Lyme disease

From Wikipedia, the free encyclopedia
  (Redirected from Lyme Disease)
Jump to: navigation, search
Lyme disease
Classification and external resources
Adult deer tick.jpg
Nymphal and adult deer ticks can be carriers of Lyme disease. Nymphs are about the size of a poppy seed.
ICD-10 A69.2
ICD-9 088.81
DiseasesDB 1531
MedlinePlus 001319
eMedicine article/330178 article/965922 article/786767
Patient UK Lyme disease
MeSH D008193

Lyme disease (Lyme borreliosis) is an infectious disease caused by at least three species of bacteria belonging to the genus Borrelia.,[1][2][3] transmitted via the bite of an infected tick. Early symptoms may include fever, headache, and fatigue. A rash occurs in 70–80% of infected persons at the site of the bite after a delay of 3–30 days (average is about 7 days), and may or may not appear as the well-publicized bull's-eye (erythema migrans). The rash is rarely painful or itchy, although it may be warm to the touch. About 20–30% of infected persons do not experience a rash.[4][5] Left untreated, later symptoms may involve the joints, heart, and central nervous system. In most cases, the infection and its symptoms are eliminated by antibiotics, especially if the illness is treated early.[6][7] Delayed or inadequate treatment can lead to more serious symptoms, which can be disabling and difficult to treat.[8]

Borrelia burgdorferi sensu stricto[9] is the main cause of Lyme disease in North America, whereas Borrelia afzelii and Borrelia garinii cause most European cases. Borrelia is transmitted to humans by the bite of infected ticks belonging to a few species of the genus Ixodes ("hard ticks").[10] Lyme disease is the most common tick-borne disease in the Northern Hemisphere.[11]

The term "chronic Lyme disease" is controversial and not recognized in the medical literature,[12] and most medical authorities advise against long-term antibiotic treatment for "chronic Lyme disease".[13][14][15]

The first known existence of the Borrelia bacteria dates back to up to 20 million years ago.[16] The disease is named after the towns of Lyme and Old Lyme, Connecticut, US, where a number of cases were identified in 1975. It was established to be a tick-borne disease in 1978, and the bacterium responsible was identified in 1981 by entomologist Dr. Willy Burgdorfer.

Signs and symptoms[edit]

This "classic" bull's-eye appearance is also called erythema migrans. A rash caused by Lyme does not always look like this. Around 20% to 30% of persons who are infected with Lyme disease may have no rash at all.[4][5]
Raised, red borders around indurated central portion

Lyme disease can affect multiple body systems and produce a range of symptoms. Not all patients with Lyme disease will have all 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).[17]

Symptoms most often occur from May to September, because the nymphal stage of the tick is responsible for most cases.[17] Asymptomatic infection exists, but occurs in less than 7% of infected individuals in the United States.[18] Asymptomatic infection may be much more common among those infected in Europe.[19][20]

Early localized infection[edit]

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 classic sign of early local infection with Lyme disease is a circular, outwardly expanding rash called erythema chronicum migrans (also erythema migrans or EM), which occurs at the site of the tick bite three to 30 days after the tick bite.[21][22] The rash is red, and may be warm, but is generally painless. Classically, the innermost portion remains dark red and becomes indurated (is thicker and firmer); the outer edge remains red; and the portion in between clears, giving the appearance of a bull's eye. However, partial clearing is uncommon, and the bull's-eye pattern more often involves central redness.[23]

The EM rash associated with early infection is found in about 80% of patients[22] and can have a range of appearances including the classic target bull's-eye lesion and nontarget appearing lesions. The 20% without the EM and the nontarget lesions can often cause misidentification of Lyme disease.[24] Patients can also experience flu-like symptoms, such as headache, muscle soreness, fever, and malaise.[25] Lyme disease can progress to later stages even in patients who do not develop a rash.[19][26]

Early disseminated infection[edit]

Within days to weeks after the onset of local infection, the Borrelia bacteria may begin to spread through the bloodstream. EM may develop at sites across the body that bear no relation to the original tick bite.[27] Another skin condition, apparently absent in North American patients, but found in Europe, is borrelial lymphocytoma, a purplish lump that develops on the ear lobe, nipple, or scrotum.[28] Other discrete symptoms include migrating pain in muscles, joints and tendons, and dizziness.

Borrelial lymphocytoma on the cheek (very uncommon)

Various acute neurological problems, termed neuroborreliosis, appear in 10–15% of untreated patients.[25][29] These include facial palsy, which is the loss of muscle tone on one or both sides of the face, as well as meningitis, which involves severe headaches, neck stiffness, and sensitivity to light. Radiculoneuritis causes shooting pains that may interfere with sleep, as well as abnormal skin sensations. Mild encephalitis may lead to memory loss, sleep disturbances, or mood changes. In addition, some case reports have described altered mental status as the only symptom seen in a few cases of early neuroborreliosis.[30] The disease may also have cardiac manifestations such as atrioventricular block.[31]

Late disseminated infection[edit]

After several months, untreated or inadequately treated patients may go on to develop severe and chronic symptoms that affect many parts of the body, including the brain, nerves, eyes, joints, and heart. Many disabling symptoms can occur, including permanent impairment of motor or sensory function of the lower extremities in extreme cases.[19] The associated nerve pain radiating out from the spine is termed Bannwarth syndrome,[32] named after Alfred Bannwarth.

The late disseminated stage is where the infection has fully spread throughout the body. Chronic neurologic symptoms occur in up to 5% of untreated patients.[25] A polyneuropathy that involves shooting pains, numbness, and tingling in the hands or feet may develop. A neurologic syndrome called Lyme encephalopathy is associated with subtle cognitive problems, such as difficulties with concentration and short-term memory. These patients may also experience fatigue.[33] Other problems, however, such as depression and fibromyalgia, are no more common in people with Lyme disease than in the general population.[33][34]

Chronic encephalomyelitis, which may be progressive, can involve cognitive impairment, 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 patients begin to feel detached from themselves or from reality.[35][36]

Lyme arthritis usually affects the knees.[37] In a minority of patients, arthritis can occur in other joints, including the ankles, elbows, wrists, hips, and shoulders. Pain is often mild or moderate, usually with swelling at the involved joint. Baker's cysts may form and rupture. In some cases, joint erosion occurs.

Acrodermatitis chronica atrophicans (ACA) is a chronic skin disorder observed primarily in Europe among the elderly.[28] 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.[38]

Cause[edit]

Deer tick life cycle
Borrelia bacteria, the causative agent of Lyme disease, magnified
Ixodes scapularis, the primary vector of Lyme disease in eastern North America

Lyme disease is caused by spirochetal bacteria from the genus Borrelia. Spirochetes are surrounded by peptidoglycan and flagella, along with an outer membrane similar to other 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.[39] 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 18 closely related species, but only three clearly cause Lyme disease: B. burgdorferi sensu stricto (predominant in North America, but also present in Europe), B. afzelii, and B. garinii (both predominant in Eurasia).[40] Some studies have also proposed B. bissettii and B. valaisiana may sometimes infect humans, but these species do not seem to be important causes of disease.[41][42]

Transmission[edit]

Lyme disease is classified as a zoonosis, as it is transmitted to humans from a natural reservoir among rodents by ticks that feed on both sets of hosts.[43] Hard-bodied ticks of the genus Ixodes are the main vectors of Lyme disease (also the vector for Babesia).[3] Most infections are caused by ticks in the nymphal stage, as they are very small and may feed for long periods of time undetected.[43] Larval ticks are very rarely infected.[44] Although deer are the preferred hosts of deer ticks, and the size of the tick population parallels that of the deer population, ticks cannot acquire Lyme disease spirochetes from deer. Rather, deer ticks acquire Borrelia microbes from infected rodents, such as the white-footed mouse, Peromyscus leucopus.[45]

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.[46] Successful infection of the mammalian host depends on bacterial expression of OspC.[47]

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% of recognized tick bites resulting in Lyme disease. Transmission may occur within 24 hours of the tick bite.[48]

In Europe, the vector is Ixodes ricinus, which is also called the sheep tick or castor bean tick.[49] In China, Ixodes persulcatus (the taiga tick) is probably the most important vector.[50] In North America, the black-legged tick or deer tick (Ixodes scapularis) is the main vector on the east coast.[44]

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 spirochaetes,[51] though it may be implicated in a related syndrome called southern tick-associated rash illness, which resembles a mild form of Lyme disease.[52]

On the West Coast of the United States, the main vector is the western black-legged tick (Ixodes pacificus).[53] The tendency of this tick species to feed predominantly on host species such as lizards that are resistant to Borrelia infection appears to diminish transmission of Lyme disease in the West.[54][55]

Transmission across the placenta during pregnancy has not been demonstrated, and no consistent pattern of teratogenicity or specific "congenital Lyme borreliosis" has been identified. 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.[56][57]

While Lyme spirochetes have been found in insects as well as ticks,[58] reports of actual infectious transmission appear to be rare.[59] Lyme spirochete DNA has been found in semen[60] and breast milk,[61] but transmission has not been known to take place through sexual contact.[62] According to the CDC, live spirochetes have not been found in breast milk, urine, or semen.[63] However, more recent studies published in 2014, suggest there might be a link.[64]

Tick-borne coinfections[edit]

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.[65] Among early Lyme disease patients, depending on their location, 2–12% will also have HGA and 2–40% will have babesiosis.[66] Ticks in certain regions, including the lands along the eastern Baltic Sea, also transmit tick-borne encephalitis.[67]

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 studied 100 ticks in rural New Jersey, and found 55% of the ticks were infected with at least one of the pathogens.[68]

Pathophysiology[edit]

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.[47][69] Many of the signs and symptoms of Lyme disease are a consequence of the immune response to the spirochete in those tissues.[25]

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.[70] 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.[47] Neutrophils, however, which are necessary to eliminate the spirochetes from the skin, fail to appear in the developing EM lesion. This allows the bacteria to survive and eventually spread throughout the body.[71]

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 disseminated disease. The spread of B. burgdorferi is aided by the attachment of the host protease plasmin to the surface of the spirochete.[72]

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.[48] 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.[73][74]

In the brain, B. burgdorferi may induce astrocytes to undergo astrogliosis (proliferation followed by apoptosis), which may contribute to neurodysfunction.[75] The spirochetes may also induce host cells to secrete products toxic to nerve cells, including quinolinic acid and the cytokines IL-6 and TNF-alpha, which can produce fatigue and malaise.[76][77][78] Both microglia and astrocytes secrete IL-6 and TNF-alpha in the presence of the spirochete.[75][79] This cytokine response may contribute to cognitive impairment.[80]

In Lyme encephalopathy, diffuse white matter pathology can disrupt grey 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 neuronal loss is less common. Resolution of MRI white matter hyperintensities after antibiotic treatment has been observed.[81]

A developing hypothesis is that the chronic secretion of stress hormones as a result of Borrelia infection may reduce the effect of neurotransmitters, or other receptors in the brain by cell-mediated proinflammatory pathways, thereby leading to the dysregulation of neurohormones, specifically glucocorticoids and catecholamines, the major stress hormones.[82][83]

This process is mediated by the hypothalamic-pituitary-adrenal axis. Additionally, 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.[84] Researchers are investigating if this neurohormone secretion is the cause of neuropsychiatric disorders developing in some patients with borreliosis.[85]

Immunological studies[edit]

Exposure to the Borrelia bacterium during Lyme disease possibly causes a long-lived and damaging inflammatory response,[86] a form of pathogen-induced autoimmune disease.[87] 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.[88][89]

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.[90][91]

Persistence[edit]

The National Institute of Health has supported research into bacterial resistance which has demonstrated persistence after antibiotic therapy in several animal models, including mice and primates. However, it was not possible to culture these bacteria and it is not known if they are infectious, or if they contribute to symptom persistence post-treatment.[92]

An in vitro study of isolated B. burgdorferi persisters published in July 2014 showed that front-line antibiotics doxycycline and amoxicillin are ineffective in eradicating persister populations, which may contribute to symptoms post-treatment. The study went on to show that 27 other drug candidates have a higher potential for eradicating these persister populations, and that those drugs may have implications in the development of treatment plans for patients suffering long-term symptoms of Lyme Disease.[93]

Diagnosis[edit]

Lyme disease is diagnosed clinically based on symptoms, objective physical findings (such as EM, facial palsy, or arthritis) or a history of possible exposure to infected ticks, as well as serological blood tests. The EM rash is not always a bull's eye, i.e., it can be solid red. When making a diagnosis of Lyme disease, health care providers should consider other diseases that may cause similar illness. Not all patients infected with Lyme disease develop the characteristic bull's-eye rash, and many may not recall a tick bite.[94]

Because of the difficulty in culturing Borrelia bacteria in the laboratory, diagnosis of Lyme disease is typically based on the clinical exam findings and a history of exposure to endemic Lyme areas.[3] The EM rash, which does not occur in all cases, is considered sufficient to establish a diagnosis of Lyme disease even when serologic blood tests are negative.[95][96] Serological testing can be used to support a clinically suspected case, but is not diagnostic by itself.[3]

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".[97] Lyme disease may be misdiagnosed as multiple sclerosis, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, lupus, Crohn's disease, HIV, or other autoimmune and neurodegenerative diseases. As all patients with later stage infection will have a positive antibody test, simple blood tests can exclude Lyme disease as a possible cause of the patients' symptoms.[98]

Laboratory testing[edit]

Several forms of laboratory testing for Lyme disease are available, some of which have not been adequately validated. The most widely used tests are serologies, which measure levels of specific antibodies in a patient's blood. These tests may be negative in early infection, as the body may not have produced a significant quantity of antibodies, but they are considered a reliable aid in the diagnosis of later stages of Lyme disease.[99] Serologic tests for Lyme disease are of limited use in people lacking objective signs of Lyme disease because of false positive results and cost.[13]

The serological laboratory tests most widely available and employed are the Western blot and ELISA. A two-tiered protocol is recommended by the Centers for Disease Control and Prevention: the sensitive ELISA test is performed first, and if it is positive or equivocal, then the more specific Western blot is run.[100] The reliability of testing in diagnosis remains controversial.[3] Studies show the Western blot IgM has a specificity of 94–96% for patients with clinical symptoms of early Lyme disease.[101][102] The initial ELISA test has a sensitivity of about 70%, and in two-tiered testing, the overall sensitivity is only 64%, although this rises to 100% in the subset of people with disseminated symptoms, such as arthritis.[103]

Erroneous test results have been widely reported in both early and late stages of the disease, and can be caused by several factors, including antibody cross-reactions from other infections, including Epstein-Barr virus and cytomegalovirus,[104] as well as herpes simplex virus.[105] The overall rate of false positives is low, only about 1 to 3%, in comparison to a false negative rate of up to 36% in the early stages of infection using two-tiered testing.[103]

Polymerase chain reaction (PCR) tests for Lyme disease have also been developed to detect the genetic material (DNA) of the Lyme disease spirochete. PCR tests are susceptible to false positive results from poor laboratory technique.[106] Even when properly performed, PCR often shows false negative results with blood and cerebrospinal fluid specimens.[107] Hence, PCR is not widely performed for diagnosis of Lyme disease, but it may have a role in diagnosis of Lyme arthritis, because it is a highly sensitive way of detecting ospA DNA in synovial fluid.[108]

With the exception of culture or PCR, no practical means for detecting the presence of the organism is currently available, as serologic studies only test for antibodies of Borrelia. 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.[109]

Western blot, ELISA, and PCR can be performed by either blood test via venipuncture or cerebrospinal fluid (CSF) via lumbar puncture. Though lumbar puncture is more definitive of diagnosis, antigen capture in the CSF is much more elusive; reportedly, CSF yields positive results in only 10–30% of patients cultured. The diagnosis of neurologic infection by Borrelia should not be excluded solely on the basis of normal routine CSF or negative CSF antibody analyses.[110]

New techniques for clinical testing of Borrelia infection have been developed, such as LTT-MELISA,[111] although the results of studies are contradictory, The first peer reviewed study assessing the diagnostic sensitivity and specificity of the test has been presented in 2012, showing potential for LTT to become a supportive diagnostic tool.[112] Others, such as focus floating microscopy, are under investigation.[113] New research indicates chemokine CXCL13 may also be a possible marker for neuroborreliosis.[114]

Some laboratories offer Lyme disease testing using assays whose accuracy and clinical usefulness have not been adequately established. These tests include urine antigen tests, PCR tests on urine, immunofluorescent staining for cell wall-deficient forms of B. burgdorferi, and lymphocyte transformation tests. The CDC does not recommend these tests, and a stated their use is "of great concern and is strongly discouraged".[107]

In addition to laboratory testing on patients, ticks can be tested after removal from the host. Several laboratories perform PCR testing on live or dead ticks for a panel of tick-borne diseases, including Borrelia, Babesia, and Ehrlichia.[115]

Imaging[edit]

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.[116] Though controversial, some evidence shows certain neuroimaging tests can provide data that are helpful in the diagnosis of a patient. Magnetic resonance imaging (MRI), as well as single-photon emission computed tomography (SPECT) are two of the tests that can identify abnormalities in the brain of a patient 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 the cortex and subcortical white matter. However, SPECT images are known to be not specific because they show a heterogeneous pattern in the imaging. The abnormalities seen in the SPECT images are very similar to those seen in patients with cerebral vacuities and Creutzfeldt-Jakob disease, which makes them questionable.[117]

Prevention[edit]

Protective clothing includes a hat, long-sleeved shirt, and long trousers tucked into socks or boots. Light-colored clothing makes the tick more easily visible before it attaches itself. People should use special care in handling and allowing outdoor pets inside homes because they can bring ticks into the house.

Permethrin sprayed on clothing kills ticks on contact, and is sold for this purpose. Insect repellents with Picaridin, IR3535, DEET, or oil of lemon eucalyptus repel ticks, as well.[118]

A community can reduce the incidence of Lyme disease by reducing the numbers of primary hosts on which the deer tick depends, such as rodents, other small mammals, and deer. Reduction of the deer population may, over time, help break the reproductive cycle of the deer ticks and their ability to flourish in suburban and rural areas.[119]

An unusual, organic approach to control of ticks and prevention of Lyme disease involves the use of domesticated guineafowl. Guineafowl are voracious consumers of insects and arachnids, and have a particular fondness for ticks. Localized use of domesticated guineafowl may reduce dependence on chemical pest-control methods.[120]

Management of host animals[edit]

Lyme and all other deer tick-borne diseases can be prevented on a regional level by reducing the deer population on which the ticks depend for reproductive success. (Although deer ticks do acquire Lyme disease pathogens from rodents and not from deer, the size of the tick population tends to parallel that of the deer population.)[45] This has been demonstrated in the communities of Monhegan, Maine[121] and Mumford Cove, Connecticut.[122]

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), the tick numbers can be brought down to levels too low to spread Lyme and other tick-borne diseases.[123] However, such a drastic reduction may be impractical in many areas. Routine veterinary control of ticks of domestic animals, including livestock, by use of chemical acaricides can contribute to reducing exposure of humans to ticks. However, the risk of acquiring Lyme disease does not depend on the existence of a local deer population, as is commonly assumed. Eliminating deer from smaller areas 2.5 ha (6.2 acres) may in fact lead to an increase in tick density and the rise of "tick-borne disease hotspots".[124]

Action can be taken to avoid getting bitten by ticks by using insect repellants, for example those that contain DEET. DEET-containing repellants are thought to be moderately effective in the prevention of tick bites.[125]

In Europe, "The reservoir species that contain the most pathogens are the European roe deer Capreolus capreolus (incompetent host for B. burgdorferi and TBE virus but important for feeding the ticks), in which two species of Rickettsia and two species of Borrelia were identified, and Sus scrofa, in which one Rickettsia and three Borrelia species were identified",[126] with high risks of coinfection in roe deer.[127]

Vaccination[edit]

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.[128] LYMErix was approved on the basis of these trials by the Food and Drug Administration (FDA) on December 21, 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.[129] Subsequently, hundreds of vaccine recipients reported they had developed autoimmune side effects. Supported by some patient 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 U.S. Centers for Disease Control, which found no connection between the vaccine and the autoimmune complaints.[130]

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,[131] in the setting of negative media coverage and fears of vaccine side effects.[130][132] The fate of LYMErix was described in the medical literature as a "cautionary tale";[132] 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."[133] 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."[130]

New vaccines are being researched using outer surface protein C (OspC) and glycolipoprotein as methods of immunization.[134][135] 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.[136]

Tick removal[edit]

Attached ticks should be removed promptly, as removal within 36 hours can reduce transmission rates.[137] Folk remedies for tick removal tend to be ineffective, offer no advantages in preventing the transfer of disease, and may increase the risks of transmission or infection.[138] The best method is simply to pull the tick out with tweezers as close to the skin as possible, without twisting, and avoiding crushing the body of the tick or removing the head from the tick's body.[139] The risk of infection increases with the time the tick is attached, and if a tick is attached for less than 24 hours, infection is unlikely. However, since these ticks are very small, especially in the nymph stage, prompt detection is quite difficult.[137]

Treatment[edit]

Antibiotics are the primary treatment.[140] The specific approach to their use is dependent on the individual affected and the stage of the disease.[140] 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.[140] Doxycycline is contraindicated in children younger than eight years of age and women who are pregnant or breastfeeding;[140] alternatives to doxycycline are amoxicillin, cefuroxime axetil, and azithromycin.[140] Individuals with early disseminated or late infection may have symptomatic cardiac disease, refractory Lyme arthritis, or neurologic symptoms like meningitis or encephalitis.[140] Intravenous administration of ceftriaxone is recommended as the first choice in these cases;[140] cefotaxime and doxycycline are available as alternatives.[140]

These treatment regimens last from one to four weeks.[140] If joint swelling persists or returns, a second round of antibiotics may be considered.[140] Outside of that, a prolonged antibiotic regimen lasting more than 28 days is not recommended as no clinical evidence shows it to be effective.[140] IgM and IgG antibody levels may be elevated for years even after successful treatment with antibiotics.[140] As antibody levels are not indicative of treatment success, testing for them is not recommended.[140]

The risk of infectious transmission increases with the duration of tick attachment.[140] It requires between 36 and 48 hours of attachment for the bacteria that causes Lyme to travel from within the tick into its saliva.[140] 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.[140]

Prognosis[edit]

For early cases, prompt[Specific Time?] treatment is usually curative.[141] However, the severity and treatment of Lyme disease may be complicated due to late diagnosis, failure of antibiotic treatment, and simultaneous infection with other tick-borne diseases (coinfections), including ehrlichiosis, babesiosis, and immune suppression[citation needed] in the patient.

A meta-analysis published in 2005 found some patients with Lyme disease have fatigue, joint or muscle pain, and neurocognitive symptoms persisting for years, despite antibiotic treatment.[8] Patients with late stage Lyme disease have been shown to experience a level of physical disability equivalent to that seen in congestive heart failure.[142]

In dogs, a serious long-term prognosis may result in glomerular disease,[143] which is a category of kidney damage that may cause chronic kidney disease.[136] 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 a complete recovery with, and sometimes without, treatment with antibiotics.[144][verification needed] In rare cases, Lyme disease can be fatal to both humans and dogs.[145]

Epidemiology[edit]

Countries with reported Lyme disease cases.

Lyme disease is endemic in Northern Hemisphere temperate regions.[146]

Africa[edit]

In northern Africa, B. burgdorferi sensu lato has been identified in Morocco, Algeria, Egypt and Tunisia.[147][148][149]

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.[150] In East Africa, two cases of Lyme disease have been reported in Kenya.[151]

Asia[edit]

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.[152][153] Borrelia has also been isolated in Mongolia.[154]

Europe[edit]

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.[155] 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.[156] Incidence in southern Europe, such as Italy and Portugal, is much lower.[157]

United Kingdom[edit]

In the United Kingdom the number of laboratory confirmed cases of Lyme disease has been rising steadily since voluntary reporting was introduced in 1986[158] when 68 cases were recorded in the UK and Republic of Ireland combined.[159] In the UK there were 23 confirmed cases in 1988 and 19 in 1990,[160] but 973 in 2009[158] and 953 in 2010.[161] Provisional figures for the first 3 quarters of 2011 show a 26% increase on the same period in 2010.[162]

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,[161] (with an average of around 15% of the infections acquired overseas[158]), while Dr Darrel Ho-Yen, Director of the Scottish Toxoplasma Reference Laboratory and National Lyme's 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."[163][164]

Despite Lyme disease (Borrelia burgdorferi infection) being a notifiable disease in Scotland[165] since January 1990[166] which should therefore be reported on the basis of clinical suspicion, it is believed that many GPs are unaware of the requirement.[167] Mandatory reporting, limited to laboratory test results only, was introduced throughout the UK in October 2010, under the Health Protection (Notification) Regulations 2010.[158]

Although there is a greater incidence of Lyme disease in the New Forest, Salisbury Plain, Exmoor, the South Downs, parts of Wiltshire and Berkshire, Thetford Forest[168] and the West coast and islands of Scotland[169] infected ticks are widespread, and can even be found in the parks of London.[160][170] 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.[171][172]

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.[173][174] 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.[175]

North America[edit]

Many studies in North America have examined ecological and environmental correlates of Lyme disease prevalence. 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 the year 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.[176] 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, and that other environmental variables showed little or no concordance between studies.[177] 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.[177]

Canada[edit]

Owing to changing climate, 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, south-west 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.[178][179][180] 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 climactic temperatures as the main driver of increased speed of spread.[181]

Mexico[edit]

A 2007 study suggests Borrelia burgdorferi infections are endemic to Mexico, from four cases reported between 1999 and 2000.[182]

United States[edit]

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

Each year, approximately 30,000 new cases are reported to the CDC however, this number is likely underestimated. 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.[183]

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.[184][185][186]

Although Lyme disease has been reported in all states except Montana,[187] 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).[188] New 2011 CDC Lyme case definition guidelines are used to determine confirmed CDC surveillance cases.[189]

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.[190] 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.[190]

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 prevalence of B. burgdorferi in local tick populations; this has since been brought into question, as some evidence has suggested lizards can become infected.[191]

Except for one study in Europe,[192] much of the data implicating lizards is based on DNA detection of the spirochete and has not demonstrated lizards are able to infect ticks feeding upon them.[191][193][194][195] 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.[55]

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.[citation needed]

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 patients 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.[citation needed]

Although Montana is the only state that has not reported a confirmed case of Lyme disease, in recent years there have been 5 to 10 cases a year of a disease similar to Lyme. 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.[187]

Lyme disease prevalence is comparable among males and females. A wide range of age groups is affected, though the number of cases is highest among 10–19-year-olds. For unknown reasons, Lyme disease is seven times more common among Asians.[196]

South America[edit]

In South America, tick-borne disease recognition and occurrence is rising. Ticks carrying B. burgdorferi sensu lato, as well as canine and human tick-borne disease, have been reported widely in Brazil, but the subspecies of Borrelia has not yet been defined.[197] The first reported case of Lyme disease in Brazil was made in 1993 in Sao Paulo.[198] B. burgdorferi sensu stricto antigens in patients have been identified in Colombia and Bolivia.[citation needed]

History[edit]

The evolutionary history of Borrelia burgdorferi genetics has been the subject of recent studies. One study has found that prior to the reforestation that accompanied post colonial farm abandonment in New England and the wholesale migration into the mid-west that occurred during the early 19th century, Lyme disease was present for thousands of years in America and had spread along with its tick hosts from the Northeast to the Midwest.[199]

John Josselyn, who visited New England in 1638 and again from 1663–1670, wrote "there be infinite numbers of tikes hanging upon the bushes in summer time that will cleave to man's garments and creep into his breeches eating themselves in a short time into the very flesh of a man. I have seen the stockins of those that have gone through the woods covered with them."[200]

This is also confirmed by the writings of Peter Kalm, a Swedish botanist who was sent to America by Linnaeus, and who found the forests of New York "abound" with ticks when he visited in 1749. When Kalm's journey was retraced 100 years later, the forests were gone and the Lyme bacterium had probably become isolated to a few pockets along the northeast coast, Wisconsin, and Minnesota.[201]

Perhaps the first detailed description of what is now known as Lyme disease appeared in the writings of Reverend Dr John Walker after a visit to the Island of Jura (Deer Island) off the west coast of Scotland in 1764.[202] He gives a good description both of the symptoms of Lyme disease (with "exquisite pain [in] the interior parts of the limbs") and of the tick vector itself, which he describes as a "worm" with a body which is "of a reddish colour and of a compressed shape with a row of feet on each side" that "penetrates the skin". Many people from this area of Great Britain immigrated to North America between 1717 and the end of the 18th century.

The examination of preserved museum specimens has found Borrelia DNA in an infected Ixodes ricinus tick from Germany that dates back to 1884, and from an infected mouse from Cape Cod that died in 1894.[201] The 2010 autopsy of Ötzi the Iceman, a 5,300-year-old mummy, revealed the presence of the DNA sequence of Borrelia burgdorferi making him the earliest known human with Lyme disease.[203]

The early European studies of what is now known as Lyme disease described its skin manifestations. The first study dates to 1883 in Breslau, Germany (now Wrocław, Poland), where physician Alfred Buchwald described a man who had suffered for 16 years with a degenerative skin disorder now known as acrodermatitis chronica atrophicans.[204]

20th century[edit]

At a 1909 research conference, Swedish dermatologist Arvid Afzelius presented a study about an expanding, ring-like lesion he had observed in an older woman following the bite of a sheep tick. He named the lesion erythema migrans.[204] The skin condition now known as borrelial lymphocytoma was first described in 1911.[205]

Neurological problems following tick bites were recognized starting in the 1920s. French physicians Garin and Bujadoux described a farmer with a painful sensory radiculitis accompanied by mild meningitis following a tick bite. A large, ring-shaped rash was also noted, although the doctors did not relate it to the meningoradiculitis. In 1930, the Swedish dermatologist Sven Hellerström was the first to propose EM and neurological symptoms following a tick bite were related.[206] In the 1940s, German neurologist Alfred Bannwarth described several cases of chronic lymphocytic meningitis and polyradiculoneuritis, some of which were accompanied by erythematous skin lesions.

Carl Lennhoff, who worked at the Karolinska Institute in Sweden, believed many skin conditions were caused by spirochetes. In 1948, he used a special stain to microscopically observe what he believed were spirochetes in various types of skin lesions, including EM (erythema migrans).[207] Although his conclusions were later shown to be erroneous, interest in the study of spirochetes was sparked. In 1949, Nils Thyresson, who also worked at the Karolinska Institute, was the first to treat ACA with penicillin.[208] In the 1950s, the relationship among tick bite, lymphocytoma, EM and Bannwarth's syndrome was recognized throughout Europe leading to the widespread use of penicillin for treatment in Europe.[209][210]

In 1970, a dermatologist in Wisconsin named Rudolph Scrimenti recognized an EM lesion in a patient after recalling a paper by Hellerström that had been reprinted in an American science journal in 1950. This was the first documented case of EM in the United States. Based on the European literature, he treated the patient with penicillin.[211]

The full syndrome now known as Lyme disease was not recognized until a cluster of cases originally thought to be juvenile rheumatoid arthritis was identified in three towns in southeastern Connecticut in 1975, including the towns Lyme and Old Lyme, which gave the disease its popular name.[212] This was investigated by physicians David Snydman and Allen Steere of the Epidemic Intelligence Service, and by others from Yale University, including Dr. Stephen Malawista, who is credited as a co-discover of the disease.[213] The recognition that the patients in the United States had EM led to the recognition that "Lyme arthritis" was one manifestation of the same tick-borne condition known in Europe.[214]

Before 1976, elements of B. burgdorferi sensu lato infection were called or known as tick-borne meningopolyneuritis, Garin-Bujadoux syndrome, Bannwarth syndrome, Afzelius' disease,[215] Montauk Knee or sheep tick fever. Since 1976 the disease is most often referred to as Lyme disease,[216][217] Lyme borreliosis or simply borreliosis.[citation needed]

In 1980, Steere, et al., began to test antibiotic regimens in adult patients with Lyme disease.[218] In the same year, New York State Health Dept. epidemiologist Jorge Benach provided Willy Burgdorfer, a researcher at the Rocky Mountain Biological Laboratory, with collections of I. dammini [scapularis] from Shelter Island, NY, a known Lyme-endemic area as part of an ongoing investigation of Rocky Mountain spotted fever. In examining the ticks for rickettsiae, Burgdorfer noticed "poorly stained, rather long, irregularly coiled spirochetes." Further examination revealed spirochetes in 60% of the ticks. Burgdorfer credited his familiarity with the European literature for his realization that the spirochetes might be the "long-sought cause of ECM and Lyme disease." Benach supplied him with more ticks from Shelter Island and sera from patients diagnosed with Lyme disease. University of Texas Health Science Center researcher Alan Barbour "offered his expertise to culture and immunochemically characterize the organism." Burgdorfer subsequently confirmed his discovery by isolating, from patients with Lyme disease, spirochetes identical to those found in ticks.[219] In June 1982, he published his findings in Science, and the spirochete was named Borrelia burgdorferi in his honor.[220]

After the identification of B. burgdorferi as the causative agent of Lyme disease, antibiotics were selected for testing, guided by in vitro antibiotic sensitivities, including tetracycline antibiotics, amoxicillin, cefuroxime axetil, intravenous and intramuscular penicillin and intravenous ceftriaxone.[221][222] The mechanism of tick transmission was also the subject of much discussion. B. burgdorferi spirochetes were identified in tick saliva in 1987, confirming the hypothesis that transmission occurred via tick salivary glands.[223]

Jonathan Edlow, Professor of Medicine at Harvard Medical School, quotes the late Ed Masters (discoverer of STARI, a Lyme-like illness) in his book Bull's-Eye, on the history of Lyme disease. Edlow writes:

Masters points out that the "track record" of the "conventional wisdom" regarding Lyme disease is not very good: "First off, they said it was a new disease, which it wasn't. Then it was thought to be viral, but it isn't. Then it was thought that sero-negativity didn't exist, which it does. They thought it was easily treated by short courses of antibiotics, which sometimes it isn't. Then it was only the Ixodes dammini tick, which we now know is not even a separate valid tick species. If you look throughout the history, almost every time a major dogmatic statement has been made about what we 'know' about this disease, it was subsequently proven wrong or underwent major modifications."[224]

Society and culture[edit]

Urbanization and other anthropogenic factors can be implicated in the spread of Lyme disease to humans. In many areas, expansion of suburban neighborhoods has led to gradual deforestation of surrounding wooded areas and increased border contact between humans and tick-dense areas. Human expansion has also resulted in reduction of predators that hunt deer as well as mice, chipmunks and other small rodents—the primary reservoirs for Lyme disease. As a consequence of increased human contact with host and vector, the likelihood of transmission of the disease has greatly increased.[225][226] Researchers are investigating possible links between global warming and the spread of vector-borne diseases, including Lyme disease.[227]

Controversy over term "chronic Lyme disease"[edit]

The term "chronic Lyme disease" is controversial and not recognized in the medical literature,[12] and most medical authorities advise against long-term antibiotic treatment for Lyme disease.[13][14][15] Studies have shown that most patients diagnosed with “chronic Lyme disease” either have no objective evidence of previous or current infection with B. burgdorferi or are patients 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 patient previously treated for Lyme disease.[228]

Other animals[edit]

Prevention of Lyme disease is an important step in keeping dogs safe in endemic areas. Prevention education and a number of preventative 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.[229]

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).[230] These acaricides target primarily the adult stages of Lyme-carrying ticks and reduce the number of reproductively active ticks in the environment.[229] Formulations of these ingredients are available in a variety of topical forms, including spot-ons, sprays, powders, impregnated collars, solutions, and shampoos.[230]

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.[231]

References[edit]

  1. ^ Westervelt, Holly James; McCaffrey, Robert (September 2002). "Neuropsychological Functioning in Chronic Lyme Disease". Neuropsychology Review 12 (3): 153–177. doi:10.1023/A:1020381913563. 
  2. ^ Samuels DS; Radolf, JD, eds. (2010). Borrelia: Molecular Biology, Host Interaction and Pathogenesis. Caister Academic Press. ISBN 978-1-904455-58-5. 
  3. ^ a b c d e Ryan KJ; Ray CG, ed. (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. pp. 434–37. ISBN 0-8385-8529-9. 
  4. ^ a b Signs and Symptoms of Lyme Disease, CDC, page last reviewed: April 12, 2011.
  5. ^ a b Arthritis and Lyme Disease, WedMD Rheumatoid Arthritis Health Center, reviewed by David Zelman, MD on Oct. 1, 2012.
  6. ^ "Ten Facts You Should Know About Lyme Disease". Infectious Diseases Society of America. May 10, 2011. Retrieved June 18, 2013. 
  7. ^ http://www.cdc.gov/lyme/signs_symptoms/index.html
  8. ^ a b Cairns V, Godwin J (December 2005). "Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms". Int J Epidemiol 34 (6): 1340–45. doi:10.1093/ije/dyi129. PMID 16040645. 
  9. ^ Hu, Linden (2009). "Clinical Manifestations of Lyme Disease in Adults". "UpToDate". UpToDate. 
  10. ^ Johnson RC (1996). "Borrelia". In Baron S, et al. Baron's Medical Microbiology (4th ed.). Univ of Texas Medical Branch. ISBN 0-9631172-1-1. PMID 21413339. 
  11. ^ Fell E (October 2000). "An update on Lyme disease and other tick-borne illnesses". Nurse Pract 25 (10): 38–40, 43–44, 47–48 passim; quiz 56–57. doi:10.1097/00006205-200025100-00003. PMID 11068777. 
  12. ^ a b Feder, HM; Johnson, BJB; O'Connell, S et al. (October 2007). "A Critical Appraisal of "Chronic Lyme Disease"" (PDF). NEJM 357 (14): 1422–30. doi:10.1056/NEJMra072023. PMID 17914043. 
  13. ^ a b c Wormser GP; Dattwyler RJ; Shapiro ED et al. (November 2006). "The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America". Clin. Infect. Dis. 43 (9): 1089–1134. doi:10.1086/508667. PMID 17029130. 
  14. ^ a b Halperin JJ, Shapiro ED, Logigian E, et al. (July 2007). "Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology 69 (1): 91–102. doi:10.1212/01.wnl.0000265517.66976.28. PMID 17522387. 
  15. ^ a b ""Chronic Lyme Disease" Fact Sheet". National Institute of Allergy and Infectious Diseases. April 17, 2009. 
  16. ^ http://news.discovery.com/human/health/lyme-disease-bacteria-older-than-the-human-race-140529.htm
  17. ^ a b Lyme disease at eMedicine
  18. ^ Steere AC, Sikand VK, Schoen RT, Nowakowski J (August 2003). "Asymptomatic infection with Borrelia burgdorferi". Clin. Infect. Dis. 37 (4): 528–32. doi:10.1086/376914. PMID 12905137.  (primary source)
  19. ^ a b c Biesiada G, Czepiel J, Leśniak MR, Garlicki A, Mach T (Dec 20, 2012). "Lyme disease: review". Arch Med Sci. 8 (6): 978–82. doi:10.5114/aoms.2012.30948. PMC 3542482. PMID 23319969. 
  20. ^ Fahrer H, Sauvain MJ, Zhioua E, Van Hoecke C, Gern LE (February 1998). "Longterm survey (7 years) in a population at risk for Lyme borreliosis: what happens to the seropositive individuals?". Eur. J. Epidemiol. 14 (2): 117–23. doi:10.1023/A:1007404620701. PMID 9556169.  (primary source)
  21. ^ Ophthalmic aspects of Lyme disease overview of Lyme disease at eMedicine
  22. ^ a b Steere, AC (2008). "Lyme borreliosis". In Fauci A, et al. "Harrison's principles of internal medicine" (17th ed.). McGraw-Hill Medical. ISBN 0-07-159991-6. 
  23. ^ Smith RP, Schoen RT, Rahn DW, et al. (March 2002). "Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans". Annals of Internal Medicine 136 (6): 421–28. doi:10.7326/0003-4819-136-6-200203190-00005. PMID 11900494.  (primary source)
  24. ^ Aucott JN, Crowder LA, Yedlin V, Kortte KB (2012). "Bull's-Eye and nontarget skin lesions of Lyme disease: an internet survey of identification of erythema migrans". Dermatol Res Pract 2012: 451727. doi:10.1155/2012/451727. PMC 3485866. PMID 23133445.  (primary source)
  25. ^ a b c d Auwaerter PG, Aucott J, Dumler JS (January 2004). "Lyme borreliosis (Lyme disease): molecular and cellular pathobiology and prospects for prevention, diagnosis and treatment". Expert Rev Mol Med 6 (2): 1–22. doi:10.1017/S1462399404007276. PMID 14987414. 
  26. ^ Steere AC, Dhar A, Hernandez J, et al. (January 2003). "Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease". Am. J. Med. 114 (1): 58–62. doi:10.1016/S0002-9343(02)01440-7. PMID 12543291.  (primary source)
  27. ^ Dandache P, Nadelman RB (June 2008). "Erythema migrans". Infect. Dis. Clin. North Am. 22 (2): 235–60, vi. doi:10.1016/j.idc.2007.12.012. PMID 18452799. 
  28. ^ a b Stanek G, Strle F (June 2008). "Lyme disease: European perspective". Infect. Dis. Clin. North Am. 22 (2): 327–39, vii. doi:10.1016/j.idc.2008.01.001. PMID 18452805. 
  29. ^ Halperin JJ (June 2008). "Nervous system Lyme disease". Infect. Dis. Clin. North Am. 22 (2): 261–74, vi. doi:10.1016/j.idc.2007.12.009. PMID 18452800. 
  30. ^ Chabria SB, Lawrason J (2007). "Altered mental status, an unusual manifestation of early disseminated Lyme disease: A case report". Journal of Medical Case Reports 1: 62. doi:10.1186/1752-1947-1-62. PMC 1973078. PMID 17688693. 
  31. ^ Stanek G, Wormser GP, Gray J, Strle F (February 2012). "Lyme borreliosis". Lancet 379 (9814): 461–73. doi:10.1016/S0140-6736(11)60103-7. PMID 21903253. 
  32. ^ Nau R, Christen HJ, Eiffert H (January 2009). "Lyme disease--current state of knowledge". Dtsch Arztebl Int 106 (5): 72–81; quiz 82, I. doi:10.3238/arztebl.2009.0072. PMC 2695290. PMID 19562015. 
  33. ^ a b Shadick NA, Phillips CB, Sangha O, et al. (December 1999). "Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease". Annals of Internal Medicine 131 (12): 919–26. doi:10.7326/0003-4819-131-12-199912210-00003. PMID 10610642. 
  34. ^ Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED (February 2000). "Long-term outcomes of persons with Lyme disease". JAMA 283 (5): 609–16. doi:10.1001/jama.283.5.609. PMID 10665700. 
  35. ^ Fallon BA, Nields JA (November 1994). "Lyme disease: a neuropsychiatric illness". Am J Psychiatry 151 (11): 1571–83. PMID 7943444. 
  36. ^ Hess A, Buchmann J, Zettl UK, et al. (March 1999). "Borrelia burgdorferi central nervous system infection presenting as an organic schizophrenialike disorder". Biol. Psychiatry 45 (6): 795. doi:10.1016/S0006-3223(98)00277-7. PMID 10188012. 
  37. ^ Puius YA, Kalish RA (June 2008). "Lyme arthritis: pathogenesis, clinical presentation, and management". Infect. Dis. Clin. North Am. 22 (2): 289–300, vi–vii. doi:10.1016/j.idc.2007.12.014. PMID 18452802. 
  38. ^ Mullegger RR (2004). "Dermatological manifestations of Lyme borreliosis". Eur J Dermatol 14 (5): 296–309. PMID 15358567. 
  39. ^ Samuels DS; Radolf, JD, eds. (2010). "Chapter 6, Structure, Function and Biogenesis of the Borrelia Cell Envelope". Borrelia: Molecular Biology, Host Interaction and Pathogenesis. Caister Academic Press. ISBN 978-1-904455-58-5. 
  40. ^ Stanek G, Reiter M (2011). "The expanding Lyme Borrelia complex - clinical significance of genomic species". Clin Microbiol Infect 17 (4): 487–93. doi:10.1111/j.1469-0691.2011.03492.x. PMID 21414082. 
  41. ^ Schneider BS, Schriefer ME, Dietrich G, Dolan MC, Morshed MG, Zeidner NS (October 2008). "Borrelia bissettii isolates induce pathology in a murine model of disease". Vector-Borne and Zoonotic Diseases 8 (5): 623–33. doi:10.1089/vbz.2007.0251. PMID 18454594. 
  42. ^ Rudenko N, Golovchenko M, Mokrácek A, et al. (October 2008). "Detection of Borrelia bissettii in cardiac valve tissue of a patient with endocarditis and aortic valve stenosis in the Czech Republic". J. Clin. Microbiol. 46 (10): 3540–3. doi:10.1128/JCM.01032-08. PMC 2566110. PMID 18650352. 
  43. ^ a b Tilly K, Rosa PA, Stewart PE (June 2008). "Biology of infection with Borrelia burgdorferi". Infect. Dis. Clin. North Am. 22 (2): 217–34, v. doi:10.1016/j.idc.2007.12.013. PMC 2440571. PMID 18452798. 
  44. ^ a b Lo Re V, Occi JL, MacGregor RR (April 2004). "Identifying the vector of Lyme disease". Am Fam Physician 69 (8): 1935–37. PMID 15117014. 
  45. ^ a b "Westport Weston Health District". 2004. Retrieved 2013-09-26. 
  46. ^ Hovius JW, van Dam AP, Fikrig E (September 2007). "Tick-host-pathogen interactions in Lyme borreliosis". Trends Parasitol. 23 (9): 434–8. doi:10.1016/j.pt.2007.07.001. PMID 17656156. 
  47. ^ a b c Steere AC, Coburn J, Glickstein L (April 2004). "The emergence of Lyme disease". J. Clin. Invest. 113 (8): 1093–101. doi:10.1172/JCI21681. PMC 385417. PMID 15085185. 
  48. ^ a b Steere AC (July 2001). "Lyme disease". N. Engl. J. Med. 345 (2): 115–25. doi:10.1056/NEJM200107123450207. PMID 11450660. 
  49. ^ de Mik EL, van Pelt W, Docters-van Leeuwen BD, van der Veen A, Schellekens JF, Borgdorff MW (April 1997). "The geographical distribution of tick bites and erythema migrans in general practice in The Netherlands". Int J Epidemiol 26 (2): 451–7. doi:10.1093/ije/26.2.451. PMID 9169184. 
  50. ^ Sun Y, Xu R (2003). "Ability of Ixodes persulcatus, Haemaphysalis concinna and Dermacentor silvarum ticks to acquire and transstadially transmit Borrelia garinii". Exp. Appl. Acarol. 31 (1-2): 151–60. doi:10.1023/B:APPA.0000005119.30172.43. PMID 14756409. 
  51. ^ Ledin KE, Zeidner NS, Ribeiro JM, et al. (March 2005). "Borreliacidal activity of saliva of the tick Amblyomma americanum". Med. Vet. Entomol. 19 (1): 90–5. doi:10.1111/j.0269-283X.2005.00546.x. PMID 15752182. 
  52. ^ Masters EJ, Grigery CN, Masters RW (June 2008). "STARI, or Masters disease: Lone Star tick-vectored Lyme-like illness". Infect. Dis. Clin. North Am. 22 (2): 361–76, viii. doi:10.1016/j.idc.2007.12.010. PMID 18452807. 
  53. ^ Clark K (November 2004). "Borrelia species in host-seeking ticks and small mammals in northern Florida". J. Clin. Microbiol. 42 (11): 5076–86. doi:10.1128/JCM.42.11.5076-5086.2004. PMC 525154. PMID 15528699. 
  54. ^ Eisen L, Eisen RJ, Lane RS (December 2004). "The roles of birds, lizards, and rodents as hosts for the western black-legged tick Ixodes pacificus". J. Vector Ecol. 29 (2): 295–308. PMID 15709249. 
  55. ^ a b Lane RS, Mun J, Eisen L, Eisen RJ (August 2006). "Refractoriness of the western fence lizard (Sceloporus occidentalis) to the Lyme disease group spirochete Borrelia bissettii". J. Parasitol. 92 (4): 691–96. doi:10.1645/GE-738R1.1. PMID 16995383. 
  56. ^ Walsh CA, Mayer EW, Baxi LV (January 2007). "Lyme disease in pregnancy: case report and review of the literature". Obstet Gynecol Surv 62 (1): 41–50. doi:10.1097/01.ogx.0000251024.43400.9a. PMID 17176487. 
  57. ^ Lakos A, Solymosi N (June 2010). "Maternal Lyme borreliosis and pregnancy outcome". Int. J. Infect. Dis. 14 (6): e494–98. doi:10.1016/j.ijid.2009.07.019. PMID 19926325. 
  58. ^ Magnarelli LA, Anderson JF (August 1988). "Ticks and biting insects infected with the etiologic agent of Lyme disease, Borrelia burgdorferi". J. Clin. Microbiol. 26 (8): 1482–6. PMC 266646. PMID 3170711. 
  59. ^ Luger SW (June 1990). "Lyme disease transmitted by a biting fly". N. Engl. J. Med. 322 (24): 1752. doi:10.1056/NEJM199006143222415. PMID 2342543. 
  60. ^ Bach G (2001). "Recovery of Lyme spirochetes by PCR in semen samples of previously diagnosed Lyme disease patients". "14th International Scientific Conference on Lyme Disease". 
  61. ^ Schmidt BL, Aberer E, Stockenhuber C, Klade H, Breier F, Luger A (March 1995). "Detection of Borrelia burgdorferi DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis". Diagn. Microbiol. Infect. Dis. 21 (3): 121–28. doi:10.1016/0732-8893(95)00027-8. PMID 7648832. 
  62. ^ Steere AC (2003-02-01). "Lyme Disease: Questions and Answers". Massachusetts General Hospital / Harvard Medical School. Archived from the original on 2008-03-07. Retrieved 2009-04-01. 
  63. ^ "CDC Lyme FAQ". CDC Lyme FAQ. Centers for Disease Control. 
  64. ^ Marianne Middelveen, Jennie Burke, Augustin Franco, Yean Wang, Peter Mayne, Eva Sapi, Cheryl Bandoski, Hilary Schlinger and Raphael Stricker (January 2014). "Lyme Disease May Be Sexually Transmitted". The Journal of Investigative Medicine 62: 280–281. Retrieved January 26, 2014. 
  65. ^ Swanson SJ, Neitzel D, Reed KD, Belongia EA (October 2006). "Coinfections acquired from ixodes ticks". Clin. Microbiol. Rev. 19 (4): 708–27. doi:10.1128/CMR.00011-06. PMC 1592693. PMID 17041141. 
  66. ^ Wormser GP (June 2006). "Clinical practice. Early Lyme disease". N. Engl. J. Med. 354 (26): 2794–801. doi:10.1056/NEJMcp061181. PMID 16807416. 
  67. ^ Lindgren E, Gustafson R (July 2001). "Tick-borne encephalitis in Sweden and climate change". Lancet 358 (9275): 16–8. doi:10.1016/S0140-6736(00)05250-8. PMID 11454371. 
  68. ^ Varde S, Beckley J, Schwartz I (1998). "Prevalence of tick-borne pathogens in Ixodes scapularis in a rural New Jersey County". Emerging Infect. Dis. 4 (1): 97–99. doi:10.3201/eid0401.980113. PMC 2627663. PMID 9452402. 
  69. ^ Pachner AR, Steiner I (June 2007). "Lyme neuroborreliosis: infection, immunity, and inflammation". Lancet Neurol 6 (6): 544–52. doi:10.1016/S1474-4422(07)70128-X. PMID 17509489. 
  70. ^ Fikrig E, Narasimhan S (April 2006). "Borrelia burgdorferi--traveling incognito?". Microbes Infect. 8 (5): 1390–9. doi:10.1016/j.micinf.2005.12.022. PMID 16698304. 
  71. ^ Xu Q, Seemanapalli SV, Reif KE, Brown CR, Liang FT (April 2007). "Increasing the recruitment of neutrophils to the site of infection dramatically attenuates Borrelia burgdorferi infectivity". Journal of Immunology 178 (8): 5109–15. doi:10.4049/jimmunol.178.8.5109. PMID 17404293. 
  72. ^ Coleman JL, Gebbia JA, Piesman J, Degen JL, Bugge TH, Benach JL (June 1997). "Plasminogen is required for efficient dissemination of B. burgdorferi in ticks and for enhancement of spirochetemia in mice". Cell 89 (7): 1111–9. doi:10.1016/S0092-8674(00)80298-6. PMID 9215633. 
  73. ^ Rupprecht TA, Koedel U, Fingerle V, Pfister HW (2008). "The pathogenesis of lyme neuroborreliosis: from infection to inflammation". Mol. Med. 14 (3-4): 205–12. doi:10.2119/2007-00091.Rupprecht (inactive March 30, 2013). PMC 2148032. PMID 18097481. 
  74. ^ Cabello FC, Godfrey HP, Newman SA (August 2007). "Hidden in plain sight: Borrelia burgdorferi and the extracellular matrix". Trends Microbiol. 15 (8): 350–54. doi:10.1016/j.tim.2007.06.003. PMID 17600717. 
  75. ^ a b Ramesh G, Alvarez AL, Roberts ED, et al. (September 2003). "Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes". Eur. Journal of Immunology 33 (9): 2539–50. doi:10.1002/eji.200323872. PMID 12938230. 
  76. ^ Halperin JJ, Heyes MP (January 1992). "Neuroactive kynurenines in Lyme borreliosis". Neurology 42 (1): 43–50. doi:10.1212/WNL.42.1.43. PMID 1531156. 
  77. ^ "Why is Chronic Lyme Disease Chronic?". Columbia University Medical Center. Retrieved 2011-02-26. 
  78. ^ Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP (January 1998). "The pathophysiologic roles of interleukin-6 in human disease". Annals of Internal Medicine 128 (2): 127–37. doi:10.7326/0003-4819-128-2-199801150-00009. PMID 9441573. 
  79. ^ Rasley A, Anguita J, Marriott I (September 2002). "Borrelia burgdorferi induces inflammatory mediator production by murine microglia". J. Neuroimmunol. 130 (1-2): 22–31. doi:10.1016/S0165-5728(02)00187-X. PMID 12225885. 
  80. ^ Wright CB, Sacco RL, Rundek T, Delman J, Rabbani L, Elkind M (2006). "Interleukin-6 is associated with cognitive function: the Northern Manhattan Study". J Stroke Cerebrovasc Dis 15 (1): 34–8. doi:10.1016/j.jstrokecerebrovasdis.2005.08.009. PMC 1382058. PMID 16501663. 
  81. ^ Fallon BA, Keilp J, Prohovnik I, Heertum RV, Mann JJ (2003). "Regional cerebral blood flow and cognitive deficits in chronic lyme disease". J Neuropsychiatry Clin Neurosci 15 (3): 326–32. doi:10.1176/appi.neuropsych.15.3.326. PMID 12928508. 
  82. ^ Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP (2005). "Cytokine dysregulation, inflammation and well-being". Neuroimmunomodulation 12 (5): 255–69. doi:10.1159/000087104. PMID 16166805. 
  83. ^ Calcagni E, Elenkov I (June 2006). "Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases". Annals of the New York Academy of Sciences 1069: 62–76. Bibcode:2006NYASA1069...62C. doi:10.1196/annals.1351.006. PMID 16855135. 
  84. ^ Gasse T; Murr C; Meyersbach P et al. (1994). "Neopterin production and tryptophan degradation in acute Lyme neuroborreliosis versus late Lyme encephalopathy". European Journal of Clinical Chemistry and Clinical Biochemistry 32 (9): 685–689. doi:10.1515/cclm.1994.32.9.685. PMID 7865624. 
  85. ^ Zajkowska J, Grygorczuk S, Kondrusik M, Pancewicz S, Hermanowska-Szpakowicz T (2006). "[New aspects of pathogenesis of Lyme borreliosis]". Przegl Epidemiol (in Polish) 60 (Suppl 1): 167–70. PMID 16909797. 
  86. ^ Ercolini AM, Miller SD (January 2009). "The role of infections in autoimmune disease". Clin. Exp. Immunol. 155 (1): 1–15. doi:10.1111/j.1365-2249.2008.03834.x. PMC 2665673. PMID 19076824. 
  87. ^ Singh SK, Girschick HJ (July 2004). "Lyme borreliosis: from infection to autoimmunity". Clin. Microbiol. Infect. 10 (7): 598–614. doi:10.1111/j.1469-0691.2004.00895.x. PMID 15214872. 
  88. ^ Oldstone MB (October 1998). "Molecular mimicry and immune-mediated diseases". FASEB J. 12 (13): 1255–65. PMID 9761770. 
  89. ^ Raveche ES; Schutzer SE; Fernandes H et al. (February 2005). "Evidence of Borrelia autoimmunity-induced component of Lyme carditis and arthritis". J. Clin. Microbiol. 43 (2): 850–56. doi:10.1128/JCM.43.2.850-856.2005. PMC 548028. PMID 15695691. 
  90. ^ Weinstein A, Britchkov M (July 2002). "Lyme arthritis and post-Lyme disease syndrome". Current Opinion in Rheumatology 14 (4): 383–87. doi:10.1097/00002281-200207000-00008. PMID 12118171. 
  91. ^ Bolz DD, Weis JJ (August 2004). "Molecular mimicry to Borrelia burgdorferi: pathway to autoimmunity?". Autoimmunity 37 (5): 387–92. doi:10.1080/08916930410001713098. PMID 15621562. 
  92. ^ "Chronic Lyme Disease". National Institute of Allergy and Infectious Diseases. Retrieved 15 October 2013. 
  93. ^ Feng, Jie; Wang, Ting; Shi, Wangliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul; Zhang, Ying. "Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library". Nature. Emerging Microbes & Infections. Retrieved 11 July 2014. 
  94. ^ Wormser G, Masters E, Nowakowski J et al. (2005). "Prospective clinical evaluation of patients from missouri and New York with erythema migrans-like skin lesions". Clin Infect Dis 41 (7): 958–65. doi:10.1086/432935. PMID 16142659. 
  95. ^ Brown SL, Hansen SL, Langone JJ (July 1999). "Role of serology in the diagnosis of Lyme disease". JAMA 282 (1): 62–66. doi:10.1001/jama.282.1.62. PMID 10404913. 
  96. ^ Hofmann H (1996). "Lyme borreliosis--problems of serological diagnosis". Infection 24 (6): 470–72. doi:10.1007/BF01713052. PMID 9007597. 
  97. ^ Pachner AR (1989). "Neurologic manifestations of Lyme disease, the new "great imitator"". Rev. Infect. Dis. 11 Suppl 6: S1482–1486. doi:10.1093/clinids/11.Supplement_6.S1482. PMID 2682960. 
  98. ^ Branda, JA; Linskey, K; Kim, YA; Steere, AC; Ferraro, MJ (Sep 2011). "Two-tiered antibody testing for Lyme disease with use of 2 enzyme immunoassays, a whole-cell sonicate enzyme immunoassay followed by a VlsE C6 peptide enzyme immunoassay.". Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 53 (6): 541–7. doi:10.1093/cid/cir464. PMID 21865190. 
  99. ^ "Lyme disease diagnosis". Centers for Disease Control and Prevention (CDC). October 7, 2008. Retrieved July 6, 2009. 
  100. ^ Wilske B (2005). "Epidemiology and diagnosis of Lyme borreliosis". Annals of Medicine 37 (8): 568–79. doi:10.1080/07853890500431934. PMID 16338759. 
  101. ^ Engstrom SM, Shoop E, Johnson RC (February 1995). "Immunoblot interpretation criteria for serodiagnosis of early Lyme disease". J. Clin. Microbiol. 33 (2): 419–27. PMC 227960. PMID 7714202. 
  102. ^ Sivak SL, Aguero-Rosenfeld ME, Nowakowski J, Nadelman RB, Wormser GP (October 1996). "Accuracy of IgM immunoblotting to confirm the clinical diagnosis of early Lyme disease". Arch. Intern. Med. 156 (18): 2105–09. doi:10.1001/archinte.156.18.2105. PMID 8862103. 
  103. ^ a b Steere AC, McHugh G, Damle N, Sikand VK (July 2008). "Prospective study of serologic tests for lyme disease". Clin. Infect. Dis. 47 (2): 188–95. doi:10.1086/589242. PMID 18532885. 
  104. ^ Goossens HA, Nohlmans MK, van den Bogaard AE (1999). "Epstein-Barr virus and cytomegalovirus infections cause false-positive results in IgM two-test protocol for early Lyme borreliosis". Infection 27 (3): 231. doi:10.1007/BF02561539. PMID 10378140. 
  105. ^ Strasfeld L, Romanzi L, Seder RH, Berardi VP (December 2005). "False-positive serological test results for Lyme disease in a patient with acute herpes simplex virus type 2 infection". Clin. Infect. Dis. 41 (12): 1826–27. doi:10.1086/498319. PMID 16288417. 
  106. ^ Molloy PJ, Persing DH, Berardi VP (August 2001). "False-positive results of PCR testing for Lyme disease". Clin. Infect. Dis. 33 (3): 412–13. doi:10.1086/321911. PMID 11438915. 
  107. ^ a b Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP (July 2005). "Diagnosis of lyme borreliosis". Clin. Microbiol. Rev. 18 (3): 484–509. doi:10.1128/CMR.18.3.484-509.2005. PMC 1195970. PMID 16020686. 
  108. ^ Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC (January 1994). "Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis". N. Engl. J. Med. 330 (4): 229–34. doi:10.1056/NEJM199401273300401. PMID 8272083. 
  109. ^ Burdash N, Fernandes J (June 1991). "Lyme borreliosis: detecting the great imitator". J Am Osteopath Assoc 91 (6): 573–74, 577–8. PMID 1874654. 
  110. ^ Coyle PK, Schutzer SE, Deng Z, et al. (November 1995). "Detection of Borrelia burgdorferi-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease". Neurology 45 (11): 2010–15. doi:10.1212/WNL.45.11.2010. PMID 7501150. 
  111. ^ Valentine-Thon E, Ilsemann K, Sandkamp M (January 2007). "A novel lymphocyte transformation test (LTT-MELISA) for Lyme borreliosis". Diagn. Microbiol. Infect. Dis. 57 (1): 27–34. doi:10.1016/j.diagmicrobio.2006.06.008. PMID 16876371. 
  112. ^ von Baehr V, Doebis C, Volk HD, von Baehr R (October 2012). "The lymphocyte transformation test for borrelia detects active lyme borreliosis and verifies effective antibiotic treatment.". Open Neurol J. 6 (2): 104–12. doi:10.2174/1874205X01206010104. PMID 23091571. 
  113. ^ Eisendle K, Grabner T, Zelger B (February 2007). "Focus floating microscopy: 'gold standard' for cutaneous borreliosis?". Am. J. Clin. Pathol. 127 (2): 213–22. doi:10.1309/3369XXFPEQUNEP5C. PMID 17210530. 
  114. ^ Cadavid D (November 2006). "The mammalian host response to borrelia infection". Wien. Klin. Wochenschr. 118 (21-22): 653–58. doi:10.1007/s00508-006-0692-0. PMID 17160603. 
  115. ^ "What You Should Know About Lyme Disease". International Lyme and Associated Diseases Society. Retrieved October 10, 2010. 
  116. ^ Hildenbrand P, Craven DE, Jones R, Nemeskal P (June 2009). "Lyme neuroborreliosis: manifestations of a rapidly emerging zoonosis". AJNR Am J Neuroradiol 30 (6): 1079–87. doi:10.3174/ajnr.A1579. PMID 19346313. 
  117. ^ Westervelt, Holly; McCaffrey, Robert (September 2002). "Neuropsychological Functioning in Chronic Lyme Disease". Neuropsychological Review 12 (3): 153–177. doi:10.1023/A:1020381913563. 
  118. ^ list of chemical repellents http://www.ewg.org/research/ewgs-guide-bug-repellents/adults#block1
  119. ^ http://www.ct.gov/caes/lib/caes/documents/publications/bulletins/b1010.pdf[full citation needed]
  120. ^ Duffy, David Cameron; Downer, Randall; Brinkley, Christie (1992). "The effectiveness of helmeted guineafowl in the control of the deer tick, the vector of Lyme disease". The Wilson Bulletin 104 (2): 342–45. JSTOR 4163159. 
  121. ^ Rand PW, Lubelczyk C, Holman MS, Lacombe EH, Smith RP (July 2004). "Abundance of Ixodes scapularis (Acari: Ixodidae) after the complete removal of deer from an isolated offshore island, endemic for Lyme Disease". J. Med. Entomol. 41 (4): 779–84. doi:10.1603/0022-2585-41.4.779. PMID 15311475. 
  122. ^ "Figure 2: Changes in deer density and cases of Lyme disease in Mumford Cove, Connecticut, 1996–2004 (CT DEP data)". Managing Urban Deer in Connecticut (2nd ed.). Connecticut Department of Environmental Protection - Wildlife Division. June 2007. p. 4. 
  123. ^ Stafford, Kirby C. (2004). Tick Management Handbook. Connecticut Agricultural Experiment Station and Connecticut Department of Public Health. p. 46. Retrieved 2007-08-21. 
  124. ^ Perkins SE, Cattadori IM, Tagliapietra V, Rizzoli AP, Hudson PJ (August 2006). "Localized deer absence leads to tick amplification". Ecology 87 (8): 1981–86. doi:10.1890/0012-9658(2006)87[1981:LDALTT]2.0.CO;2. PMID 16937637. 
  125. ^ Staub D, Debrunner M, Amsler L, Steffen R (2002). "Effectiveness of a repellent containing DEET and EBAAP for preventing tick bites". Wilderness Environ Med 13 (1): 12–20. doi:10.1580/1080-6032(2002)013[0012:EOARCD]2.0.CO;2. PMID 11929056. 
  126. ^ Wodecka, B., Rymaszewska, A., & Skotarczak, B. (2013), Host and pathogen DNA identification in blood meals of nymphal Ixodes ricinus ticks from forest parks and rural forests of Poland. Experimental and Applied Acarology, 1-13 (résumé).
  127. ^ Overzier E, Pfister K, Herb I, Mahling M, Böck G Jr, Silaghi C (2013) Detection of tick-borne pathogens in roe deer (Capreolus capreolus), in questing ticks (Ixodes ricinus), and in ticks infesting roe deer in southern Germany. Ticks Tick Borne Dis. 2013 Jun; 4(4):320-8. Epub 2013 Apr 6. (abstract)
  128. ^ Poland GA, Jacobson RM (March 2001). "The prevention of Lyme disease with vaccine". Vaccine 19 (17-19): 2303–08. doi:10.1016/S0264-410X(00)00520-X. PMID 11257352. 
  129. ^ Rowe, Claudia (June 13, 1999). "Lukewarm Response To New Lyme Vaccine". The New York Times. Retrieved July 11, 2008. 
  130. ^ a b c Abbott A (February 2006). "Lyme disease: uphill struggle". Nature 439 (7076): 524–25. doi:10.1038/439524a. PMID 16452949. 
  131. ^ "Sole Lyme Vaccine Is Pulled Off Market". The New York Times. February 28, 2002. Retrieved July 11, 2008. 
  132. ^ a b Nigrovic LE, Thompson KM (January 2007). "The Lyme vaccine: a cautionary tale". Epidemiol. Infect. 135 (1): 1–8. doi:10.1017/S0950268806007096. PMC 2870557. PMID 16893489. 
  133. ^ "When a vaccine is safe". Nature 439 (7076): 509. February 2006. Bibcode:2006Natur.439Q.509.. doi:10.1038/439509a. PMID 16452935. 
  134. ^ Earnhart CG, Marconi RT (2007). "An octavalent lyme disease vaccine induces antibodies that recognize all incorporated OspC type-specific sequences". Hum Vaccin 3 (6): 281–89. doi:10.4161/hv.4661. PMID 17921702. 
  135. ^ Pozsgay V, Kubler-Kielb J (February 2007). "Synthesis of an experimental glycolipoprotein vaccine against Lyme disease". Carbohydr. Res. 342 (3-4): 621–26. doi:10.1016/j.carres.2006.11.014. PMC 2709212. PMID 17182019. 
  136. ^ a b Brooks, DVM, Wendy C. "Lyme Disease". Veterinary Information Network. Retrieved 10 February 2012. 
  137. ^ a b Piesman J, Dolan MC (May 2002). "Protection against lyme disease spirochete transmission provided by prompt removal of nymphal Ixodes scapularis (Acari: Ixodidae)". J. Med. Entomol. 39 (3): 509–12. doi:10.1603/0022-2585-39.3.509. PMID 12061448. 
  138. ^ http://www.tickbitepreventionweek.org/tick-removal.html
  139. ^ Zeller JL, Burke AE, Glass RM (June 2007). "JAMA patient page. Lyme disease". JAMA 297 (23): 2664. doi:10.1001/jama.297.23.2664. PMID 17579234. 
  140. ^ a b c d e f g h i j k l m n o p Wright WF, Riedel DJ, Talwani R, Gilliam BL (June 2012). "Diagnosis and management of Lyme disease". Am Fam Physician 85 (11): 1086–93. PMID 22962880. 
  141. ^ Krause PJ, Foley DT, Burke GS, Christianson D, Closter L, Spielman A (December 2006). "Reinfection and relapse in early Lyme disease". Am. J. Trop. Med. Hyg. 75 (6): 1090–94. PMID 17172372. 
  142. ^ Klempner MS, Hu LT, Evans J, et al. (July 2001). "Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease". N. Engl. J. Med. 345 (2): 85–92. doi:10.1056/NEJM200107123450202. PMID 11450676. 
  143. ^ "Glomerular Disease". The Merck Veterinary Manual. Retrieved 11 Feb 2012. 
  144. ^ Staubinger, PhD, R. "Lyme Disease". Sirius Dog. Retrieved 10 Feb 2012. [unreliable source?]
  145. ^ Fatal cases of Lyme disease reported in the medical literature include:
  146. ^ Higgins R (August 2004). "Emerging or re-emerging bacterial zoonotic diseases: bartonellosis, leptospirosis, Lyme borreliosis, plague". Rev. - Off. Int. Epizoot. 23 (2): 569–81. PMID 15702720. 
  147. ^ Bouattour A, Ghorbel A, Chabchoub A, Postic D (2004). "Situation de la borreuose de lyme au maghreb" [Lyme borreliosis situation in North Africa]. Arch Inst Pasteur Tunis (in French) 81 (1-4): 13–20. PMID 16929760. 
  148. ^ Dsouli N, Younsi-Kabachii H, Postic D, Nouira S, Gern L, Bouattour A (July 2006). "Reservoir role of lizard Psammodromus algirus in transmission cycle of Borrelia burgdorferi sensu lato (Spirochaetaceae) in Tunisia". J. Med. Entomol. 43 (4): 737–42. doi:10.1603/0022-2585(2006)43[737:RROLPA]2.0.CO;2. PMID 16892633. 
  149. ^ Helmy N (August 2000). "Seasonal abundance of Ornithodoros (O.) savignyi and prevalence of infection with Borrelia spirochetes in Egypt". J Egypt Soc Parasitol 30 (2): 607–19. PMID 10946521. 
  150. ^ Fivaz BH, Petney TN (September 1989). "Lyme disease--a new disease in southern Africa?". J S Afr Vet Assoc 60 (3): 155–58. PMID 2699499. 
  151. ^ Jowi JO, Gathua SN (May 2005). "Lyme disease: report of two cases". East Afr Med J 82 (5): 267–69. doi:10.4314/eamj.v82i5.9318. PMID 16119758. 
  152. ^ Li M, Masuzawa T, Takada N, et al. (July 1998). "Lyme disease Borrelia species in northeastern China resemble those isolated from far eastern Russia and Japan". Appl. Environ. Microbiol. 64 (7): 2705–09. PMC 106449. PMID 9647853. 
  153. ^ Masuzawa T (December 2004). "Terrestrial distribution of the Lyme borreliosis agent Borrelia burgdorferi sensu lato in East Asia". Jpn. J. Infect. Dis. 57 (6): 229–35. PMID 15623946. 
  154. ^ Walder G, Lkhamsuren E, Shagdar A, et al. (May 2006). "Serological evidence for tick-borne encephalitis, borreliosis, and human granulocytic anaplasmosis in Mongolia". Int. Journal of Medical Microbiology. 296 Suppl 40: 69–75. doi:10.1016/j.ijmm.2006.01.031. PMID 16524782. 
  155. ^ Rizzoli A, Hauffe H, Carpi G, Vourc HG, Neteler M, Rosa R (2011). "Lyme borreliosis in Europe". Euro Surveill. 16 (27). PMID 21794218. 
  156. ^ Smith R, Takkinen J (2006). "Lyme borreliosis: Europe-wide coordinated surveillance and action needed?". Euro Surveill. 11 (6): E060622.1. PMID 16819127. 
  157. ^ Lopes de Carvalho I, Núncio MS (2006). "Laboratory diagnosis of Lyme borreliosis at the Portuguese National Institute of Health (1990–2004)". Euro Surveill. 11 (10): 257–60. PMID 17130658. 
  158. ^ a b c d "Epidemiology of Lyme borreliosis in the UK". HPA. Retrieved 2012-12-15. 
  159. ^ Muhlemann MF, Wright DJ (January 1987). "Emerging pattern of Lyme disease in the United Kingdom and Irish Republic". Lancet 1 (8527): 260–62. doi:10.1016/S0140-6736(87)90074-2. PMID 2880076. 
  160. ^ a b Lyme Disease Hansard 1991-11-11
  161. ^ a b "Tick Lyme disease off your holiday list" (Press release). Health Protection Agency. 14 April 2011. Retrieved March 29, 2013. 
  162. ^ "Concern about rise in Lyme disease cases". Lyme Disease Action. 2011-12-15. Retrieved 2012-12-15. 
  163. ^ Cassidy, Frank (14 March 2011). "Tayside revealed as a Lyme disease hotspot as cases soar". Press and Journal. 
  164. ^ "Lyme disease: A clear and present danger". RCN. 2009-04-28. Retrieved 2012-12-15. 
  165. ^ "Guidance on Part 2 - Notifiable Diseases, Notifiable Organisms and Health Risk States". Scotland.gov.uk. 2012-09-10. Retrieved 2012-12-15. 
  166. ^ Lyme Disease Hansard, 1997-02-03
  167. ^ Tick-Borne Disease, Risk and Realit BADA-UK, Wendy Fox, 2010
  168. ^ "Lyme borreliosis in England and Wales: 2009". HPA. Retrieved 2012-12-15. 
  169. ^ "Zoonoses report UK 2009". DEFRA. 24 January 2011. 
  170. ^ Overview Tick Bite Prevention Week
  171. ^ Haywood GA, O'Connell S, Gray HH (July 1993). "Lyme carditis: a United Kingdom perspective". Br Heart J 70 (1): 15–16. doi:10.1136/hrt.70.1.15. PMC 1025222. PMID 8037992. 
  172. ^ Guy EC, Bateman DE, Martyn CN, Heckels JE, Lawton NF (March 1989). "Lyme disease: prevalence and clinical importance of Borrelia burgdorferi specific IgG in forestry workers". Lancet 1 (8636): 484–86. doi:10.1016/S0140-6736(89)91377-9. PMID 2563850. 
  173. ^ Smith FD, Ballantyne R, Morgan ER, Wall R (March 2012). "Estimating Lyme disease risk using pet dogs as sentinels". Comp. Immunol. Microbiol. Infect. Dis. 35 (2): 163–67. doi:10.1016/j.cimid.2011.12.009. PMID 22257866. Lay summaryBristol University (25 January 2012). 
  174. ^ "Lyme disease risk from dogs 'higher than thought'". BBC News Online. 24 January 2012. 
  175. ^ The London climate change adaptation strategy - Draft report Greater London Authority, August 2008
  176. ^ John S. Brownstein, Theodore R. Holford and Durland Fish (2005). "Effect of Climate Change on Lyme Disease Risk in North America". Ecohealth 2 (1): 38–46. doi:10.1007/s10393-004-0139-x. PMC 2582486. PMID 19008966. 
  177. ^ a b Killilea, Mary E.; Swei, Andrea; Lane, Robert S.; Briggs, Cheryl J.; Ostfeld, Richard S. (2008). "Spatial Dynamics of Lyme Disease: A Review". EcoHealth 5 (2): 167–195. doi:10.1007/s10393-008-0171-3. 
  178. ^ BC Ministry of Agriculture. "Ticks and Humans in British Columbia". Agf.gov.bc.ca. Retrieved 2012-12-15. 
  179. ^ "Lyme Disease Fact Sheet". Phac-aspc.gc.ca. 2012-07-04. Retrieved 2012-12-15. 
  180. ^ Ogden NH, Lindsay LR, Morshed M, Sockett PN, Artsob H (June 2009). "The emergence of Lyme disease in Canada". CMAJ 180 (12): 1221–24. doi:10.1503/cmaj.080148. PMC 2691438. PMID 19506281. 
  181. ^ Leighton, Patrick A; Koffi, Jules K; Pelcat, Yann; Lindsay, L Robbin; Ogden, Nicholas H (2012). "Predicting the speed of tick invasion: An empirical model of range expansion for the Lyme disease vector Ixodes scapularis in Canada". Journal of Applied Ecology 49 (2): 457–64. doi:10.1111/j.1365-2664.2012.02112.x. 
  182. ^ Gordillo-Pérez, Guadalupe; Torres, Javier; Solórzano-Santos, Fortino; de Martino, Sylvie; Lipsker, Dan; Velázquez, Edmundo (Oct 2007), Borrelia burgdorferi Infection and Cutaneous Lyme Disease, Mexico, Emerg Infect Dis [serial on the Internet], doi:10.3201/eid1310.060630 
  183. ^ Lyme Disease, Centers for Disease Control and Prevention,http://www.cdc.gov/lyme/stats/humanCases.html
  184. ^ CDC (January 4, 2012). "Reported Lyme disease cases by state, 2000-2010". Centers for Disease Control and Prevention (CDC). Retrieved April 29, 2012. 
  185. ^ "Lyme disease--United States, 2003–2005". MMWR Morb. Mortal. Wkly. Rep. 56 (23): 573–76. June 2007. PMID 17568368. 
  186. ^ Bacon RM, Kugeler KJ, Mead PS (October 2008). "Surveillance for Lyme disease--United States, 1992–2006". MMWR Surveill Summ 57 (10): 1–9. PMID 18830214. 
  187. ^ a b Robbins, Jim (May 20, 2003). "Montana Lab Tries to Identify Tick-Borne Disease". The New York Times. 
  188. ^ "Lyme Disease Data". Centers for Disease Control and Prevention (CDC).
  189. ^ "Lyme disease (Borrelia burgdorferi) 2011 case definition". U.S. Centers for Disease Control and Prevention. 
  190. ^ a b "Lyme disease (Borrelia burgdorferi) 2008 case definition". U.S. Centers for Disease Control and Prevention. 
  191. ^ a b Swanson KI, Norris DE (2007). "Detection of Borrelia burgdorferi DNA in lizards from Southern Maryland". Vector-Borne and Zoonotic Diseases 7 (1): 42–49. doi:10.1089/vbz.2006.0548. PMID 17417956. 
  192. ^ Richter D, Matuschka FR (July 2006). "Perpetuation of the Lyme disease spirochete Borrelia lusitaniae by lizards". Appl. Environ. Microbiol. 72 (7): 4627–32. doi:10.1128/AEM.00285-06. PMC 1489336. PMID 16820453. 
  193. ^ Giery ST, Ostfeld RS (June 2007). "The role of lizards in the ecology of Lyme disease in two endemic zones of the northeastern United States". J. Parasitol. 93 (3): 511–17. doi:10.1645/GE-1053R1.1. PMID 17626342. 
  194. ^ Amore G, Tomassone L, Grego E, et al. (March 2007). "Borrelia lusitaniae in immature Ixodes ricinus (Acari: Ixodidae) feeding on common wall lizards in Tuscany, central Italy". J. Med. Entomol. 44 (2): 303–07. doi:10.1603/0022-2585(2007)44[303:BLIIIR]2.0.CO;2. PMID 17427701. 
  195. ^ Majláthová V, Majláth I, Derdáková M, Víchová B, Pet'ko B (December 2006). "Borrelia lusitaniae and green lizards (Lacerta viridis), Karst Region, Slovakia". Emerging Infect. Dis. 12 (12): 1895–901. doi:10.3201/eid1212.060784. PMC 3291370. PMID 17326941. 
  196. ^ Lyme disease fact sheet Analysis of CDC data on VoxHealth. Retrieved on 2013-30-1
  197. ^ Mantovani E, Costa IP, Gauditano G, Bonoldi VL, Higuchi ML, Yoshinari NH (April 2007). "Description of Lyme disease-like syndrome in Brazil. Is it a new tick borne disease or Lyme disease variation?". Braz. J. Med. Biol. Res. 40 (4): 443–56. doi:10.1590/S0100-879X2006005000082. PMID 17401487. 
  198. ^ Yoshinari NH, Oyafuso LK, Monteiro FG, et al. (1993). "Doença de Lyme: Relato de um caso observado no Brasil" [Lyme disease. Report of a case observed in Brazil]. Rev Hosp Clin Fac Med Sao Paulo (in Portuguese) 48 (4): 170–74. PMID 8284588. 
  199. ^ Hoen AG, Margos G, Bent SJ, et al. (September 2009). "Phylogeography of Borrelia burgdorferi in the eastern United States reflects multiple independent Lyme disease emergence events". Proc. Natl. Acad. Sci. U.S.A. 106 (35): 15013–18. Bibcode:2009PNAS..10615013H. doi:10.1073/pnas.0903810106. JSTOR 40484546. PMC 2727481. PMID 19706476. Lay summaryYaleNews (August 10, 2009). 
  200. ^ Josselyn, John (1670). An Account of Two Voyages to New-England Made during the Years 1638, 1663. page 92
  201. ^ a b Drymon, MM (2008). Disguised as the devil: how Lyme disease created witches and changed history. pp. 51–52. ISBN 978-0-615-20061-3. 
  202. ^ Summerton N (1995). "Lyme disease in the eighteenth century". BMJ 311 (7018): 1478. doi:10.1136/bmj.311.7018.1478. 
  203. ^ Hall, Stephen S (November 2011). "Iceman Autopsy". National Geographic. Retrieved October 17, 2011. 
  204. ^ a b Marcus, Karl (1910). "Verhandlungen der dermatologischen Gesellschaft zu Stockholm". Archiv für Dermatologie und Syphilis 101 (2–3): 403–06. doi:10.1007/BF01832773. 
  205. ^ Burckhardt JL (1911). "Zur Frage der Follikel- und Keimzentrenbildung in der Haut". Frankfurter Zeitschrift fur Pathologie (in German) 6: 352–59. 
  206. ^ Hellerström S (1930). "Erythema chronicum migrans Afzelii". Archiv Dermatologie and Venereologie (Stockholm) (in German) 11: 315–21. 
  207. ^ Lenhoff C (1948). "Spirochetes in aetiologically obscure diseases". Acta Derm. Venereol. 28: 295–324. 
  208. ^ Thyresson N (1949). "The penicillin treatment of acrodermatitis atrophicans chronica (Herxheimer)". Acta Derm. Venereol. 29 (6): 572–621. PMID 18140373. 
  209. ^ Bianchi GE (1950). "Die Penicillinbehandlung der Lymphozytome" [Penicillin therapy of lymphocytoma]. Dermatologica (in German) 100 (4-6): 270–73. doi:10.1159/000257185. PMID 15421023. 
  210. ^ Paschoud JM (1954). "Lymphocytom nach Zeckenbiss" [Lymphocytoma after tick bite]. Dermatologica (in German) 108 (4-6): 435–37. PMID 13190934. 
  211. ^ Scrimenti RJ (July 1970). "Erythema chronicum migrans". Arch Dermatol 102 (1): 104–05. doi:10.1001/archderm.102.1.104. PMID 5497158. 
  212. ^ Steere AC (November 2006). "Lyme borreliosis in 2005, 30 years after initial observations in Lyme Connecticut". Wien. Klin. Wochenschr. 118 (21-22): 625–33. doi:10.1007/s00508-006-0687-x. PMID 17160599. 
  213. ^ Weir, William (2013-09-19). "Lyme Disease Pioneer Stephen Malawista Dies". Hartford Courant. Retrieved 2013-10-14. 
  214. ^ Sternbach G, Dibble CL (1996). "Willy Burgdorfer: Lyme disease". J Emerg Med 14 (5): 631–34. doi:10.1016/S0736-4679(96)00143-6. PMID 8933327. 
  215. ^ Bolognia JL; Jorizzo JL ; Rapini RP (2007). Dermatology (2nd ed.). St. Louis: Mosby. ISBN 978-1-4160-2999-1.  [page needed]
  216. ^ Mast WE, Burrows WM (November 1976). "Erythema chronicum migrans and 'lyme arthritis'". JAMA 236 (21): 2392. doi:10.1001/jama.236.21.2392d. PMID 989847. 
  217. ^ Steere AC; Malawista SE; Snydman DR et al. (1977). "Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three connecticut communities". Arthritis Rheum. 20 (1): 7–17. doi:10.1002/art.1780200102. PMID 836338. 
  218. ^ Steere AC, Hutchinson GJ, Rahn DW, et al. (July 1983). "Treatment of the early manifestations of Lyme disease". Annals of Internal Medicine 99 (1): 22–26. doi:10.7326/0003-4819-99-1-22. PMID 6407378. 
  219. ^ Burgdorfer W (1984). "Discovery of the Lyme disease spirochete and its relation to tick vectors". Yale J Biol Med 57 (4): 515–20. PMC 2590008. PMID 6516454. 
  220. ^ Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Davis JP (June 1982). "Lyme disease-a tick-borne spirochetosis?". Science 216 (4552): 1317–19. Bibcode:1982Sci...216.1317B. doi:10.1126/science.7043737. PMID 7043737. 
  221. ^ Luft BJ, Volkman DJ, Halperin JJ, Dattwyler RJ (1988). "New chemotherapeutic approaches in the treatment of Lyme borreliosis". Annals of the New York Academy of Sciences 539: 352–61. Bibcode:1988NYASA.539..352L. doi:10.1111/j.1749-6632.1988.tb31869.x. PMID 3056203. 
  222. ^ Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ (December 1990). "Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis". Lancet 336 (8728): 1404–06. doi:10.1016/0140-6736(90)93103-V. PMID 1978873. 
  223. ^ Ribeiro JM, Mather TN, Piesman J, Spielman A (March 1987). "Dissemination and salivary delivery of Lyme disease spirochetes in vector ticks (Acari: Ixodidae)". J. Med. Entomol. 24 (2): 201–05. PMID 3585913. 
  224. ^ Edlow, Jonathan A (2003). Bull's-eye: unraveling the medical mystery of Lyme disease. Yale University Press. ISBN 0-300-09867-7. [page needed]
  225. ^ LoGiudice K, Ostfeld RS, Schmidt KA, Keesing F (January 2003). "The ecology of infectious disease: effects of host diversity and community composition on Lyme disease risk". Proc. Natl. Acad. Sci. U.S.A. 100 (2): 567–71. Bibcode:2003PNAS..100..567L. doi:10.1073/pnas.0233733100. PMC 141036. PMID 12525705. 
  226. ^ Patz JA, Daszak P, Tabor GM, et al. (July 2004). "Unhealthy landscapes: Policy recommendations on land use change and infectious disease emergence". Environ. Health Perspect. 112 (10): 1092–98. doi:10.1289/ehp.6877. PMC 1247383. PMID 15238283. 
  227. ^ Khasnis AA, Nettleman MD (2005). "Global warming and infectious disease". Arch. Med. Res. 36 (6): 689–96. doi:10.1016/j.arcmed.2005.03.041. PMID 16216650. 
  228. ^ Marques, Adriana (June 2008). "Chronic Lyme Disease: An appraisal". Infect Dis Clin North Am 22 (2): 341–60. doi:10.1016/j.idc.2007.12.011. PMC 2430045. PMID 18452806. 
  229. ^ a b Little SE, Heise SR, Blagburn BL, Callister SM, Mead PS (April 2010). "Lyme borreliosis in dogs and humans in the USA". Trends Parasitol. 26 (4): 213–18. doi:10.1016/j.pt.2010.01.006. PMID 20207198. 
  230. ^ a b Krupka I, Straubinger RK (November 2010). "Lyme borreliosis in dogs and cats: background, diagnosis, treatment and prevention of infections with Borrelia burgdorferi sensu stricto". Vet. Clin. North Am. Small Anim. Pract. 40 (6): 1103–19. doi:10.1016/j.cvsm.2010.07.011. PMID 20933139. 
  231. ^ Hahn, Jeffrey. "Ticks and Their Control". Regents of the University of Minnesota. 

Further reading[edit]

External links[edit]