Lyme disease

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 the knee, on the trunk, under clothing straps, or in children's hair, ears or neck.[29][3] Most people who get infected do not remember seeing a tick or a 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).[29][3][30] The rash is usually circular or oval, red or bluish, and may have an elevated or darker center.[3][31][32] 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.[30][31][32] 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.[3]

The EM 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 has disappeared. Lyme can progress to later stages without these symptoms or a rash.[3]

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.[37]

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.[29] Transient muscle pains and joint pains are also common.[29]

In about 10–15% of untreated people Lyme causes neurological problems known as neuroborreliosis.[38] 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.[37][39] 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.[40] After several months neuroborreliosis can also present otolaryngological symptoms. Up to 76.5% of these otolaryngological present as tinnitus, the most common symptom. Vertigo and dizziness (53.7%) and hearing loss (16.7%) were the next most common symptoms.[41] In children partial loss of vision may also occur.[37] Cranial neuritis is an inflammation of cranial nerves. When due to Lyme it most typically causes facial palsy, impairing blinking, smiling and chewing on one or both sides of the face. It may also cause intermittent double vision.[37][40] 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.[39][42] Mononeuritis multiplex is an inflammation causing similar symptoms in one or more unrelated peripheral nerves.[38][37] 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.[37][39]

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.[37][43] Lyme radiculopathy is reported half as frequently, but many cases may be unrecognized.[44] 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.[39][42] 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.[42] In extreme cases, permanent impairment of motor or sensory function of the lower limbs may occur.[36] In European children, the most common manifestations are facial palsy (in 55%), other cranial neuritis, and lymphocytic meningitis (in 27%).[39]

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.[45][46] Symptoms may include heart palpitations (in 69% of people), dizziness, fainting, shortness of breath, and chest pain.[45] Other symptoms of Lyme disease may also be present, such as EM rash, joint aches, facial palsy, headaches, or radicular pain.[45] In some people, however, carditis may be the first manifestation of Lyme disease.[45] 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.[45][46] In 10–15% of people, Lyme causes myocardial complications such as cardiomegaly, left ventricular dysfunction, or congestive heart failure.[45]

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.[47]

Lyme arthritis occurs in up to 60% of untreated people, typically starting about six months after infection.[29] It usually affects only one or a few joints, often a knee or possibly the hip, other large joints, or the temporomandibular joint.[37][48] There is usually large joint effusion and swelling, but only mild or moderate pain.[37] Without treatment, swelling and pain typically resolve over time but periodically return.[37] Baker's cysts may form and rupture.

In early US studies of Lyme disease, a rare peripheral neuropathy was described that included numbness, tingling or burning starting at the feet or hands and over time possibly moving up the limbs. In a later analysis that discovered poor documentation of this manifestation, experts wondered if it exists at all in the US or is merely very rare.[37][49]

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.[50] However, problems such as depression and fibromyalgia are as common in people with Lyme disease as in the general population.[51][52]

Acrodermatitis chronica atrophicans (ACA) is a chronic skin disorder observed primarily in Europe among the elderly.[47] 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.[53] ACA is also associated with peripheral neuropathy.[49]

Deer tick life cycle

Ixodes scapularis, the primary vector of Lyme disease in eastern North America

There are three stages in the life cycle of a tick. Larva, nymph, and adult. During the nymph stage, ticks most frequently transmit Lyme disease and are usually most active in late spring and early summer in regions where the climate is mild. During the adult stage, Lyme disease transmission is less common due to the fact that it is less possible for adult ticks to bite humans and because they tend to be larger in size and therefore can be easily seen and removed.[60]

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.[61] Hard-bodied ticks of the genus Ixodes are the vectors of Lyme disease (also the vector for Babesia).[62] 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.[61] Nymphal ticks are generally the size of a poppy seed and sometimes with a dark head and a translucent body.[63] Or, the nymphal ticks can be darker.[64] (The younger larval ticks are very rarely infected.[65]) 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.[66] Areas where Lyme is common are expanding.[67]

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.[68] Successful infection of the mammalian host depends on bacterial expression of OspC.[69]

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.[70]

Tick Ixodes ricinus, developmental stages

In Europe, the main vector is Ixodes ricinus, which is also called the sheep tick or castor bean tick.[71] In China, Ixodes persulcatus (the taiga tick) is probably the most important vector.[72] In North America, the black-legged tick or deer tick (Ixodes scapularis) is the main vector on the East Coast.[65]

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,[73] though it may be implicated in a related syndrome called southern tick-associated rash illness, which resembles a mild form of Lyme disease.[74]

On the West Coast of the United States, the main vector is the western black-legged tick (Ixodes pacificus).[75] 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.[76][77]

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.[78][79][80][81][82]

There is no scientific evidence to support Lyme disease transmission via blood transfusion, sexual contact, or breast milk.[83]

Ticks that transmit B. burgdorferi to humans can also carry and transmit several other parasites, such as Babesia microti and Anaplasma phagocytophilum, which cause the diseases babesiosis and human granulocytic anaplasmosis (HGA), respectively.[84] Among people with early Lyme disease, depending on their location, 2–12% will also have HGA and 2–40% will have babesiosis.[85] Ticks in certain regions, including the lands along the eastern Baltic Sea, also transmit viruses that cause tick-borne encephalitis.[86]

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 detected two pathogens in 10% of the ticks.[87]

Exposure to the Borrelia bacterium during Lyme disease possibly causes a long-lived and damaging inflammatory response,[102] a form of pathogen-induced autoimmune disease.[103] 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.[104][105]

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.[106][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.[115] 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.[116] 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.[37] 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.[116] A positive IgM and negative IgG test result after the first month of infection is generally indicative of a false-positive result.[117] The number of IgM antibodies usually collapses 4–6 months after infection, while IgG antibodies can remain detectable for years.[116]

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.[40][37][42] Additionally, the immune system produces antibodies against Lyme inside the intrathecal space, which contains the CSF.[37][42] 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).[39] 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.[118] American guidelines consider CSF analysis optional when symptoms appear to be confined to the peripheral nervous system (PNS), e.g. facial palsy without overt meningitis symptoms.[37][119] 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.[42] In infection involving the PNS, electromyography and nerve conduction studies can be used to monitor objectively the response to treatment.[40]

In Lyme carditis, electrocardiograms are used to evidence heart conduction abnormalities, while echocardiography may show myocardial dysfunction.[45] 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.[45]

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.[120][39] 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.[121][39] 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.[122] 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.[39]

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.[123] The use of nanotrap particles for their detection is being looked at and the OspA has been linked to active symptoms of Lyme.[124][125] 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.[126]

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.[121]

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.[127] 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.[128]

Community clinics have been reported to misdiagnose 23–28% of Erythema migrans (EM) rashes and 83% of other objective manifestations of early Lyme disease.[112] EM rashes are often misdiagnosed as spider bites, cellulitis, or shingles.[112] Many misdiagnoses are credited to the widespread misconception that EM rashes should look like a bull's eye.[3] Actually, the key distinguishing features of the EM rash are the speed and extent to which it expands, respectively up to 2–3 cm/day and a diameter of at least 5 cm, and in 50% of cases more than 16 cm. The rash expands away from its center, which may or may not look different or be separated by ring-like clearing from the rest of the rash.[29][30] Compared to EM rashes, spider bites are more common in the limbs, tend to be more painful and itchy or become swollen, and some may cause necrosis (sinking dark blue patch of dead skin).[29][3] Cellulitis most commonly develops around a wound or ulcer, is rarely circular, and is more likely to become swollen and tender.[29][3] EM rashes often appear at sites that are unusual for cellulitis, such as the armpit, groin, abdomen, or back of knee.[29] Like Lyme, shingles often begins with headache, fever, and fatigue, which are followed by pain or numbness. However, unlike Lyme, in shingles these symptoms are usually followed by appearance of rashes composed of multiple small blisters along with a nerve's dermatome, and shingles can also be confirmed by quick laboratory tests.[129]

Facial palsy caused by Lyme disease (LDFP) is often misdiagnosed as Bell's palsy.[43] Although Bell's palsy is the most common type of one-sided facial palsy (about 70% of cases), LDFP can account for about 25% of cases of facial palsy in areas where Lyme disease is common.[43] Compared to LDFP, Bell's palsy much less frequently affects both sides of the face.[43] Even though LDFP and Bell's palsy have similar symptoms and evolve similarly if untreated, corticosteroid treatment is beneficial for Bell's Palsy, while being detrimental for LDFP.[43] Recent history of exposure to a likely tick habitat during warmer months, EM rash, viral-like symptoms such as headache and fever, and/or palsy in both sides of the face should be evaluated for the likelihood of LDFP; if it is more than minimal, empiric therapy with antibiotics should be initiated, without corticosteroids, and reevaluated upon completion of laboratory tests for Lyme disease.[43]

Unlike viral meningitis, Lyme lymphocytic meningitis tends to not cause fever, last longer, and recur.[40][37] Lymphocytic meningitis is also characterized by possibly co-occurring with EM rash, facial palsy, or partial vision obstruction and having much lower percentage of polymorphonuclear leukocytes in CSF.[37]

Lyme radiculopathy affecting the limbs is often misdiagnosed as a radiculopathy caused by nerve root compression, such as sciatica.[112][130] Although most cases of radiculopathy are compressive and resolve with conservative treatment (e.g., rest) within 4–6 weeks, guidelines for managing radiculopathy recommend first evaluating risks of other possible causes that, although less frequent, require immediate diagnosis and treatment, including infections such as Lyme and shingles.[131] A history of outdoor activities in likely tick habitats in the last 3 months possibly followed by a rash or viral-like symptoms, and current headache, other symptoms of lymphocytic meningitis, or facial palsy would lead to suspicion of Lyme disease and recommendation of serological and lumbar puncture tests for confirmation.[131]

Lyme radiculopathy affecting the trunk can be misdiagnosed as myriad other conditions, such as diverticulitis and acute coronary syndrome.[44][112] Diagnosis of late-stage Lyme disease is often complicated by a multifaceted appearance and nonspecific symptoms, prompting one reviewer to call Lyme the new "great imitator".[132] As all people with later-stage infection will have a positive antibody test, simple blood tests can exclude Lyme disease as a possible cause of a person's symptoms.[133]

Removal of a tick using tweezers

Attached ticks should be removed promptly. Risk of infection increases with time of attachment, but in North America risk of Lyme disease is small if the tick is removed within 36 hours.[146] CDC recommends inserting a fine-tipped tweezer between the skin and the tick, grasping very firmly, and pulling the closed tweezer straight away from the skin without twisting, jerking, squeezing or crushing the tick.[147] After tick removal, any tick parts remaining in the skin should be removed with a clean tweezer, if possible.[147] The wound and hands should then be cleaned with alcohol or soap and water.[147] The tick may be disposed by placing it in a container with alcohol, sealed bag, tape or flushed down the toilet.[147] The bitten person should write down where and when the bite happened so that this can be informed to a doctor if the person gets a rash or flu-like symptoms in the following several weeks.[147] CDC recommends not using fingers, nail polish, petroleum jelly or heat on the tick to try to remove it.[147]

In Australia, where the Australian paralysis tick is prevalent, the Australasian Society of Clinical Immunology and Allergy recommends not using tweezers to remove ticks, because if the person is allergic, anaphylaxis could result.[148] Instead, a product should be sprayed on the tick to cause it to freeze and then drop off.[148] A doctor would use liquid nitrogen, but products available from chemists for freezing warts can be used instead.[149] Another method originating from Australia consists in using about 20 cm of dental floss or fishing line for slowly tying an overhand knot between the skin and the tick and then pulling it away from the skin.[150][151]

The risk of infectious transmission increases with the duration of tick attachment.[29] It requires between 36 and 48 hours of attachment for the bacteria that causes Lyme to travel from within the tick into its saliva.[29] If a deer tick that is sufficiently likely to be carrying Borrelia is found attached to a person and removed, and if the tick has been attached for 36 hours or is engorged, a single dose of doxycycline administered within the 72 hours after removal may reduce the risk of Lyme disease. It is not generally recommended for all people bitten, as development of infection is rare: about 50 bitten people would have to be treated this way to prevent one case of erythema migrans (i.e. the typical rash found in about 70–80% of people infected).[3][29]

Several landscaping practices may reduce the risk of tick bites in residential yards.[145][152] These include keeping lawns mowed, removing leaf litter and weeds, and avoiding the use of ground cover.[145] A 3-ft-wide rock or woodchip barrier is recommended to separate lawns from wood piles, woodlands, stone walls, and shrubs.[152] Without vegetation on the barrier, ticks will tend not to cross it; acaricides may also be sprayed on it to kill ticks.[152] 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.[152] Materials such as wood decking, concrete, bricks, gravel or woodchips used on the ground under patios and playgrounds would discourage ticks there.[145] An 8-ft-high fence may be added to keep deer away from the tick-safe zone.[152][145]

Outdoor 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.[153][154] 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.[155]

Ticks can feed upon the blood of a wide array of possible host species, including lizards, birds, mice, cats, dogs, deer, cattle and humans. The extent to which a tick can feed, reproduce, and spread will depend on the type and availability of its hosts. Whether it will spread disease is also affected by its available hosts. Some species, such as lizards, are referred to as "dilution hosts" because they don't tend to support Lyme disease pathogens and so decrease the likelihood that the disease will be passed on by ticks feeding on them. White-tailed deer are both a food source and a "reproductive host", where ticks tend to mate. The white-footed mouse is a reservoir host in which the pathogen for Lyme disease can survive. Availability of hosts can have significant impacts on the transmission of Lyme disease. A greater diversity of hosts, or of those that don't support the pathogen, tends to decrease the likelihood that the disease will be transmitted.[156]

In the United States, one approach to reducing the incidence of Lyme and other deer tick-borne diseases has been to greatly reduce 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,[157] and following deer control in Mumford Cove, Connecticut.[158] Advocates have suggested reducing the deer population to levels of 8 to 10 deer per square mile, compared to levels of 60 or more deer per square mile in the areas of the country with the highest Lyme disease rates.[159]

Others have noted that while deer are reproductive hosts, they are not Borrelia burgdorferi reservoirs. Researchers have suggested that smaller, less obviously visible Lyme reservoirs, like white-footed mice and Eastern chipmunks, may more strongly impact Lyme disease occurrence. Ecosystem studies in New York state suggest that white-footed mice thrive when forests are broken into smaller isolated chunks of woodland with fewer rodent predators. With more rodents harboring the disease, the odds increase that a tick will feed on a disease-harboring rodent and that someone will pick up a disease-carrying tick in their garden or walking in the woods. Data indicates that the smaller the wooded area, the more ticks it will contain and the likely they are to carry Lyme disease, supporting the idea that deforestation and habitat fragmentation affect ticks, hosts and disease transmission.[156]

Tick-borne diseases are estimated to affect ~80 % of cattle worldwide.[160] They also affect cats, dogs, and other pets. Routine veterinary control of ticks of domestic animals through the use of acaricides has been suggested as a way to reduce exposure of humans to ticks. However, chemical control with acaricides is now criticized on a number of grounds. Ticks appear to develop resistance to acaricides; acaricides are costly; and there are concerns over their toxicity and the potential for chemical residues to affect food and the environment.[161]

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).[162] 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.[162] "The reservoir species that contain the most pathogens are the European roe deer Capreolus capreolus;[163] "it does not appear to serve as a major reservoir of B. burgdorferi" thought Jaenson & al. (1992)[164] (incompetent host for B. burgdorferi and TBE virus) but it is important for feeding the ticks,[165] as red deer and wild boars (Sus scrofa),[166] in which one Rickettsia and three Borrelia species were identified",[163] with high risks of coinfection in roe deer.[167] Nevertheless, in the 2000s, in roe deer in Europe "two species of Rickettsia and two species of Borrelia were identified".[166]

The vaccine LYMErix was available from 1998 to 2002. The recombinant vaccine against Lyme disease, based on the outer surface protein A (OspA) of B. burgdorferi with aluminum hydroxide as adjuvant, was developed by SmithKline Beecham. In clinical trials involving more than 10,000 people, the vaccine was found to confer protective immunity to Lyme disease in 76% of adults after three doses with only mild or moderate and transient adverse effects.[169][170] On 21 December 1998, the Food and Drug Administration (FDA) approved LYMErix on the basis of these trials for persons of ages 15 through 70.[170][168]

Following approval of the vaccine, its entry into clinical practice was slow for a variety of reasons, including its cost, which was often not reimbursed by insurance companies.[171] 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.[172]

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,[173] in the setting of negative media coverage and fears of vaccine side effects.[172][174] The fate of LYMErix was described in the medical literature as a "cautionary tale";[174] 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."[175] 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."[172][176]

The hexavalent (OspA) protein subunit-based vaccine candidate VLA15 was developed by Valneva. It was granted fast track designation by the U.S. Food and Drug Administration in July 2017.[177][178] In April 2020 Pfizer paid $130 million for the rights to the vaccine, and the companies are developing it together, performing multiple phase 2 trials.[179]

A phase 3 trial of VLA15 was scheduled for late 2022, recruiting volunteers at test sites located across the northeastern United States and in Europe.[180][181] Participants were scheduled to receive an initial three-dose series of vaccines over the course of five to nine months, followed by a booster dose after twelve months, with both the initial series and the booster dose scheduled to be complete before the year's peak Lyme disease season.[181]

An mRNA vaccine designed to cause a strong fast immune response to tick saliva allowed the immune system to detect and remove the ticks from test animals before they were able to transmit the infectious bacteria.[182] The vaccine contains mRNAs for the body to build 19 proteins in tick saliva which, by enabling quick development of erythema (itchy redness) at the bite site, protects guinea pigs against Lyme disease. It also protected the test animals if the tick is not removed if only one tick, but not three, remain attached.[183][184]

Canine vaccines have been formulated and approved for the 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.[185]

In northern Africa, B. burgdorferi sensu lato has been identified in Morocco, Algeria, Egypt and Tunisia.[203][204][205]

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.[206] In East Africa, two cases of Lyme disease have been reported in Kenya.[207]

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.[208][209] Borrelia has also been isolated in Mongolia.[210]

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.[211] 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.[212] Number of cases in southern Europe, such as Italy and Portugal, is much lower.[213] Diagnosed cases in some Western countries, such as Iceland, are rising.[214]

In the United Kingdom the number of laboratory confirmed cases of Lyme disease has been rising steadily since voluntary reporting was introduced in 1986[215] when 68 cases were recorded in the UK and Ireland combined.[216] In the UK there were 23 confirmed cases in 1988 and 19 in 1990,[217] but 973 in 2009[215] and 953 in 2010.[218] Provisional figures for the first 3 quarters of 2011 show a 26% increase on the same period in 2010.[219]

It is thought, however, that the actual number of cases is significantly higher than suggested by the above figures, with the UK's Health Protection Agency estimating that there are between 2,000 and 3,000 cases per year,[218] (with an average of around 15% of the infections acquired overseas[215]), while Dr Darrel Ho-Yen, Director of the Scottish Toxoplasma Reference Laboratory and National Lyme Disease Testing Service, believes that the number of confirmed cases should be multiplied by 10 "to take account of wrongly diagnosed cases, tests giving false results, sufferers who weren't tested, people who are infected but not showing symptoms, failures to notify and infected individuals who don't consult a doctor."[220][221]

Despite Lyme disease (Borrelia burgdorferi infection) being a notifiable disease in Scotland[222] since January 1990[223] which should therefore be reported on the basis of clinical suspicion, it is believed that many GPs are unaware of the requirement.[224] Mandatory reporting, limited to laboratory test results only, was introduced throughout the UK in October 2010, under the Health Protection (Notification) Regulations 2010.[215]

Although there is a greater number of cases of Lyme disease in the New Forest, Salisbury Plain, Exmoor, the South Downs, parts of Wiltshire and Berkshire, Thetford Forest[225] and the West coast and islands of Scotland,[226] infected ticks are widespread, and can even be found in the parks of London.[217][227] A 1989 report found that 25% of forestry workers in the New Forest were seropositive, as were between 2% and 4–5% of the general local population of the area.[228][229]

Tests on pet dogs carried out throughout the country in 2009 indicated that around 2.5% of ticks in the UK may be infected, considerably higher than previously thought.[230][231] It is thought that global warming may lead to an increase in tick activity in the future, as well as an increase in the amount of time that people spend in public parks, thus increasing the risk of infection.[232]

Many studies in North America have examined ecological and environmental correlates of the number of people affected by Lyme disease. A 2005 study using climate suitability modelling of I. scapularis projected that climate change would cause an overall 213% increase in suitable vector habitat by 2080, with northward expansions in Canada, increased suitability in the central U.S., and decreased suitable habitat and vector retraction in the southern U.S.[233] A 2008 review of published studies concluded that the presence of forests or forested areas was the only variable that consistently elevated the risk of Lyme disease whereas other environmental variables showed little or no concordance between studies.[234] The authors argued that the factors influencing tick density and human risk between sites are still poorly understood, and that future studies should be conducted over longer time periods, become more standardized across regions, and incorporate existing knowledge of regional Lyme disease ecology.[234]

The range of ticks able to carry Lyme disease has expanded from a limited area of Ontario to include areas of southern Quebec, Manitoba, northern Ontario, southern New Brunswick, southwest Nova Scotia and limited parts of Saskatchewan and Alberta, as well as British Columbia. Cases have been reported as far east as the island of Newfoundland.[111][235][236][237] A model-based prediction by Leighton et al. (2012) suggests that the range of the I. scapularis tick will expand into Canada by 46 km/year over the next decade, with warming climatic temperatures as the main driver of increased speed of spread.[238]

A 2007 study suggests Borrelia burgdorferi infections are endemic to Mexico, from four cases reported between 1999 and 2000.[239]

CDC map showing the risk of Lyme disease in the United States, particularly its concentration in the Northeast Megalopolis and western Wisconsin

In 2019, according to the CDC, there were approximately 35,000 confirmed and probable cases in the U.S. with incidences occurring in almost every state.[240] The CDC is currently conducting research on evaluation and diagnostics of the disease and preliminary results suggest the number of new cases to be around 300,000.[241][242]

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. Of cases reported to the United States CDC, the ratio of Lyme disease infection is 7.9 cases for every 100,000 persons. In the ten states where Lyme disease is most common, the average was 31.6 cases for every 100,000 persons for the year 2005.[243][244][245]

Although Lyme disease has been reported in all states[241][246] about 99% of all reported cases are confined to just five geographic areas (New England, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central).[247] New 2011 CDC Lyme case definition guidelines are used to determine confirmed CDC surveillance cases.[248]

Effective January 2008, the CDC gives equal weight to laboratory evidence from 1 a positive culture for B. burgdorferi; 2) two-tier testing (ELISA screening and Western blot confirming); or 3) single-tier IgG (old infection) Western blot.[249] Previously, the CDC only included laboratory evidence based on (1) and (2) in their surveillance case definition. The case definition now includes the use of Western blot without prior ELISA screen.[249]

The number of reported cases of the disease has been increasing, as are endemic regions in North America. For example, B. burgdorferi sensu lato was previously thought to be hindered in its ability to be maintained in an enzootic cycle in California, because it was assumed the large lizard population would dilute the number of people affected by B. burgdorferi in local tick populations; this has since been brought into question, as some evidence has suggested lizards can become infected.[250]

Except for one study in Europe,[251] much of the data implicating lizards is based on DNA detection of the spirochete and has not demonstrated that lizards are able to infect ticks feeding upon them.[250][252][253][254] As some experiments suggest lizards are refractory to infection with Borrelia, it appears likely their involvement in the enzootic cycle is more complex and species-specific.[77]

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

Several similar but apparently distinct conditions may exist, caused by various species or subspecies of Borrelia in North America. A regionally restricted condition that may be related to Borrelia infection is southern tick-associated rash illness (STARI), also known as Masters disease. Amblyomma americanum, known commonly as the lone-star tick, is recognized as the primary vector for STARI. In some parts of the geographical distribution of STARI, Lyme disease is quite rare (e.g., Arkansas), so people in these regions experiencing Lyme-like symptoms—especially if they follow a bite from a lone-star tick—should consider STARI as a possibility. It is generally a milder condition than Lyme and typically responds well to antibiotic treatment.[255]

In recent years there have been 5 to 10 cases a year of a disease similar to Lyme occurring in Montana. It occurs primarily in pockets along the Yellowstone River in central Montana. People have developed a red bull's-eye rash around a tick bite followed by weeks of fatigue and a fever.[246]

Lyme disease effects are comparable among males and females. A wide range of age groups is affected, though the number of cases is highest among 10- to 19-year-olds. For unknown reasons, Lyme disease is seven times more common among Asians.[256]

In South America, tick-borne disease recognition and occurrence is rising. In Brazil, a Lyme-like disease known as Baggio–Yoshinari syndrome was identified, caused by microorganisms that do not belong to the B. burgdorferi sensu lato complex and transmitted by ticks of the Amblyomma and Rhipicephalus genera.[257] The first reported case of BYS in Brazil was made in 1992 in Cotia, São Paulo.[258]

The term "chronic Lyme disease" is controversial and not recognized in the medical literature,[290] and most medical authorities advise against long-term antibiotic treatment for Lyme disease.[37][119][291] Studies have shown that most people diagnosed with "chronic Lyme disease" either have no objective evidence of previous or current infection with B. burgdorferi or are people who should be classified as having post-treatment Lyme disease syndrome (PTLDS), which is defined as continuing or relapsing non-specific symptoms (such as fatigue, musculoskeletal pain, and cognitive complaints) in a person previously treated for Lyme disease.[292]

The 2008 documentary Under Our Skin is known for promoting conspiracy theories about "chronic Lyme disease".[293]

Prevention of Lyme disease is an important step in keeping dogs safe in endemic areas. Prevention education and a number of preventive measures are available. First, for dog owners who live near or who often frequent tick-infested areas, routine vaccinations of their dogs is an important step.[294]

Another crucial preventive measure is the use of persistent acaricides, such as topical repellents or pesticides that contain triazapentadienes (Amitraz), phenylpyrazoles (Fipronil), or permethrin (pyrethroids).[295] These acaricides target primarily the adult stages of Lyme-carrying ticks and reduce the number of reproductively active ticks in the environment.[294] Formulations of these ingredients are available in a variety of topical forms, including spot-ons, sprays, powders, impregnated collars, solutions, and shampoos.[295]

Examination of a dog for ticks after being in a tick-infested area is an important precautionary measure to take in the prevention of Lyme disease. Key spots to examine include the head, neck, and ears.[296]

In dogs, a serious long-term prognosis may result in glomerular disease,[297] which is a category of kidney damage that may cause chronic kidney disease.[185] Dogs may also experience chronic joint disease if the disease is left untreated. However, the majority of cases of Lyme disease in dogs result in complete recovery with, and sometimes without, treatment with antibiotics.[298] In rare cases, Lyme disease can be fatal to both humans and dogs.[299]