was due to the bite of an Ixodes tick. He also concluded that meningitis signs and symptoms occur in a number of cases; this rash is now known as erythema migrans (EM), the skin rash found in early stage Lyme disease.[2] In 1911, Andrew Balfour, a Scottish parasitologist of the Wellcome Research Laboratory in Khartoum, identified “infective granules” or spore-type “cysts” as the cause of persistence of spirochetal infection in Sudanese Fowl.[3] In 1913, B. Lipschütz, an Austrian dermatologist, described similar rash as erythema chronicum migrans (ECM). In 1915, tick-borne relapsing fever (Borrelia hermsii) was first reported in the U.S following recognition of five human patients in Colorodo. This led to an increased interest in tick-borne infections in the U.S.[4] In the 1920s, Garin and Bujadoux, French physicians, described a patient with meningoencephalitis, painful sensory radiculitis, and erythema migrans following a tick bite, and postulated that the symptoms were due to a spirochetal infection.[5] In the 1940s, Alfred Bannwarth, a German neurologist, described several cases of chronic lymphocytic meningitis and polyradiculoneuritis, some of which were accompanied by erythematous skin lesions.[5]

• In 1948, Carl Lennhoff, a Swedish dermatologist, observed spirochete-like structures in skin specimens.^[6]
• In the 1950s, relations between tick bites, lymphocytoma, EM, and Bannwarth’s syndrome were seen throughout Europe, leading to the use of penicillin for treatment.^[7][8][9]
• In 1970, Rudolph Scrimenti, a U.S. physician from Wisconsin, reported the first case of erythema migrans in U.S. and treated it with penicillin based on European literature.^[10]
• In the United States, Lyme disease was not recognized until a cluster of cases was identified in three towns in Southeastern Connecticut in 1975. These towns included Lyme and Old Lyme, which gave Lyme disease its popular name.^[11] The cases were originally thought to be juvenile rheumatoid arthritis. This was further investigated by Dr. David Snydman and Dr. Allen C. Steere of the Epidemic Intelligence Service, and by others from Yale University. They recognized that the patients in the United States had erythema migrans and “Lyme arthritis” was one manifestation of the same tick-borne condition known in Europe.^[12]
• Before 1976, elements of B. burgdorferi sensu lato complex infection were known as “tickborne meningopolyneuritis,” “Garin-Bujadoux syndrome,” “Bannworth syndrome,” “Lymphocytic meningoradiculitis,” “Afzelius syndrome,” “Montauk Knee” or “sheep tick fever.” Since 1976, the disease has been most often referred to as Lyme disease, Lyme borreliosis, or simply borreliosis.^[13][14]
• In 1976, Jay Sanford, a former physician at the Walter Reed Army Institute of Research, published a chapter in the book The Biology of Parasitic Spirochetes. In it, Dr. Sanford stated: “The ability of borrelia, especially tick-borne strains, to persist in the brain and in the eye during remission after treatment with arsenic or with penicillin or even after apparent cure, is well known.” ^[15]
• In 1980, Allen C. Steere, a rheumatologist at Yale University, and his colleagues began to test antibiotic regimens in adult patients with Lyme disease.^[16]
• In 1981, Jorge L. Benach, a pathologist at the State University of New York at Stony Brook identified a novel spirochete which was cultured from the midgut of Ixodes ticks in Shelter Island, New York, and subsequently from patients with Lyme disease. Soon after, the infectious agent was isolated by Willy Burgdorfer, a researcher at the National Institutes of Health, who specialized in the study of microorganisms such as Borrelia and Rickettsia. The spirochete was named Borrelia burgdorferi in his honor. Willy Burgdorfer and Alan Barbour were partners in the successful effort to culture the spirochete.^[17]
• After identification of B. burgdorferi as the causative agent of Lyme disease, antibiotics were selected for testing, guided by in vitro antibiotic sensitivities, including tetracycline antibiotics, amoxicillin, cefuroxime axetil, intravenous and intramuscular penicillin, and intravenous ceftriaxone.^[18][19]
• In 1987, B. burgdorferi spirochetes were identified in tick saliva, confirming the hypothesis that transmission occurred via tick salivary glands.^[20]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Lyme disease can be classified into three stages. The first stage is localized Lyme disease, the second is disseminated Lyme disease, and the third is late disseminated Lyme disease. During stage 1, the patient can develop erythema migrans rash. Ten to twenty percent of the patients who have Lyme disease can develop post treatment Lyme disease syndrome. There are various genospecies of Borrelia burgdorferi sensu lato complex that can cause Lyme disease. A novel spirochete, Borrelia mayonii, has been recently discovered to be responsible for Lyme disease.

• Stage 1 is called early localized Lyme disease. The infection is not yet widespread throughout the body.
• Stage 2 is called early disseminated Lyme disease. The bacteria have begun to spread throughout the body.
• Stage 3 is called late disseminated Lyme disease. The bacteria have spread throughout the body.

• The majority of cases of Lyme disease are caused by Borrelia burgdorferi sensu lato (s.l.) complex. There are 18 genospecies in Borrelia burgdorferi sensu lato (s.l.) complex. Out of these, only 7 infect humans (genotype 3 commonly and 4 occasionally).^[1]

• However, B. mayonii has recently been discovered to be responsible for development of Lyme disease.^[2]
• The following table demonstrates key clinical and epidemiological features that distinguish B. burgdorferi from B. mayonii:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Ilan Dock, B.S.

Lyme disease is the most commonly reported vector-borne illness in the United States. In 2015, it was the sixth most common nationally notifiable disease. The number of people diagnosed with Lyme disease each year in the United States is around 30,000. This disease is concentrated heavily in the Northeast and upper Midwest. Lyme disease has a seasonal variation and incidence increases during months of May to August.

• Lyme disease is the most common tick-borne disease in North America and Europe, and one of the fastest-growing infectious diseases in the United States.
• The number of people diagnosed with Lyme disease each year in the United States is around 30,000.^[1]
• In the United States, the incidence of Lyme disease is 8.1 per 100,000 individuals as per data collected by the Center for Disease Control (CDC) in 2016.^[2]
• In the fourteen states where Lyme disease is most common, the average was 40.4 cases for every 100,000 persons in the year 2015.^[1][3]
• Although Lyme disease has now been reported in the majority of states in the U.S, about 95% of all reported cases are confined to just five geographic areas including New England, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central.^[3]

• The prevalence of infection in adult ticks is more than nymph stage ticks in pathogens infectious to humans, but the majority of infections are caused by ticks in the nymph stage during the late spring and summer.^[4][5]
• This is the reason for an increase in the incidence of Lyme disease during the months of May to August.

• The number of reported cases of the disease has been increasing, as is the number of endemic regions in North America.
• B. burgdorferi sensu lato has been maintained in enzootic cycles in California as well as other regions throughout North America, Europe, and North Africa. Indeed, the DNA of Borrelia has been detected in lizards, indicating that they can be infected.^[6]

• In Europe, cases of B. burgdorferi sensu lato infected ticks are found predominantly in Norway, Netherlands, Germany, France, Italy, Slovenia, and Poland, but have been isolated in almost every country on the continent. Lyme disease statistics for Europe can be found at the Eurosurveillance website.
• B. burgdorferi sensu lato infested ticks are being found more frequently in Japan, as well as in northwest China and far eastern Russia.^[7][8] Borrelia has been isolated in Mongolia as well.^[9]
• In South America, tick-borne disease recognition and occurrence is rising.
• Ticks carrying B. burgdorferi sensu lato, as well as canine and human tick-borne disease, have been reported widely in Brazil, but the subspecies of Borrelia have not yet been defined.^[10] The first reported case of Lyme disease in Brazil was in 1993 in Sao Paulo.^[11]
• B. burgdorferi sensu stricto antigens in patients have been identified in Colombia and Bolivia.
• In Northern Africa, B. burgdorferi sensu lato has been identified in Morocco, Algeria, Egypt, and Tunisia.^[12][13][14]
• In Western and sub-Saharan Africa, tick-borne relapsing fever was first identified by the British physicians Joseph Dutton and John Todd in 1905. Borrelia in the manifestation of Lyme disease in this region is presently unknown but evidence indicates that Lyme disease may occur in humans in sub-Saharan Africa. The abundance of hosts and tick vectors would favor the establishment of Lyme infection in Africa.^[15] In East Africa, two cases of Lyme disease have been reported in Kenya.^[16]
• In Australia there is no definitive evidence for the existence of B. burgdorferi or for any other tick-borne spirochete that may be responsible for a local syndrome being reported as Lyme disease.^[17] Cases of neuroborreliosis have been documented in Australia but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial.
• Data shows that Northern hemisphere temperate regions are most endemic for Lyme disease.^[18][19]

• There’s a higher incidence of infection among children and infants of less than a year to 15 years.
• Another peak occurs in individuals between the ages of 40 to 55 years.

• On average, there is a higher incidence among males than females.
• However, among people aged 70 and higher, females tend to have a higher incidence of infection.

• Lyme disease is more prevalent in the Caucasian population.^[20]

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Borrelia burgdorferi is species of bacteria of the spirochete class of the genus Borrelia. B. burgdorferi is predominant in North America, but also exists in Europe, and is the causative agent of Lyme disease. It is a zoonotic, vector-borne disease transmitted by ticks and is named after the researcher Willy Burgdorfer who first isolated the bacterium in 1982. B. burgdorferi is one of the few pathogenic bacteria that can survive without iron, having replaced all of its iron-sulphur cluster enzymes with enzymes that use manganese, thus avoiding the problem many pathogenic bacteria face in acquiring iron. B. burgdorferi infections have been linked to non-Hodgkin lymphomas.^[1]

• Lyme disease, or Lyme borreliosis, is caused by Gram negative spirochetal bacteria from the genus Borrelia, which has at least 37 known species, 12 of which are Lyme related, and an unknown number of genomic strains. Borrelia species known to cause Lyme disease are collectively known as Borrelia burgdorferi sensu lato complex.

• Borrelia are microaerophillic and slow-growing—the primary reason for the long delays when diagnosing Lyme disease—and have been found to have greater strain diversity than previously estimated.^[2] The strains differ in clinical symptoms and/or presentation as well as geographic distribution.^[3]

• Except for Borrelia recurrentis (which causes louse-borne relapsing fever and is transmitted by the human body louse), all known species are believed to be transmitted by ticks.^[4]

• On February 2016, a second, a new organism, B. mayonii, has been reported for causing Lyme disease (see B. mayonii here).

• Borrelia mayonii causes similar symptoms to Borrelia burgdorferi.
• However, unlike B. burgdorferi, B. mayonii may induce a quick onset of nausea and vomiting.
• The rash associated with this new organism is also different from the conventional, bulls-eye rash. The rash associated with B. mayonii has been reported as a diffuse rash, covering the entire body in “red spots.”^[5]

B. burgdorferi is a highly specialized, motile, two-membrane, spiral-shaped spirochete ranging from about 9 to 32 micrometers in length. It is often described as gram-negative and has an outer membrane with lipopolysaccharide (LPS), though it stains only weakly in the Gram stain. B. burgdorferi is a microaerophilic organism, requiring little oxygen to survive. It lives primarily as an extracellular pathogen, although it can also hide intracellularly (see Mechanisms of persistence section).

Like other spirochetes such as T. pallidum (the agent of syphilis), B. burgdorferi has an axial filament composed of flagella which run lengthways between its cell wall and outer membrane. This structure allows the spirochete to move efficiently in corkscrew fashion through viscous media, such as connective tissue. As a result, B. burgdorferi can disseminate throughout the body within days to weeks of infection, penetrating deeply into tissue where the immune system and antibiotics may not be able to eradicate the infection.

B. burgdorferi is very slow growing, with a doubling time of 12-18 hours^[6] (in contrast to pathogens such as Streptococcus and Staphylococcus, which have a doubling time of 20-30 minutes). Since most antibiotics kill bacteria only when they are dividing, this longer doubling time necessitates the use of relatively longer treatment courses for Lyme disease. Antibiotics are most effective during the growth phase, which for B. burgdorferi occurs in four-week cycles.

The outer membrane of Borrelia burgdorferi is composed of various unique outer surface proteins (Osp) that have been characterized (OspA through OspF). They are presumed to play a role in virulence.

OspA and OspB are by far the most abundant outer surface proteins.

The OspA and OspB genes encode the major outer membrane proteins of the B. burgdorferi. The two Osp proteins show a high degree of sequence similarity, indicating a recent evolutionary event. Molecular analysis and sequence comparison of OspA and OspB with other proteins has revealed similarity to the signal peptides of prokaryotic lipoproteins.^[7]Virtually all spirochetes in the midgut of an unfed nymph tick express OspA.

OspC is an antigen-detection of its presence by the host organism and can stimulate an immune response. While each individual bacterial cell contains just one copy of the gene encoding OspC, populations of B. burgdorferi have shown high levels of variation among individuals in the gene sequence for OspC.^[8] OspC is likely to play a role in transmission from vector to host, since it has been observed that the protein is only expressed in the presence of mammalian blood or tissue.^[9]

The functions of OspD are unknown.

OspE and OspF are structurally arranged in tandem as one transcriptional unit under the control of a common promoter.^[10]

In transmission to the mammalian host, when the nymphal tick begins to feed, and the spirochetes in the midgut begin to multiply rapidly, most spirochetes cease expressing OspA on their surface. Simultaneous with the disappearance of OspA, the spirochete population in the midgut begins to express a OspC. Upregulation of OspC begins during the first day of feeding and peaks 48 hours after attachment.^[11]

A tick’s life cycle is composed of four stages: hatching (egg), nymph (six legged), nymph (eight legged), and an adult.

Ticks require blood meal to survive through their life cycle.

Hosts for tick blood meals include mammals, birds, reptiles, and amphibians. Ticks will most likely transfer between different hosts during the different stages of their life cycle.

Humans are most often targeted during the nymph and adult stages of the life cycle.

Life cycle is also dependent on seasonal variation.

Ticks will go from eggs to larva during the summer months, infecting bird or rodent host during the larval stage.

Larva will infect the host from the summer until the following spring, at which point they will progress into the nymph stage.

During the nymph stage, a tick will most likely seek a mammal host (including humans).

A nymph will remain with the selected host until the following fall at which point it will progress into an adult.

As an adult, a tick will feed on a mammalian host. However unlike previous stages, ticks will prefer larger mammals over rodents.

The average tick life cycle requires three years for completion.

Different species will undergo certain variations within their individual life cycles. ^[12]

The life-cycle concept encompassing reservoirs and infections in multiple hosts has recently been expanded to encompass forms of the spirochete which differ from the motile corkscrew form, and these include cystic forms spheroplast-like, straighted non-coiled bacillary forms which are immotile due to flagellin mutations and granular forms coccoid in profile. The model of Plasmodium species Malaria with multiple parasitic profiles demonstrable in various host insects and mammals is a hypothesized model for a similarly complex proposed Borrelia spirochete life cycle. ^{[13] [14]}

Whereas B. burgdorferi is most associated with deer tick and the white footed mouse,^[15] B. afzelii is most frequently detected in rodent-feeding vector ticks, B. garinii and B. valaisiana appear to be associated with birds. Both rodents and birds are competent reservoir hosts for Borrelia burgdorferi sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative immune complement pathway of various host species may determine its reservoir host association.

Urbanization and other anthropogenic factors can be implicated in the spread of the Lyme disease into the human population. In many areas, expansion of suburban neighborhoods has led to the gradual deforestation of surrounding wooded areas and increasing “border” contact between humans and tick-dense areas. Human expansion has also resulted in a gradual reduction of the predators that normally hunt deer as well as mice, chipmunks and other small rodents — the primary reservoirs for Lyme disease. As a consequence of increased human contact with host and vector, the likelihood of transmission of Lyme to residents of endemic area has greatly increased.^[16][17] Researchers are also investigating possible links between global warming and the spread of vector-borne diseases including Lyme disease.^[18]

The deer tick (Ixodes scapularis, the primary vector in the northeastern U.S.) has a two-year life cycle, first progressing from larva to nymph, and then from nymph to adult. The tick feeds only once at each stage. In the fall, large acorn forests attract deer as well as mice, chipmunks and other small rodents infected with B. burgdorferi. During the following spring, the ticks lay their eggs. The rodent population then “booms.” Tick eggs hatch into larvae, which feed on the rodents; thus the larvae acquire infection from the rodents. (Note: At this stage, it is proposed that tick infestation may be controlled using acaricides (miticide).

Adult ticks may also transmit disease to humans. After feeding, female adult ticks lay their eggs on the ground, and the cycle is complete. On the west coast, Lyme disease is spread by the western black-legged tick (Ixodes pacificus), which has a different life cycle.

The risk of acquiring Lyme disease does not depend on the existence of a local deer population, as is commonly assumed. New research suggests that eliminating deer from smaller areas (less than 2.5 hectares or 6.2 acres) may in fact lead to an increase in tick density and the rise of “tick-borne disease hotspots”.^[19]

The following table demonstrates key clinical and epidemiological features that distinguish B. burgdorferi from B. mayonii:^[20][21]

• 
  Histopathology showing Borrelia burgdorferi spirochetes in Lyme disease. – Source: Public Health Image Library (PHIL). ^[22]
• 
  White-footed mouse, Peromyscus leucopus, which is a host of ticks thatare known to carry the bacteria, Borrelia burgdorferi, responsible for Lyme disease. – Source: Public Health Image Library (PHIL). ^[22]
• 
  “Corkscrew-shaped” bacteria known as Borrelia burgdorferi, which is the pathogen responsible for causing Lyme disease (400x mag). – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Dorsal view of an adult female western blacklegged tick, whichs transmit Borrelia burgdorferi (agent of Lyme disease). – Source: Public Health Image Library (PHIL). ^[22]
• 
  Dorsal view of an adult female western blacklegged tick, whichs transmit Borrelia burgdorferi (agent of Lyme disease). – Source: Public Health Image Library (PHIL). ^[22]
• 
  Dorsal view of engorged female tick, extracted from the skin of a pet cat (26X mag). – Source: Public Health Image Library (PHIL). ^[22]
• 
  Dorsal view of engorged female tick in the process of obtaining its blood meal (207X magnification). – Source: Public Health Image Library (PHIL). ^[22]
• 
  Scanning electron micrographic (SEM) image depicts dorsal view of engorged female tick (201X magnification). – Source: Public Health Image Library (PHIL). ^[22]
• 
  Photomicrographic montage using the immunofluorescent antibody technique (IFA) used to produce this B. burgdorferi multicolored image. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Lateral view of female deer tick, Ixodes scapularis, with its abdomen engorged with a host blood meal. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Peripheral blood from a newborn child indicates the presence of numerous Borrelia hermsii spirochetes (arrows), consistent with a tickborne relapsing fever (TBRF) infection. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Dorsal view of a soft tick, Ornithodoros hermsi, which is a known vector for the disease tick-borne relapsing fever (TBRF) (6.5x mag). – Source: Public Health Image Library (PHIL). ^[22]
• 
  Deer tick, Ixodes scapularis. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Borrelia burgdorferi bacteria derived from a pure culture. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Dorsal view of engorged female tick in the process of obtaining its blood meal (201x mag). – Source: Public Health Image Library (PHIL). ^[22]
• 
  Dorsal view of engorged female tick, extracted from the skin of a pet cat (26x mag). – Source: Public Health Image Library (PHIL). ^[22]
• 
  Male Dermacentor sp. tick found upon a cat (95x mag). – Source: Public Health Image Library (PHIL). ^[22]
• 
  Dorsal view of male Dermacentor sp. tick found on a cat (3043x mag). – Source: Public Health Image Library (PHIL). ^[22]
• 
  Dorsal view of a female “lone star tick”, Amblyomma americanum. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Anterior view of engorged female “lone star tick”, Amblyomma americanum. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Ventral view of engorged female “lone star tick” Amblyomma americanum. – Source: Public Health Image Library (PHIL). ^[22]
• 
  “Corkscrew-shaped” bacteria known as Borrelia burgdorferi, the pathogen responsible for causing Lyme disease (400x mag). – Source: Public Health Image Library (PHIL). ^[22]
• 
  White-footed mouse, Peromyscus leucopus, which is a wild rodent reservoir host of ticks, which are known to carry the bacteria, Borrelia burgdorferi, responsible for Lyme disease. – Source: Public Health Image Library (PHIL). ^[22]
• 
  This photograph of a whitetail deer, Odocoileus virginianus, was taken during a Lyme disease field investigation in 1993. – Source: Public Health Image Library (PHIL). ^[22]
• 
  This is a dorsal view of the “soft tick” Carios kelleyi, formerly Ornithodoros kelleyi, or the “Bat Tick”. – Source: Public Health Image Library (PHIL). ^[22]
• 
  This is a dorsal view of the “soft tick” Carios kelleyi, formerly Ornithodoros kelleyi, or the “Bat Tick”. – Source: Public Health Image Library (PHIL). ^[22]
• 
  This is a female “Lone star tick”, Amblyomma americanum, and is found in the southeastern and midatlantic United States. – Source: Public Health Image Library (PHIL). ^[22]
• 
  These “black-legged ticks”, Ixodes scapularis, also referred to as I. dammini, are found on a wide rage of hosts including mammals, birds and reptiles. – Source: Public Health Image Library (PHIL). ^[22]
• 
  Histopathology showing Borrelia burgdorferi spirochetes in Lyme disease. Dieterle silver stain. – Source: Public Health Image Library (PHIL). ^[22]
• 
  “Corkscrew-shaped” bacteria known as Borrelia burgdorferi, which is the pathogen responsible for causing Lyme disease (400x mag). – Source: Public Health Image Library (PHIL). ^[22]

• Allen Steere
• Jorge Benach

• NCBI Borrelia Taxonomy Browser
• Borrelia Microbe Wiki Page
• Borrelia burgdoferi B31 Genome Page==External links==
• Atlas of Borrelia (images of spirochetal, spheroplast and granular forms)
• NCBI Taxonomy Browser – Borrelia
• Borrelia burgdoferi B31 Genome Page
• Borrelia Garinii PBi Genome Page
• Borrelia Afzelli PKo Gemonme Page
• CDC – Vector Interactions and Molecular Adaptations of Lyme Disease and Relapsing Fever Spirochetes Associated with Transmission by Ticks

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Lyme disease must be differentiated from babesiosis, leptospirosis, mononucleosis, viral meningitis, and chronic diseases such as SLE, fibromyalgia, and chronic fatigue syndrome.Lyme disease must be differentiated from other diseases that may cause arthralgia, fever, and skin manifestations and that are associated with a history of tick exposure. Lyme disease should also be differentiated from other causes of infectious arthritis as well as acute arthritis.

Lyme disease must be differentiated from other diseases that may cause arthralgia, fever, and skin manifestations and that are associated with a history of tick exposure.

Lyme disease can be differentiated from other causes of acute arthritis on the basis of synovial fluid analysis.

• Allergic reaction to the tick
• Babesiosis
• Chronic fatigue syndrome (CFS)
• Depression
• Fibromyalgia
• Human granulocytic anaplasmosis (HGA)
• Leptospirosis
• Mononucleosis
• Other insect bites
• Reiter’s syndrome
• Rheumatoid arthritis
• Scleroderma
• Systemic lupus erythematosus (SLE)
• Tick-borne diseases
• Viral meningitis^[17]

Lyme disease must be differentiated from other causes of rash and arthritis^[18][19][20]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Ilan Dock, B.S.

Because Lyme disease is a tick-borne disease, an individual is at a heightened risk of contracting it when traveling or residing within endemic regions. Risk within endemic regions is higher during the spring and summer months, with peaks in June and July. Other factors that may increase the risk of contracting Lyme disease include owning a domesticated animal such as a dog or cat, as both of these pets may be potential hosts for a blacklegged tick. In summary, individuals who spend much of their time outdoors and/or have pets that go outdoors and who live in endemic regions, are at a higher risk of contracting tick-borne diseases.

Individuals who spend time outdoors and/or have pets that go outdoors in endemic regions are at risk for tick-borne disease. ^[1]

• Individuals with frequent exposure to dogs and who reside near wooded areas or areas with high grass may also be at increased risk of tick-borne infection.
• Individuals with outdoor occupations and who work outside with bare or exposed skin are at a high risk of contracting Lyme disease.
• Failing to remove a tick as soon as you see it on your skin (the longer a tick is attached to your skin, the greater your risk of developing Lyme disease) also increases risk of developing Lyme disease.^[2]

• About 95% of all reported cases are confined to 14 states including Connecticut, Delaware, Maine, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, Vermont, Virginia, and Wisconsin.^[3][4]
• Any individual traveling or living within these five geographic areas including New England, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central is at a heightened risk of exposure to Lyme disease.

• The majority of Lyme disease cases are reported during the summer months of May to August.
• Case incidence increases in May (estimated 20,000 cases reported between the years 2001-2015), peaks in June and July (estimated 70,000-80,000 cases reported between the years 2001-2015), and tapers off in August (just above 30,000 cases reported between the years 2001-2015).

• Cases of blood transfusion and organ transplantation have been recorded as methods of transmission but this is a rare mode of transmission. ^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Lyme disease may present as a red, expanding rash called erythema migrans (EM) along with flu-like symptoms such as fatigue, arthralgia, myalgias, headache, fever and/or chills, stiff neck, anorexia, and regional lymphadenopathy. EM resolves in approximately 28 days in untreated patients. Lyme disease is effectively managed by prompt treatment.

Untreated infection may spread from the site of the bite to other parts of the body, producing a range of symptoms including neurological, cardiac and dermatological manifestations. Many of these symptoms will resolve over a period of weeks to months, even without treatment. However, lack of treatment can result in additional complications. Lyme arthritis is the most frequently presented symptom in late disseminated Lyme disease.

Prognosis is mainly affected by a failure to treat in a timely manner as well as simultaneous infections with other tick-borne diseases. Sometimes, patients with Lyme disease have symptoms that last months to years after treatment with antibiotics. These symptoms includes muscle and joint pains, cognitive defects, sleep disturbance, or fatigue. The condition is referred to as post-treatment Lyme disease syndrome (PTLDS).

• Patients develops red, expanding rash called erythema migrans (EM).
• Flu-like symptoms such as fatigue, arthralgia, myalgias, headache, fever and/or chills, stiff neck, anorexia, and regional lymphadenopathy may be present.

• Some people may get these flu-like symptoms in addition to an EM rash, but in some, these flu-like symptoms may be the only evidence of infection.

• Some people get a small bump or redness at the site of a tick bite that goes away in 1-2 days, like a mosquito bite. This is not a sign that one has Lyme disease. However, ticks can spread other organisms that may cause a different type of rash. For example, Southern tick-associated rash illness (STARI) causes a rash with a very similar appearance.^[1]

• EM occurs in approximately 70-80% of infected persons and begins at the site of a tick bite after a delay of 3-30 days (average is about 7 days).
• Early EM may be homogenously erythematous without any central clearing.

• EM gradually expands over a period of several days, and can reach up to 12 inches (30 cm) across. Parts of the rash may clear as it enlarges, resulting in a bullseye appearance.

• The rash usually feels warm to touch but is rarely itchy or painful.

• EM lesions may appear on any area of the body but is present the majority of the time on the axilla, inguinal region, or popliteal fossa.
• EM resolves in approximately 28 days in untreated patients.^[2]

• Untreated infection may spread from the site of the bite to other parts of the body, producing a range of symptoms including:
  • Multiple EM lesions in other areas of the body. Multiple lesions are secondary to dissemination and are not to be confused with multiple tick bites^[3]
  • Facial or Bell’s palsy
  • Severe headaches and neck stiffness due to meningitis
  • Pain and swelling in the large joints (such as knees)
  • Shooting pains that may interfere with sleep
  • Heart palpitations and dizziness due to changes in heartbeat

• Many of these symptoms will resolve over a period of weeks to months, even without treatment. However, lack of treatment can result in additional complications.

• Lyme arthritis is the hallmark of stage 3 Lyme disease.
• Lyme arthritis is the most frequently presented symptom in late disseminated Lyme disease.
• Lyme arthritis is not necessarily preceded by erythema migrans.
• Approximately 60% of patients with untreated infection may begin to have intermittent attacks of arthritis with severe joint pain and swelling.^[4]
• Intermittent attacks of Lyme arthritis range from 3 days to 11.5 months with a mean of 3 months.^[5]
• During early years of illness, attacks of Lyme arthritis are more frequent and longer in duration. Both frequency and duration of attacks subsequently decrease.
• There may be months or years of complete remission between each attack of Lyme arthritis.
• The majority of the time, Lyme arthritis involves large joints. The most commonly affected joint is knee joint, but any joint can be affected including the shoulder, ankle, elbow, temporomandibular joint, and wrist.
• Lyme arthritis manifests differently than other causes of arthritis and must be distinguished from other causes of arthralgias.
• Up to 5% of untreated patients may develop chronic neurological complaints months to years after infection. These include shooting pains, numbness or tingling in the hands and/or feet, and short-term memory disturbances.

Stage 3 or late disseminated Lyme disease can cause long-term joint inflammation (Lyme arthritis) and heart rhythm problems. Brain and nervous system problems are also possible, and may include:

• Decreased concentration
• Memory disorders
• Nerve damage
• Numbness
• Pain
• Paralysis of the face muscles
• Sleep disorders
• Vision problems

• Approximately 10-20% of patients with Lyme disease have symptoms that last months to years even after treatment with antibiotics.
• These symptoms can include muscle and joint pains, cognitive defects, sleep disturbance, or fatigue.
• The cause of these symptoms is not known, but these symptoms are believed to be due residual damage to tissues and the immune system that occurred during the infection, similar to complications and autoimmune responses that occur in other infections including:
  • Campylobacter (Guillain-Barre syndrome)
  • Chlamydia (Reiter’s syndrome)
  • Strep throat (rheumatic heart disease)
• In contrast, some believe that these symptoms are due to persistent B. burgdorferi infection.
• This condition is referred to as post-treatment Lyme disease syndrome (PTLDS).
• It is observed that prolonged antibiotic therapy is not helpful and can be harmful for persons with PTLDS.
• Patients with PLTDS get better with time.

• For early cases, prompt treatment is usually curative.^[6]
• However, the severity and treatment of Lyme disease may be complicated due to:
  • Late diagnosis
  • Failure of antibiotic treatment
  • Coinfection with other tick-borne diseases including Ehrlichiosis and Babesiosis^[7]
  • Immune suppression in the patient
• A meta-analysis published in 2005 found that some patients with Lyme disease have fatigue, joint and/or muscle pain, and neurocognitive symptoms persisting for years despite antibiotic treatment.^[8]
• Patients with late stage Lyme disease have been shown to experience a level of physical disability equivalent to that seen in congestive heart failure.^[9]
• Though rare, Lyme disease can be fatal.^{[10][11][12][13]}
• The first CDC recognized death from Lyme disease was Amanda Schmidt, age 11.^[14]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

There is insufficient evidence to recommend routine screening for Lyme disease.

There is insufficient evidence to recommend routine screening for Lyme disease.

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