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Lyme disease, also known as Lyme borreliosis, is an infectious disease caused by the Borrelia bacterium which is spread by ticks.[2] The most common sign of infection is an expanding red rash, known as erythema migrans, that appears at the site of the tick bite about a week after it occurred.[1] The rash is typically neither itchy nor painful.[1] Approximately 70–80% of infected people develop a rash.[1] Other early symptoms may include fever, headache and tiredness.[1] If untreated, symptoms may include loss of the ability to move one or both sides of the face, joint pains, severe headaches with neck stiffness, or heart palpitations, among others.[1] Months to years later, repeated episodes of joint pain and swelling may occur.[1] Occasionally, people develop shooting pains or tingling in their arms and legs.[1] Despite appropriate treatment, about 10 to 20% of people develop joint pains, memory problems, and tiredness for at least six months.[1][5]

Lyme disease is transmitted to humans by the bites of infected ticks of the genus Ixodes.[6] In the United States, ticks of concern are usually of the Ixodes scapularis type, and must be attached for at least 36 hours before the bacteria can spread.[7][8] In Europe, ticks of the Ixodes ricinus type may spread the bacteria more quickly.[8][9]Lyme disease, also known as Lyme borreliosis, is an infectious disease caused by the Borrelia bacterium which is spread by ticks.[2] The most common sign of infection is an expanding red rash, known as erythema migrans, that appears at the site of the tick bite about a week after it occurred.[1] The rash is typically neither itchy nor painful.[1] Approximately 70–80% of infected people develop a rash.[1] Other early symptoms may include fever, headache and tiredness.[1] If untreated, symptoms may include loss of the ability to move one or both sides of the face, joint pains, severe headaches with neck stiffness, or heart palpitations, among others.[1] Months to years later, repeated episodes of joint pain and swelling may occur.[1] Occasionally, people develop shooting pains or tingling in their arms and legs.[1] Despite appropriate treatment, about 10 to 20% of people develop joint pains, memory problems, and tiredness for at least six months.[1][5]

Lyme disease is transmitted to humans by the bites of infected ticks of the genus Ixodes.[6] In the United States, ticks of concern are usually of the Ixodes scapularis type, and must be attached for at least 36 hours before the bacteria can spread.[7][8] In Europe, ticks of the Ixodes ricinus type may spread the bacteria more quickly.[8][9] In North America, the bacteria Borrelia burgdorferi and Borrelia mayonii cause Lyme disease.[2][10] In Europe and Asia, Borrelia afzelii and Borrelia garinii are also causes of the disease.[2] The disease does not appear to be transmissible between people, by other animals, or through food.[7] Diagnosis is based upon a combination of symptoms, history of tick exposure, and possibly testing for specific antibodies in the blood.[3][11] Blood tests are often negative in the early stages of the disease.[2] Testing of individual ticks is not typically useful.[12]

Prevention includes efforts to prevent tick bites such as by wearing clothing to cover the arms and legs, and using DEET-based insect repellents.[2] Using pesticides to reduce tick numbers may also be effective.[2] Ticks can be removed using tweezers.[13] If the removed tick was full of blood, a single dose of doxycycline may be used to prevent development of infection, but is not generally recommended since development of infection is rare.[2] If an infection develops, a number of antibio

Lyme disease is transmitted to humans by the bites of infected ticks of the genus Ixodes.[6] In the United States, ticks of concern are usually of the Ixodes scapularis type, and must be attached for at least 36 hours before the bacteria can spread.[7][8] In Europe, ticks of the Ixodes ricinus type may spread the bacteria more quickly.[8][9] In North America, the bacteria Borrelia burgdorferi and Borrelia mayonii cause Lyme disease.[2][10] In Europe and Asia, Borrelia afzelii and Borrelia garinii are also causes of the disease.[2] The disease does not appear to be transmissible between people, by other animals, or through food.[7] Diagnosis is based upon a combination of symptoms, history of tick exposure, and possibly testing for specific antibodies in the blood.[3][11] Blood tests are often negative in the early stages of the disease.[2] Testing of individual ticks is not typically useful.[12]

Prevention includes efforts to prevent tick bites such as by wearing clothing to cover the arms and legs, and using DEET-based insect repellents.[2] Using pesticides to reduce tick numbers may also be effective.[2] Ticks can be removed using tweezers.[13] If the removed tick was full of blood, a single dose of doxycycline may be used to prevent development of infection, but is not generally recommended since development of infection is rare.[2] If an infection develops, a number of antibiotics are effective, including doxycycline, amoxicillin, and cefuroxime.[2] Standard treatment usually lasts for two or three weeks.[2] Some people develop a fever and muscle and joint pains from treatment which may last for one or two days.[2] In those who develop persistent symptoms, long-term antibiotic therapy has not been found to be useful.[2][14]

Lyme disease is the most common disease spread by ticks in the Northern Hemisphere.[15] It is estimated to affect 300,000 people a year in the United States and 65,000 people a year in Europe.[2][4] Infections are most common in the spring and early summer.[2] Lyme disease was diagnosed as a separate condition for the first time in 1975 in Old Lyme, Connecticut.[16] It was originally mistaken for juvenile rheumatoid arthritis.[16] The bacterium involved was first described in 1981 by Willy Burgdorfer.[17] Chronic symptoms following treatment are well described and are known as "post-treatment Lyme disease syndrome" (PTLDS).[14] PTLDS is different from chronic Lyme disease; a term no longer supported by the scientific community and used in different ways by different groups.[14][18] Some healthcare providers claim that PTLDS is caused by persistent infection, but this is not believed to be true because no evidence of persistent infection can be found after standard treatment.[19] A vaccine for Lyme disease was marketed in the United States between 1998 and 2002, but was withdrawn from the market due to poor sales.[2][20][21] Research is ongoing to develop new vaccines.[2]

Lyme disease can affect multiple body systems and produce a broad range of symptoms. Not everyone with Lyme disease has all of the symptoms, and many of the symptoms are not specific to Lyme disease but can occur with other diseases, as well.

The incubation period from infection to the onset of symptoms is usually one to two weeks, but can be much shorter (days), or much longer (months to years).[26] Lyme symptoms most often occur from May to September, because the nymphal stage of the tick is responsible for most cases.[26] Asymptomatic infection exists, but occurs in less than 7% of infected individuals in the United States.[27] Asymptomatic infection may be much more common among those infected in Europe.[28]

Early localized infection

Early localized infection can occur when the infection has not yet spread throughout the body. Only the site where the infection has first come into contact with the skin is affected. The initial sign of about 80% of Lyme infections is an Erythema migrans (EM) rash at the site of a tick bite, often near skin folds, such as the armpit, groin, or back of knee, on the trunk, under clothing straps, or in children's hair, ear, or neck.[22][2] Most people who get infected do not remember seeing a tick or the bite. The rash appears typically one or two weeks (range 3–32 days) after the bite and expands 2–3 cm per day up to a diameter of 5–70 cm (median 16 cm).[22][2][23] The rash is usually circular or oval, red or bluish, and may have an elevated or darker center.[2][24][25] In about 79% of cases in Europe but only 19% of cases in endemic areas of the U.S., the rash gradually clears from the center toward the edges, possibly forming a "bull's eye" pattern.[23][24][25] The rash may feel warm but usually is not itchy, is rarely tender or painful, and takes up to four weeks to resolve if untreated.[2]

The EM (Erythema migrans) rash is often accompanied by symptoms of a viral-like illness, including fatigue, headache, body aches, fever, and chills, but usually not nausea or upper-respiratory problems. These symptoms may also appear without a rash, or linger after the rash disappears. Lyme can progress to later stages without these symptoms or a rash.[2]

People with high fever for more than two days or whose other symptoms of viral-like illness do not improve despite antibiotic treatment for Lyme disease, or who have abnormally low levels of white or red cells or platelets in the blood, should be investigated for possible coinfection with other tick-borne diseases, such as ehrlichiosis and babesiosis.[29]

Early disseminated infection

Within days to weeks after the onset of local infection, the Borrelia bacteria may spread through the lymphatic system or bloodstream. In 10-20% of untreated cases, EM rashes develop at sites across the body that bear no relation to the original tick bite.[22] Transient muscle pains and joint pains are also common.[22]

In about 10-15% of untreated people, Lyme causes neurological problems known as neuroborreliosis.[30] Early neuroborreliosis typically appears 4–6 weeks (range 1–12 weeks) after the tick bite and involves some combination of lymphocytic meningitis, cranial neuritis, radiculopathy and/or mononeuritis multiplex.[29][31] Lymphocytic meningitis causes characteristic changes in the cerebrospinal fluid (CSF) and may be accompanied for several weeks by variable headache and, less commonly, usually mild meningitis signs such as inability to flex the neck fully and intolerance to bright lights, but typically no or only very low fever.[32] In children, partial loss of vision may also occur.[29] Cranial neuritis is an inflammation of cranial nerves. When due to Lyme, it most typically causes facial palsy impairing blinking, smiling, and chewing in one or both sides of the face. It may also cause intermittent double vision.[29][32] Lyme radiculopathy is an inflammation of spinal nerve roots that ofte

The incubation period from infection to the onset of symptoms is usually one to two weeks, but can be much shorter (days), or much longer (months to years).[26] Lyme symptoms most often occur from May to September, because the nymphal stage of the tick is responsible for most cases.[26] Asymptomatic infection exists, but occurs in less than 7% of infected individuals in the United States.[27] Asymptomatic infection may be much more common among those infected in Europe.[28]

Early localized infection can occur when the infection has not yet spread throughout the body. Only the site where the infection has first come into contact with the skin is affected. The initial sign of about 80% of Lyme infections is an Erythema migrans (EM) rash at the site of a tick bite, often near skin folds, such as the armpit, groin, or back of knee, on the trunk, under clothing straps, or in children's hair, ear, or neck.[22][2] Most people who get infected do not remember seeing a tick or the bite. The rash appears typically one or two weeks (range 3–32 days) after the bite and expands 2–3 cm per day up to a diameter of 5–70 cm (median 16 cm).[22][2][23] The rash is usually circular or oval, red or bluish, and may have an elevated or darker center.[2][24][25] In about 79% of cases in Europe but only 19% of cases in endemic areas of the U.S., the rash gradually clears from the center toward the edges, possibly forming a "bull's eye" pattern.[23][24][25] The rash may feel warm but usually is not itchy, is rarely tender or painful, and takes up to four weeks to resolve if untreated.[2]

The EM (Erythema migrans) rash is often accompanied by symptoms of a viral-like illness, including fatigue, headache, body aches, fever, and chills, but usually not nausea or upper-respiratory problems. These symptoms may also appear without a rash, or linger after the rash disappe

The EM (Erythema migrans) rash is often accompanied by symptoms of a viral-like illness, including fatigue, headache, body aches, fever, and chills, but usually not nausea or upper-respiratory problems. These symptoms may also appear without a rash, or linger after the rash disappears. Lyme can progress to later stages without these symptoms or a rash.[2]

People with high fever for more than two days or whose other symptoms of viral-like illness do not improve despite antibiotic treatment for Lyme disease, or who have abnormally low levels of white or red cells or platelets in the blood, should be investigated for possible coinfection with other tick-borne diseases, such as ehrlichiosis and babesiosis.[29]

Within days to weeks after the onset of local infection, the Borrelia bacteria may spread through the lymphatic system or bloodstream. In 10-20% of untreated cases, EM rashes develop at sites across the body that bear no relation to the original tick bite.[22] Transient muscle pains and joint pains are also common.[22]

In about 10-15% of untreated people, Lyme causes neurological problems known as neuroborreliosis.[30] Early neuroborreliosis typically appears 4–6 weeks (range 1–12 weeks) after the ti

In about 10-15% of untreated people, Lyme causes neurological problems known as neuroborreliosis.[30] Early neuroborreliosis typically appears 4–6 weeks (range 1–12 weeks) after the tick bite and involves some combination of lymphocytic meningitis, cranial neuritis, radiculopathy and/or mononeuritis multiplex.[29][31] Lymphocytic meningitis causes characteristic changes in the cerebrospinal fluid (CSF) and may be accompanied for several weeks by variable headache and, less commonly, usually mild meningitis signs such as inability to flex the neck fully and intolerance to bright lights, but typically no or only very low fever.[32] In children, partial loss of vision may also occur.[29] Cranial neuritis is an inflammation of cranial nerves. When due to Lyme, it most typically causes facial palsy impairing blinking, smiling, and chewing in one or both sides of the face. It may also cause intermittent double vision.[29][32] Lyme radiculopathy is an inflammation of spinal nerve roots that often causes pain and less often weakness, numbness, or altered sensation in the areas of the body served by nerves connected to the affected roots, e.g. limb(s) or part(s) of trunk. The pain is often described as unlike any other previously felt, excruciating, migrating, worse at night, rarely symmetrical, and often accompanied by extreme sleep disturbance.[31][33] Mononeuritis multiplex is an inflammation causing similar symptoms in one or more unrelated peripheral nerves.[30][29] Rarely, early neuroborreliosis may involve inflammation of the brain or spinal cord, with symptoms such as confusion, abnormal gait, ocular movements, or speech, impaired movement, impaired motor planning, or shaking.[29][31]

In North America, facial palsy is the typical early neuroborreliosis presentation, occurring in 5-10% of untreated people, in about 75% of cases accompanied by lymphocytic meningitis.[29][34] Lyme radiculopathy is reported half as frequently, but many cases may be unrecognized.[35] In European adults, the most common presentation is a combination of lymphocytic meningitis and radiculopathy known as Bannwarth syndrome, accompanied in 36-89% of cases by facial palsy.[31][33] In this syndrome, radicular pain tends to start in the same body region as the initial erythema migrans rash, if there was one, and precedes possible facial palsy and other impaired movement.[33] In extreme cases, permanent impairment of motor or sensory function of the lower limbs may occur.[28] In European children, the most common manifestations are facial palsy (in 55%), other cranial neuritis, and lymphocytic meningitis (in 27%).[31]

In about 4-10% of untreated cases in the U.S. and 0.3-4% of untreated cases in Europe, typically between June and December, about one month (range 4 days-7 months) after the tick bite, the infection may cause heart complications known as Lyme carditis.[36][37] Symptoms may include heart palpitations (in 69% of people), dizziness, fainting, shortness of breath, and chest pain.[36] Other symptoms of Lyme disease may also be present, such as EM rash, joint aches, facial palsy, headaches, or radicular pain.[36] In some people, however, carditis may be the first manifestation of Lyme disease.[36] Lyme carditis in 19-87% of people adversely impacts the heart's electrical conduction system, causing atrioventricular block that often manifests as heart rhythms that alternate within minutes between abnormally slow and abnormally fast.[36][37] In 10-15% of people, Lyme causes myocardial complications such as cardiomegaly, left ventricular dysfunction, or congestive heart failure.[36]

Another skin condition, found in Europe but not in North America, is borrelial lymphocytoma, a purplish lump that develops on the ear lobe, nipple, or scrotum.[38]

After several months, untreated or inadequately treated people may go on to develop chronic symptoms that affect many parts of the body, including the joints, nerves, brain, eyes, and heart.

Lyme arthritis occurs in up to 60% of untreated people, typically starting about six months after infection.[22] It usually affects only one or a few joints, often a knee or possibly the hip, other large joints, or the [22] It usually affects only one or a few joints, often a knee or possibly the hip, other large joints, or the temporomandibular joint.[29][39] There is usually large joint effusion and swelling, but only mild or moderate pain.[29] Without treatment, swelling and pain typically resolve over time but periodically return.[29] Baker's cysts may form and rupture. In some cases, joint erosion occurs.

Chronic neurologic symptoms occur in up to 5% of untreated people.[40] A peripheral neuropathy or polyneuropathy may develop, causing abnormal sensations such as numbness, tingling or burning starting at the feet or hands and over time possibly moving up the limbs. A test may show reduced sensation of vibrations in the feet. An affected person may feel as if wearing a stocking or glove without actually doing so.[29]

A neurologic syndrome called Lyme encephalopathy is associated with subtle memory and cognitive difficulties, insomnia, a general sense of feeling unwell, and changes in personality.[41] However, problems such as depression and fibromyalgia are as common in people with Lyme disease as in the general population.[42][43]

Lyme can cause a chronic encephalomyelitis that resembles multiple sclerosis. It may be progressive and can involve cognitive impairment, brain fog, migraines, balance issues, weakness in the legs, awkward gait, facial palsy, bladder problems, vertigo, and back pain. In rare cases, untreated Lyme disease may cause frank psychosis, which has been misdiagnosed as schizophrenia or bipolar disorder. Panic attacks and anxiety can occur; also, delusional behavior may be seen, including somatoform delusions, sometimes accompanied by a depersonalization or derealization syndrome, where the people begin to feel detached from themselves or from reality.[44][45]

Acrodermatitis chronica atrophicans (ACA) is a chronic skin disorder observed primarily in Europe among the elderly.[38] ACA begins as a reddish-blue patch of discolored skin, often on the backs of the hands or feet. The lesion slowly atrophies over several weeks or months, with the skin becoming first thin and wrinkled and then, if untreated, completely dry and hairless.[46]

Lyme disease is caused by spirochetes, spiral bacteria from the genus Borrelia. Spirochetes are surrounded by peptidoglycan and flagella, along with an outer membrane similar to Gram-negative bacteria. Because of their double-membrane envelope, Borrelia bacteria are often mistakenly described as Gram negative despite the considerable differences in their envelope components from Gram-negative bacteria.[47] The Lyme-related Borrelia species are collectively known as Borrelia burgdorferi sensu lato, and show a great deal of genetic diversity.

B. burgdorferi sensu lato is made up of 21 closely related species, but only four clearly cause Lyme disease: B. mayonii (found in North America), B. burgdorferi sensu stricto (predominant in North America, but also present in Europe), B. afzelii, and B. garinii (both predominant in Eurasia).[48][49][10] Some studies have also proposed that B. bissettii and B. valaisiana may sometimes infect humans, but these species do not seem to be important causes of disease.[50][51]

Transmission

Lyme disease is classified as a zoonosis, as it is transmitted to humans from a natural reservoir among small mammals and birds by ticks that feed on both sets of hosts.[52] Hard-bodied ticks of the genus Ixodes are the main vectors of Lyme disease (also the vector for Babesia).[53] Most infections are caused by ticks in the nymphal stage, because they are very small and thus may feed for long periods of time undetected.[52] Nymphal ticks are generally the size of a poppy seed and sometimes with a dark head and a translucent body.[54] Or, the nymphal ticks can be darker.[55] (The younger larval ticks are very rarely infected.[56]) Although deer are the preferred hosts of adult deer ticks, and tick populations are much lower in the absence of deer, ticks generally do not acquire Borrelia from deer, instead they obtain them from infected small mammals such as the white-footed mo

B. burgdorferi sensu lato is made up of 21 closely related species, but only four clearly cause Lyme disease: B. mayonii (found in North America), B. burgdorferi sensu stricto (predominant in North America, but also present in Europe), B. afzelii, and B. garinii (both predominant in Eurasia).[48][49][10] Some studies have also proposed that B. bissettii and B. valaisiana may sometimes infect humans, but these species do not seem to be important causes of disease.[50][51]

Lyme disease is classified as a zoonosis, as it is transmitted to humans from a natural reservoir among small mammals and birds by ticks that feed on both sets of hosts.[52] Hard-bodied ticks of the genus Ixodes are the main vectors of Lyme disease (also the vector for Babesia).[53] Most infections are caused by ticks in the nymphal stage, because they are very small and thus may feed for long periods of time undetected.[52] Nymphal ticks are generally the size of a poppy seed and sometimes with a dark head and a translucent body.[54] Or, the nymphal ticks can be darker.[55] (The younger larval ticks are very rarely infected.[56]) Although deer are the preferred hosts of adult deer ticks, and tick populations are much lower in the absence of deer, ticks generally do not acquire Borrelia from deer, instead they obtain them from infected small mammals such as the white-footed mouse, and occasionally birds.[57] Areas where Lyme is common are expanding.[58]

Within the tick midgut, the Borrelia's outer surface protein A (OspA) binds to the tick receptor for OspA, known as TROSPA. When the tick feeds, the Borrelia downregulates OspA and upregulates OspC, another surface protein.

Within the tick midgut, the Borrelia's outer surface protein A (OspA) binds to the tick receptor for OspA, known as TROSPA. When the tick feeds, the Borrelia downregulates OspA and upregulates OspC, another surface protein. After the bacteria migrate from the midgut to the salivary glands, OspC binds to Salp15, a tick salivary protein that appears to have immunosuppressive effects that enhance infection.[59] Successful infection of the mammalian host depends on bacterial expression of OspC.[60]

Tick bites often go unnoticed because of the small size of the tick in its nymphal stage, as well as tick secretions that prevent the host from feeling any itch or pain from the bite. However, transmission is quite rare, with only about 1.2 to 1.4 percent of recognized tick bites resulting in Lyme disease.[61]

In Europe, the vector is Ixodes ricinus, which is also called the sheep tick or castor bean tick.[62] In China, Ixodes persulcatus (the taiga tick) is probably the most important vector.[63] In North America, the black-legged tick or deer tick (Ixodes scapularis) is the main vector on the East Coast.[56]

The lone star tick (Amblyomma americanum), which is found throughout the Southeastern United States as far west as Texas, is unlikely to transmit the Lyme disease spirochetes,[64] though it may be implicated in a related syndrome called southern tick-associated rash illness, which resembles a mild form of Lyme disease.[65]

On the West Coast of the United States, the main vector is the western black-legged tick (Ixodes pacificus).[66] The tendency of this tick species to feed predominantly on host species such as the Western Fence Lizard that are resistant to Borrelia infection appears to diminish transmission of Lyme disease in the West.[67][68]

Transmission can occur across the placenta during pregnancy and as with a number of other spirochetal diseases, adverse pregnancy outcomes are possible with untreated infection; prompt treatment with antibiotics reduces or eliminates this risk.[69][70][71][72][73]

While Lyme spirochetes have been found in insects, as well as ticks,[74] reports of actual infectious transmission appear to be rare.[75] Lyme spirochete DNA has been found in semen[76] and breast milk.[77] However, according to the CDC, live spirochetes have not been found in breast milk, urine, or semen and thus is not sexually transmitted.[78]

Ticks that transmit B. burgdorferi to humans can also carry and transmit several other parasites, such as Theileria microti and Anaplasma phagocytophilum, which cause the diseases babesiosis and human granulocytic anaplasmosis (HGA), respectively.[79] Among people with early Lyme disease, depending on their location, 2–12% will also have HGA and 2–40% will have babesiosis.[80] Ticks in certain regions, including the lands along the eastern Baltic Sea, also transmit tick-borne encephalitis.[81]

Coinfections complicate Lyme symptoms, especially diagnosis and treatment. It is possible for a tick to carry and transmit one of the coinfections and not Borrelia, making diagnosis difficult and often elusive. The Centers for Disease Control and Prevention studied 100 ticks in rural New J

Coinfections complicate Lyme symptoms, especially diagnosis and treatment. It is possible for a tick to carry and transmit one of the coinfections and not Borrelia, making diagnosis difficult and often elusive. The Centers for Disease Control and Prevention studied 100 ticks in rural New Jersey, and found 55% of the ticks were infected with at least one of the pathogens.[82]

B. burgdorferi can spread throughout the body during the course of the disease, and has been found in the skin, heart, joints, peripheral nervous system, and central nervous system.[60][83] Many of the signs and symptoms of Lyme disease are a consequence of the immune response to spirochete in those tissues.[40]

B. burgdorferi is injected into the skin by the bite of an infected Ixodes tick. Tick saliva, which accompanies the spirochete into the skin during the feeding process, contains substances that disrupt the immune response at the site of the bite.B. burgdorferi is injected into the skin by the bite of an infected Ixodes tick. Tick saliva, which accompanies the spirochete into the skin during the feeding process, contains substances that disrupt the immune response at the site of the bite.[84] This provides a protective environment where the spirochete can establish infection. The spirochetes multiply and migrate outward within the dermis. The host inflammatory response to the bacteria in the skin causes the characteristic circular EM lesion.[60] Neutrophils, however, which are necessary to eliminate the spirochetes from the skin, fail to appear in necessary numbers in the developing EM lesion, mostly due to the fact that tick saliva also inhibits neutrophil function. This allows the bacteria to survive and eventually spread throughout the body.[85]

Days to weeks following the tick bite, the spirochetes spread via the bloodstream to joints, heart, nervous system, and distant skin sites, where their presence gives rise to the variety of symptoms of the disseminated disease. The spread of B. burgdorferi is aided by the attachment of the host protease plasmin to the surface of the spirochete.[86]

If untreated, the bacteria may persist in the body for months or even years, despite the production of B. burgdorferi antibodies by the immune system.[87] The spirochetes may avoid the immune response by decreasing expression of surface proteins that are targeted by antibodies, antigenic variation of the VlsE surface protein, inactivating key immune components such as complement, and hiding in the extracellular matrix, which may interfere with the function of immune factors.[88][89]

In the brain, B. burgdorferi may induce astrocytes to undergo astrogliosis (proliferation followed by apoptosis), which may contribute to neurodysfunction.[90] The spirochetes may also induce host cells to secrete quinolinic acid, which stimulates the NMDA receptor on nerve cells, which may account for the fatigue and malaise observed with Lyme encephalopathy.[91] In addition, diffuse white matter pathology during Lyme encephalopathy may disrupt gray matter connections, and could account for deficits in attention, memory, visuospatial ability, complex cognition, and emotional status. White matter disease may have a greater potential for recovery than gray matter disease, perhaps because the neuronal loss is less common. Resolution of MRI white matter hyperintensities after antibiotic treatment has been observed.[92]

Tryptophan, a precursor to serotonin, appears to be reduced within the central nervous system in a number of infectious diseases that affect the brain, including Lyme.[93] Researchers are investigating if this neurohormone secretion is the cause of neuropsychiatric disorders developing in some people with borreliosis.[94]

Exposure to the Borrelia bacterium during Lyme disease possibly causes a long-lived and damaging inflammatory response,[95] a form of pathogen-induced autoimmune disease.[96] The production of this reaction might be due to a form of molecular mimicry, where Borrelia avoids being killed by the immune system by resembling normal parts of the body's tissues.[97][98]

Chronic symptoms from an autoimmune reaction could explain why some symptoms persist even after the spirochetes have been eliminated from the body. This hypothesis may explain why chronic arthritis persists after antibiotic therapy, similar to rheumatic fever, but its wider appl

Chronic symptoms from an autoimmune reaction could explain why some symptoms persist even after the spirochetes have been eliminated from the body. This hypothesis may explain why chronic arthritis persists after antibiotic therapy, similar to rheumatic fever, but its wider application is controversial.[99][100]

Lyme disease is diagnosed based on symptoms, objective physical findings (such as erythema migrans (EM) rash, facial palsy, or arthritis), history of possible exposure to infected ticks, and possibly laboratory tests.[2][22] People with symptoms of early Lyme disease should have a total body skin examination for EM rashes and asked whether EM-type rashes had manifested within the last 1–2 months.[29] Presence of an EM rash and recent tick exposure (i.e., being outdoors in a likely tick habitat where Lyme is common, within 30 days of the appearance of the rash) are sufficient for Lyme diagnosis; no laboratory confirmation is needed or recommended.[2][22][101][102] Most people who get infected do not remember a tick or a bite, and the EM rash need not look like a bull's eye (most EM rashes in the U.S. do not) or be accompanied by any other symptoms.[2][103] In the U.S., Lyme is most common in the New England and Mid-Atlantic states and parts of Wisconsin and Minnesota, but it is expanding into other areas.[58] Several bordering areas of Canada also have high Lyme risk.[104]

In the absence of an EM rash or history of tick exposure, Lyme diagnosis depends on laboratory confirmation.[53]

In the absence of an EM rash or history of tick exposure, Lyme diagnosis depends on laboratory confirmation.[53][105] The bacteria that cause Lyme disease are difficult to observe directly in body tissues and also difficult and too time-consuming to grow in the laboratory.[2][53] The most widely used tests look instead for presence of antibodies against those bacteria in the blood.[106] A positive antibody test result does not by itself prove active infection, but can confirm an infection that is suspected because of symptoms, objective findings, and history of tick exposure in a person.[53] Because as many as 5-20% of the normal population have antibodies against Lyme, people without history and symptoms suggestive of Lyme disease should not be tested for Lyme antibodies: a positive result would likely be false, possibly causing unnecessary treatment.[29][31]

In some cases, when history, signs, and symptoms are strongly suggestive of early disseminated Lyme disease, empiric treatment may be started and reevaluated as laboratory test results become available.[34][107]

Tests for antibodies in the blood by ELISA and Western blot is the most widely used method for Lyme diagnosis. A two-tiered protocol is recommended by the Centers for Disease Control and Prevention (CDC): the sensitive ELISA test is performed first, and if it is positive or equivocal, then the more specific Western blot is run.[108] The immune system takes some time to produce antibodies in quantity. After Lyme infection onset, antibodies of types IgM and IgG usually can first be detected respectively at 2–4 weeks and 4–6 weeks, and peak at 6–8 weeks.[109] When an EM rash first appears, detectable antibodies may not be present. Therefore, it is recommended that testing not be performed and diagnosis be based on the presence of the EM rash.[29] Up to 30 days after suspected Lyme infection onset, infection can be confirmed by detection of IgM or IgG antibodies; after that, it is recommended that only IgG antibodies be considered.[109] A positive IgM and negative IgG test result after the first month of infection is generally indicative of a false positive result.[110] The number of IgM antibodies usually collapses 4–6 months after infection, while IgG antibodies can remain detectable for years.[109]

Other tests may be used in neuroborreliosis cases. In Europe, neuroborreliosis is usually caused by Borrelia garinii and almost always involves lymphocytic pleocytosis, i.e. the densities of Other tests may be used in neuroborreliosis cases. In Europe, neuroborreliosis is usually caused by Borrelia garinii and almost always involves lymphocytic pleocytosis, i.e. the densities of lymphocytes (infection-fighting cells) and protein in the cerebrospinal fluid (CSF) typically rise to characteristically abnormal levels, while glucose level remains normal.[32][29][33] Additionally, the immune system produces antibodies against Lyme inside the intrathecal space, which contains the CSF.[29][33] Demonstration by lumbar puncture and CSF analysis of pleocytosis and intrathecal antibody production are required for definite diagnosis of neuroborreliosis in Europe (except in cases of peripheral neuropathy associated with acrodermatitis chronica atrophicans, which usually is caused by Borrelia afzelii and confirmed by blood antibody tests).[31] In North America, neuroborreliosis is caused by Borrelia burgdorferi and may not be accompanied by the same CSF signs; they confirm a diagnosis of central nervous system (CNS) neuroborreliosis if positive, but do not exclude it if negative.[111] American guidelines consider CSF analysis optional when symptoms appear to be confined to the peripheral nervous system (PNS), e.g. facial palsy without overt meninigitis symptoms.[29][112] Unlike blood and intrathecal antibody tests, CSF pleocytosis tests revert to normal after infection ends and therefore can be used as objective markers of treatment success and inform decisions on whether to retreat.[33] In infection involving the PNS, electromyography and nerve conduction studies can be used to monitor objectively the response to treatment.[32]

In Lyme carditis, electrocardiograms are used to evidence heart conduction abnormalities, while echocardiography may show myocardial dysfunction.[36] Biopsy and confirmation of Borrelia cells in myocardial tissue may be used in specific cases but are usually not done because of risk of the procedure.[36]

Polymerase chain reaction (PCR) tests for Lyme disease have also been developed to detect the genetic material (DNA) of the Lyme disease spirochete. Culture or PCR are the current means for detecting the presence of the organism, as serologic studies only test for antibodies of Borrelia. PCR has the advantage of being much faster than culture. However, PCR tests are susceptible to false positive results, e.g. by detection of debris of dead Borrelia cells or specimen contamination.[113][31] Even when properly performed, PCR often shows false negative results because few Borrelia cells can be found in blood and cerebrospinal fluid (CSF) during infection.[114][31] Hence, PCR tests are recommended only in special cases, e.g. diagnosis of Lyme arthritis, because it is a highly sensitive way of detecting ospA DNA in synovial fluid.[115] Although sensitivity of PCR in CSF is low, its use may be considered when intrathecal antibody production test results are suspected of being falsely negative, e.g. in very early (< 6 weeks) neuroborreliosis or in immunosuppressed people.[31]

Several other forms of laboratory testing for Lyme disease are available, some of which have not been adequately validated. OspA antigens, shed by live Borrelia bacteria into urine, are a promising technique being studied.[116] The use of nanotrap particles for their detection is being looked at and the OspA has been linked to active symptoms of Lyme.[117][118] High titers of either immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies to Borrelia antigens indicate disease, but lower titers can be misleading, because the IgM antibodies may remain after the initial infection, and IgG antibodies may remain for years.[119]

The CDC does not recommend urine antigen tests, PCR tests on urine, immunofluorescent staining for cell-wall-deficient forms of B. burgdorferi, and lymphocyte transformation tests.[114]

Neuroimaging is controversial in whether it provides specific patterns unique to neuroborreliosis, but may aid in differential diagnosis and in understanding the pathophysiology of the disease.[120] Though controversial, some evidence shows certain neuroimaging tests can provide data that are helpful in the diagnosis of a person. Magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) are two of the tests that can identify abnormalities in the brain of a person affected with this disease. Neuroimaging findings in an MRI include lesions in the periventricular white matter, as well as enlarged ventricles and cortical atrophy. The findings are considered somewhat unexceptional because the lesions have been found to be reversible following antibiotic treatment. Images produced using SPECT show numerous areas where an insufficient amount of blood is being delivered to the cortex and subcortical white matter. However, SPECT images are known to be nonspecific because they show a heterogeneous pattern in the imaging. The abnormalities seen in the SPECT images are very similar to those seen in people with cerebral vacuities and Creutzfeldt–Jakob disease, which makes them questionable.[121]

Differential diagnosis

Several l

Several landscaping practices may reduce risk of tick bites in residential yards.[138][145] The lawn should be kept mowed, leaf litter and weeds removed and groundcover use avoided.[138] Woodlands, shrubs, stone walls and wood piles should be separated from the lawn by a 3-ft-wide rock or woodchip barrier.[145] Without vegetation on the barrier, ticks will tend not to cross it; acaricides may also be sprayed on it to kill ticks.[145] A sun-exposed tick-safe zone at least 9 ft from the barrier should concentrate human activity on the yard, including any patios, playgrounds and gardening.[145] Materials such as wood decking, concrete, bricks, gravel or woodchips may be used on the ground under patios and playgrounds so as to discourage ticks there.[138] An 8-ft-high fence may be added to keep deer away from the tick-safe zone.[145][138]

Occupational exposureOutdoor workers are at risk of Lyme disease if they work at sites with infected ticks. This includes construction, landscaping, forestry, brush clearing, land surveying, farming, railroad work, oil field work, utility line work, park or wildlife management.[146][147] U.S. workers in the northeastern and north-central states are at highest risk of exposure to infected ticks. Ticks may also transmit other tick-borne diseases to workers in these and other regions of the country. Worksites with woods, bushes, high grass or leaf litter are likely to have more ticks. Outdoor workers should be most careful to protect themselves in the late spring and summer when young ticks are most active.[148]

Host animals

Lyme and other deer tick

Lyme and other deer tick-borne diseases can sometimes be reduced by greatly reducing the deer population on which the adult ticks depend for feeding and reproduction. Lyme disease cases fell following deer eradication on an island, Monhegan, Maine,[149] and following deer control in Mumford Cove, Connecticut.[150] It is worth noting that eliminating deer may lead to a temporary increase in tick density.[151]

For example, in the U.S., reducing the deer population to levels of 8 to 10 per square mile (from the current levels of 60 or more deer per square mile in the areas of the country with the highest Lyme disease rates) may reduce tick numbers and reduce the spread of Lyme and other tick-borne diseases.[152] However, such a drastic reduction may be very difficult to implement in many areas, and low to moderate densities of deer or other large mammal hosts may continue to feed sufficient adult ticks to maintain larval densities at high levels. Routine veterinary control of ticks of domestic animals, including livestock, by use of acaricides can contribute to reducing exposure of humans to ticks.

In Europe, known reservoirs of Borrelia burgdorferi were 9 small mammals, 7 medium-sized mammals and 16 species of birds (including passerines, sea-birds and pheasants).[153] These animals seem to transmit spirochetes to ticks and thus participate in the natural circulation of B. burgdorferi in Europe. The house mouse is also suspected as well as other species of small rodents, particularly in Eastern Europe and Russia.[153] "The reservoir species that contain the most pathogens are the European roe deer Capreolus capreolus;[154] "it does not appear to serve as a major reservoir of B. burgdorferi" thought Jaenson & al. (1992)[155] (incompetent host for B. burgdorferi and TBE virus) but it is important for feeding the ticks,[156] as red deer and wild boars (Sus scrofa),[157] in which one Rickettsia and three Borrelia species were identified",[154] with high risks of coinfection in roe deer.[158] Nevertheless, in the 2000s, in roe deer in Europe "two species of Rickettsia and two species of Borrelia were identified".[157]

A recombinant vaccine against Lyme disease, based on the outer surface protein A (ospA) of B. burgdorferi, was developed by SmithKline Beecham. In clinical trials involving more than 10,000 people, the vaccine, called LYMErix, was found to confer protective immunity to Borrelia in 76% of adults and 100% of children with only mild or moderate and transient adverse effects.[159] LYMErix was approved on the basis of these trials by the Food and Drug Administration (FDA) on 21 December 1998.

Following approval of the vaccine, its entry in clinical practice was slow for a variety of reasons, including its cost, which was often not reimbursed by insurance companies.[

Following approval of the vaccine, its entry in clinical practice was slow for a variety of reasons, including its cost, which was often not reimbursed by insurance companies.[160] Subsequently, hundreds of vaccine recipients reported they had developed autoimmune and other side effects. Supported by some advocacy groups, a number of class-action lawsuits were filed against GlaxoSmithKline, alleging the vaccine had caused these health problems. These claims were investigated by the FDA and the Centers for Disease Control, which found no connection between the vaccine and the autoimmune complaints.[161]

Despite the lack of evidence that the complaints were caused by the vaccine, sales plummeted and LYMErix was withdrawn from the U.S. market by GlaxoSmithKline in February 2002,[162] in the setting of negative media coverage and fears of vaccine side effects.[161][163] The fate of LYMErix was described in the medical literature as a "cautionary tale";[163] an editorial in Nature cited the withdrawal of LYMErix as an instance in which "unfounded public fears place pressures on vaccine developers that go beyond reasonable safety considerations."[20] The original developer of the OspA vaccine at the Max Planck Institute told Nature: "This just shows how irrational the world can be ... There was no scientific justification for the first OspA vaccine LYMErix being pulled."[161]

Vaccines have been formulated and approved for prevention of Lyme disease in dogs. Currently, three Lyme disease vaccines are available. LymeVax, formulated by Fort Dodge Laboratories, contains intact dead spirochetes which expose the host to the organism. Galaxy Lyme, Intervet-Schering-Plough's vaccine, targets proteins OspC and OspA. The OspC antibodies kill any of the bacteria that have not been killed by the OspA antibodies. Canine Recombinant Lyme, formulated by Merial, generates antibodies against the OspA protein so a tick feeding on a vaccinated dog draws in blood full of anti-OspA antibodies, which kill the spirochetes in the tick's gut before they are transmitted to the dog.[164]

A hexavalent (OspA) protein subunit-based vaccine candidate VLA15 was granted fast track designation by the U.S. Food and Drug Administration in 2017 which will allow further study.[165]

Antibiotics are the primary treatment.[2][22] The specific approach to their use is dependent on the individual affected and the stage of the disease.[22] For most people with early localized infection, oral administration of doxycycline is widely recommended as the first choice, as it is effective against not only Borrelia bacteria but also a variety of other illnesses carried by ticks.[22] People taking doxycycline should avoid sun exposure because of higher risk of sunburns.[29] Doxycycline is contraindicated in children younger than eight years of age and women who are pregnant or breastfeeding;[22] alternatives to doxycycline are amoxicillin, cefuroxime axetil, and azithromycin.[22] Azithromicyn is recommended only in case of intolerance to the other antibiotics.[29] The standard treatment for cellulitis, cephalexin, is not useful for Lyme disease.[29] When it is unclear if a rash is caused by Lyme or cellulitis, the IDSA recommends treatment with cefuroxime or amoxicillin/clavulanic acid, as these are effective against both infections.[29] Individuals with early disseminated or late Lyme infection may have symptomatic cardiac disease, Lyme arthritis, or neurologic symptoms like facial palsy, radiculopathy, meningitis, or peripheral neuropathy.[22] Intravenous administration of ceftriaxone is recommended as the first choice in these cases;[22] cefotaxime and doxycycline are available as alternatives.[22]

These treatment regimens last from one to four weeks.[22] Neurologic complications of Lyme disease may be treated with [22] Neurologic complications of Lyme disease may be treated with doxycycline as it can be taken by mouth and has a lower cost, although in North America evidence of efficacy is only indirect.[112] In case of failure, guidelines recommend retreatment with injectable ceftriaxone.[112] Several months after treatment for Lyme arthritis, if joint swelling persists or returns, a second round of antibiotics may be considered; intravenous antibiotics are preferred for retreatment in case of poor response to oral antibiotics.[22][29] Outside of that, a prolonged antibiotic regimen lasting more than 28 days is not recommended as no evidence shows it to be effective.[22][166] IgM and IgG antibody levels may be elevated for years even after successful treatment with antibiotics.[22] As antibody levels are not indicative of treatment success, testing for them is not recommended.[22]

Facial palsy may resolve without treatment; however, antibiotic treatment is recommended to stop other Lyme complications.[29] Corticosteroids are not recommended when facial palsy is caused by Lyme disease.[34] In those with facial palsy, frequent use of artificial tears while awake is recommended, along with ointment and a patch or taping the eye closed when sleeping.[34][167]

About a third of people with Lyme carditis need a temporary pacemaker until their heart conduction abnormality resolves, and 21% need to be hospitalized.[36] Lyme carditis should not be treated with corticosteroids.[36]

People with Lyme arthritis should limit their level of physical activity to avoid damaging affected joints, and in case of limping should use crutches.[168] Pain associated with Lyme disease may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs).[29] Corticosteroid joint injections are not recommended for Lyme arthritis that is being treated with antibiotics.[29][168] People with Lyme arthritis treated with intravenous antibiotics or two months of oral antibiotics who continue to have joint swelling two months after treatment and have negative PCR test for Borrelia DNA in the synovial fluid are said to have antibiotic-refractory Lyme arthritis; this is more common after infection by certain Borrelia strains in people with certain genetic and immunologic characteristics.[29][168] Antibiotic-refractory Lyme arthritis may be symptomatically treated with NSAIDs, disease-modifying antirheumatic drugs (DMARDs), or arthroscopic synovectomy.[29] Physical therapy is recommended for adults after resolution of Lyme arthritis.[168]

People receiving treatment should be advised that reinfection is possible and how to prevent it.[107]

Lyme disease's typical first sign, the erythema migrans (EM) rash, resolves within several weeks even without treatment.[2] However, in untreated people, the infection often disseminates to the nervous system, heart, or joints, possibly causing permanent damage to body tissues.[29]

People who receive recommended antibiotic treatment within several days of appearance of an initial EM rash have the best prospects.[105] Recovery may not be total or immediate. The percentage o

People who receive recommended antibiotic treatment within several days of appearance of an initial EM rash have the best prospects.[105] Recovery may not be total or immediate. The percentage of people achieving full recovery in the United States increases from about 64–71% at end of treatment for EM rash to about 84–90% after 30 months; higher percentages are reported in Europe.[169][170] Treatment failure, i.e. persistence of original or appearance of new signs of the disease, occurs only in a few people.[169] Remaining people are considered cured but continue to experience subjective symptoms, e.g. joint or muscle pains or fatigue.[171] These symptoms usually are mild and nondisabling.[171]

People treated only after nervous system manifestations of the disease may end up with objective neurological deficits, in addition to subjective symptoms.[29] In Europe, an average of 32–33 months after initial Lyme symptoms in people treated mostly with doxycycline 200 mg for 14–21 days, the percentage of people with lingering symptoms was much higher among those diagnosed with neuroborreliosis (50%) than among those with only an EM rash (16%).[172] In another European study, 5 years after treatment for neuroborreliosis, lingering symptoms were less common among children (15%) than adults (30%), and in the latter was less common among those treated within 30 days of the first symptom (16%) than among those treated later (39%); among those with lingering symptoms, 54% had daily activities restricted and 19% were on sick leave or incapacitated.[173]

Some data suggest that about 90% of Lyme facial palsies treated with antibiotics recover fully a median of 24 days after appearing and most of the rest recover with only mild abnormality.[174][175] However, in Europe 41% of people treated for facial palsy had other lingering symptoms at followup up to 6 months later, including 28% with numbness or altered sensation and 14% with fatigue or concentration problems.[175] Palsies in both sides of the face are associated with worse and longer time to recovery.[174][175] Historical data suggests that untreated people with facial palsies recover at nearly the same rate, but 88% subsequently have Lyme arthritis.[174][176] Other research shows that synkinesis (involuntary movement of a facial muscle when another one is voluntarily moved) can become evident only 6–12 months after facial palsy appears to be resolved, as damaged nerves regrow and sometimes connect to incorrect muscles.[177] Synkinesis is associated with corticosteroid use.[177] In longer-term follow-up, 16–23% of Lyme facial palsies do not fully recover.[177]

In Europe, about a quarter of people with Bannwarth syndrome (Lyme radiculopathy and lymphocytic meningitis) treated with intravenous ceftriaxone for 14 days an average of 30 days after first symptoms had to be retreated 3–6 months later because of unsatisfactory clinical response or continued objective markers of infection in cerebrospinal fluid; after 12 months, 64% recovered fully, 31% had nondisabling mild or infrequent symptoms that did not require regular use of analgesics, and 5% had symptoms that were disabling or required substantial use of analgesics.[33] The most common lingering nondisabling symptoms were headache, fatigue, altered sensation, joint pains, memory disturbances, malaise, radicular pain, sleep disturbances, muscle pains, and concentration disturbances. Lingering disabling symptoms included facial palsy and other impaired movement.[33]

Recovery from late neuroborreliosis tends to take longer and be less complete than from early neuroborreliosis, probably because of irreversible neurologic damage.[29]

About half the people with Lyme carditis progress to complete heart block, but it usually resolves in a week.[36] Other Lyme heart conduction abnormalities resolve typically within 6 weeks.[36] About 94% of people have full recovery, but 5% need a permanent pacemaker and 1% end up with persistent heart block (the actual percentage may be higher because of unrecognized cases).[36] Lyme myocardial complications usually are mild and self-limiting.[36] However, in some cases Lyme carditis can be fatal.[36]

Recommended antibiotic treatments are effective in about 90% of Lyme arthritis cases, although it can take several months for inflammation to resolve and a second round of antibiotics is often necessary.[29] Antibiotic-refractory Lyme arthritis also eventually resolves, typically within 9–14 months (range 4 months – 4 years); DMARDs or synovectomy can accelerate recovery.[168]

Reinfection is not uncommon. In a U.S. study, 6–11% of people treated for an EM rash had another EM rash within 30 months.[169] The second rash typically is due to infection by a different Borrelia strain.[178]

People who have nonspecific, subjective symptoms such as fatigue, joint and muscle aches, or cognitive difficulties for more than six months after recommended treatment for Lyme disease are said to have post-treatment Lyme disease syndrome. As of 2016 the reason for the lingering symptoms was not known; the condition is generally managed similarly to fibromyalgia or chronic fatigue syndrome.[179]

Lyme disease occurs regularly in Northern Hemisphere temperate regions.[180]

Africa

In northern Africa, B. burgdorferi sensu lato has been identified in Morocco, Algeria, Egypt and Tunisia.[181][182][183]

Lyme disease in sub-Saharan Africa is presently unknown, but evidence indicates it may occur in humans in this region. The abundance of hosts and tick vectors would favor the establishment of Lyme infection in Africa.[184] In East Africa, two cases of Lyme disease have been reported in Kenya.Morocco, Algeria, Egypt and Tunisia.[181][182][183]

Lyme disease in sub-Saharan Africa is presently unknown, but evidence indicates it may occur in humans in this region. The abundance of hosts and tick vectors would favor the establishment of Lyme infection in Africa.[184] In East Africa, two cases of Lyme disease have been reported in Kenya.[185]

B. burgdorferi sensu lato-infested ticks are being found more frequently in Japan, as well as in northwest China, Nepal, Thailand and far eastern Russia.[186][187] Borrelia has also been isolated in Mongolia.[188]

Europe

In Europe, Lyme disease is caused by infection with one or more pathogenic European genospecies of the spirochaete B. burgdorferi sensu lato, mainly transmitted by the tick Ixodes ricinus.[189] Cases of B. burgdorferi sensu lato-infected ticks are found predominantly in central Europe, particularly in Slovenia and Austria, but have been isolated in almost every country on the continent.[190] Number of cases in southern Europe, such as Italy and Portugal, is much lower.[191]

United Kingdom