Lyme disease

Lyme disease, or Lyme borreliosis,^[1] is an emerging infectious disease caused by at least three species of bacteria belonging to the genus Borrelia.^[2][3] Borrelia burgdorferi sensu stricto^[4] is the main cause of Lyme disease in the United States, whereas Borrelia afzelii and Borrelia garinii cause most European cases. The disease is named after the town of Lyme, Connecticut, USA, where a number of cases were identified in 1975. Although Allen Steere realized that Lyme disease was a tick-borne disease in 1978, the cause of the disease remained a mystery until 1981, when B. burgdorferi was identified by Willy Burgdorfer.

Lyme disease is the most common tick-borne disease in the Northern Hemisphere. Borrelia is transmitted to humans by the bite of infected ticks belonging to a few species of the genus Ixodes ("hard ticks").^[5] Early symptoms may include fever, headache, fatigue, depression, and a characteristic circular skin rash called erythema migrans. 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] Delayed or inadequate treatment can lead to the more serious symptoms, which can be disabling and difficult to treat.^[7] Lyme disease is a biosafety level 2 disease.

Signs and symptoms

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). Symptoms most often occur from May through September, because the nymphal stage of the tick is responsible for most cases.^[8] Asymptomatic infection exists, but occurs in less than 7% of infected individuals in the United States.^[9] Asymptomatic infection may be much more common among those infected in Europe.^[10]

Early localized infection

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 thirty days after the tick bite.^[11][12] The rash is red, and may be warm, but is generally painless. Classically, the innermost portion remains dark red and becomes indurated; the outer edge remains red; and the portion in between clears, giving the appearance of a bullseye. However, partial clearing is uncommon, and the bullseye pattern more often involves central redness.^[13]

EM is thought to occur in about 80% of infected patients.^[12] Patients can also experience flu-like symptoms, such as headache, muscle soreness, fever, and malaise.^[14] Lyme disease can progress to later stages even in patients who do not develop a rash.^[15]

Early disseminated infection

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.^[16] Another skin condition, which is apparently absent in North American patients, but occurs in Europe, is borrelial lymphocytoma, a purplish lump that develops on the ear lobe, nipple, or scrotum.^[17] Other discrete symptoms include migrating pain in muscles, joints, and tendons, and heart palpitations and dizziness caused by changes in heartbeat.

Various acute neurological problems, termed neuroborreliosis, appear in 10–15% of untreated patients.^[14][18] 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.^[19]

Late persistent infection

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 paraplegia in the most extreme cases.^[20]

Chronic neurologic symptoms occur in up to 5% of untreated patients.^[14] 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 profound fatigue.^[21] However, other problems, such as depression and fibromyalgia, are no more common in people who have been infected with Lyme than in the general population.^[21][22] 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 mis-diagnosed as schizophrenia or bipolar disorder. Panic attacks and anxiety can occur; there may also be delusional behavior, including somatoform delusions, sometimes accompanied by a depersonalization or derealization syndrome, where the patients begin to feel detached from themselves or from reality.^[23][24]

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.^[25]

Lyme arthritis usually affects the knees.^[26] In a minority of patients, arthritis can occur in other joints, including the ankles, elbows, wrist, 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.^[17] 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.^[27]

Cause

Lyme disease is caused by Gram-negative, spirochetal bacteria from the genus Borrelia. At least 11 Borrelia species have been discovered, twelve of which are known to be Lyme-related.^{[28][29][30][31]} The Borrelia species that cause Lyme disease are collectively known as Borrelia burgdorferi sensu lato, and show a great deal of genetic diversity.^[32]

The group Borrelia burgdorferi sensu lato, made up of three closely related species, are probably responsible for the large majority of cases: B. burgdorferi sensu stricto (predominant in North America, but also present in Europe), B. afzelii, and B. garinii (both predominant in Eurasia).^[28] 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.^[33][34]

Transmission

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.^[35] Hard-bodied ticks of the genus Ixodes are the main vectors of Lyme disease.^[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.^[35] Larval ticks are very rarely infected.^[36] 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; this may be because an infected tick must be attached for at least a day for transmission to occur.^[37]

In Europe, the vector is Ixodes ricinus, which is also called the sheep tick or castor bean tick.^[38] In China, Ixodes persulcatus (the taiga tick) is probably the most important vector.^[39] In North America, the black-legged tick or deer tick (Ixodes scapularis) is the main vector on the east coast.^[36] 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 Spirochaete Borrelia burgdorferi,^[40] though it may be implicated in a related syndrome called southern tick-associated rash illness, which resembles a mild form of Lyme disease.^[41] On the West Coast of the United States, the main vector is the western black-legged tick (Ixodes pacificus).^[42] 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.^[43][44]

While Lyme spirochetes have been found in insects as well as ticks,^[45] reports of actual infectious transmission appear to be rare.^[46] Lyme spirochetes have been found in semen^[47] and breast milk,^[48] but transmission has not been known to take place through sexual contact.^[49] 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.^[50][51] Pregnant Lyme-disease patients cannot be treated with the first-choice antibiotic, doxycycline (see below), as it is potentially harmful for the fetus. Instead, erythromycin is usually given; it is less effective against the disease but harmless for the fetus.^[50]

Tick-borne coinfections

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.^[52] Among early Lyme disease patients, depending on their location, 2–12% will also have HGA and 2–40% will have babesiosis.^[53] Ticks in certain regions, including the landscapes along the eastern Baltic Sea, also transmit tick-borne encephalitis.^[54]

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.^[55]

Pathophysiology

Borrelia burgdorferi can spread throughout the body during the course of the disease, and has been found in the skin, heart, joint, peripheral nervous system, and central nervous system.^[56][57] Many of the signs and symptoms of Lyme disease are a consequence of the immune response to the spirochete in those tissues.^[14]

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.^[58] 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.^[56] 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.^[59]

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.^[60] 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.^[37] 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.^[61][62]

In the brain, B. burgdorferi may induce astrocytes to undergo astrogliosis (proliferation followed by apoptosis), which may contribute to neurodysfunction.^[63] 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.^[64][65][66] Both microglia and astrocytes secrete IL-6 and TNF-alpha in the presence of the spirochete.^[63][67] This cytokine response may contribute to cognitive impairment.^[68]

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.^[69][70] This process is mediated via the hypothalamic-pituitary-adrenal axis. Additionally tryptophan, a precursor to serotonin, appears to be reduced within the central nervous system (CNS) in a number of infectious diseases that affect the brain, including Lyme.^[71] Researchers are investigating if this neurohormone secretion is the cause of neuropsychiatric disorders developing in some patients with borreliosis.^[72]

Immunological studies

Exposure to the Borrelia bacterium during Lyme disease possibly causes a long-lived and damaging inflammatory response,^[73] a form of pathogen-induced autoimmune disease.^[74] The production of this reaction might be due to a form of molecular mimicry, where Borrelia avoid being killed by the immune system by resembling normal parts of the body's tissues.^[75][76] It is therefore possible that if some chronic symptoms come from an autoimmune reaction, this could explain why some symptoms persist even after the spirochetes have been eliminated from the body. This hypothesis may explain chronic arthritis that persists after antibiotic therapy, similar to rheumatic fever, but its wider application is controversial.^[77][78]

Diagnosis

Lyme disease is diagnosed clinically based on symptoms, objective physical findings (such as erythema migrans, 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 bullseye, ie, it can be red all the way across. 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 will develop the characteristic bullseye rash, and many may not recall a tick bite.^[79]

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.^[80][81] 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."^[82] Lyme disease may be misdiagnosed as multiple sclerosis, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, lupus, Crohn's disease or other autoimmune and neurodegenerative diseases.

Laboratory testing

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.^[83] Serologic tests for Lyme disease are of limited use in people lacking objective signs of Lyme disease because of false positive results and cost.^[84]

The serological laboratory tests most widely available and employed are the Western blot and ELISA. A two-tiered protocol is recommended by the CDC: the sensitive ELISA test is performed first, and if it is positive or equivocal, then the more specific Western blot is run.^[85] 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.^[86][87] 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.^[88] ELISA testing, however, is typically done against region-specific epitopes, and may report a false negative if the patient has been infected with Borrelia from another region than that in which the patient is tested.^[89]

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,^[90] as well as herpes simplex virus.^[91] The overall rate of false positives is low, only about 1 to 3%, in comparison to a false negative rate of up to 36% using two-tiered testing.^[88]

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.^[92] Even when properly performed, PCR often shows false negative results with blood and cerebrospinal fluid (CSF) specimens.^[93] 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.^[94] With the exception of PCR, there is currently no practical means for detecting the presence of the organism, 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.^[95]

Western blot, ELISA and PCR can be performed by either blood test via venipuncture or 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.^[96]

New techniques for clinical testing of Borrelia infection have been developed, such as LTT-MELISA,^[97] although the results of studies are contradictory, and there is no study assessing the diagnostic sensitivity and specificity of the test.^[98] Others, such as focus floating microscopy, are under investigation.^[99] New research indicates chemokine CXCL13 may also be a possible marker for neuroborreliosis.^[100]

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 Borrelia burgdorferi, and lymphocyte transformation tests. The CDC does not recommend these tests, and a 2005 review by Aguero-Rosenfeld et al. in Clinical Microbiology Reviews stated their use is "of great concern and is strongly discouraged".^[93]

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.^[101]

Imaging

Neuroimaging does not provide specific patterns unique to neuroborreliosis, but may aid in differential diagnosis and in understanding the pathophysiology of the disease.^[102]

Prevention

Protective clothing includes a hat, long-sleeved shirts 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.

Attached ticks should be removed promptly, as removal within 36 hours can reduce transmission rates.^[103] One study concluded that a single dose of doxycycline given within 72 hours after a high-risk tick exposure can prevent the development of Lyme disease.^[104]

A community can prevent 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.^[105]

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.^[106]

Management of host animals

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. This has been demonstrated in the communities of Monhegan, Maine^[107] and Mumford Cove, Connecticut.^[108] The black-legged or deer tick (Ixodes scapularis) depends on the white-tailed deer for successful reproduction.

For example, in the US, 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.^[109] However, such a drastic reduction may be impractical in many areas.

Vaccination

A recombinant vaccine against Lyme disease, based on the outer surface protein A (OspA) of B. burgdorferi, was developed by GlaxoSmithKline. 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.^[110] LYMErix was approved on the basis of these trials by the U.S. 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.^[111] 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 (CDC), who found no connection between the vaccine and the autoimmune complaints.^[112]

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,^[113] in the setting of negative media coverage and fears of vaccine side effects.^[112][114] The fate of LYMErix was described in the medical literature as a "cautionary tale";^[114] 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."^[115] 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."^[112]

New vaccines are being researched using outer surface protein C (OspC) and glycolipoprotein as methods of immunization.^[116][117] Vaccines are available for dogs.^[118]

Tick removal

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. 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 body.^[119] 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.^[103]

Treatment

Antibiotics are the primary treatment for Lyme disease; the most appropriate antibiotic treatment depends upon the patient and the stage of the disease.^[3] According to the Infectious Diseases Society of America (IDSA) guidelines, the antibiotics of choice are doxycycline (in adults), amoxicillin (in children), erythromycin (for pregnant women) and ceftriaxone, with treatment lasting 10 to 28 days.^[120] Alternative choices are cefuroxime and cefotaxime.^[3] Treatment of pregnant women is similar, but tetracycline should not be used.^[120]

A double blind, randomized, placebo-controlled multicenter clinical study indicated three weeks of treatment with intravenous ceftriaxone, followed by 100 days of treatment with oral amoxicillin did not improve symptoms any more than just three weeks of treatment with ceftriaxone. The researchers noted the outcome should not be evaluated after the initial antibiotic treatment, but rather 6–12 months afterwards. In patients with chronic posttreatment symptoms, persistent positive levels of antibodies did not seem to provide any useful information for further care of the patient.^[121]

In later stages, the bacteria disseminate throughout the body and may cross the blood-brain barrier, making the infection more difficult to treat. Late diagnosed Lyme is treated with oral or intravenous antibiotics, frequently ceftriaxone for a minimum of four weeks. Minocycline is also indicated for neuroborreliosis for its ability to cross the blood-brain barrier.^[122]

Prognosis

For early cases, prompt treatment is usually curative.^[123] 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 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.^[7] Patients with late stage Lyme disease have been shown to experience a level of physical disability equivalent to that seen in congestive heart failure.^[124] In rare cases, Lyme disease can be fatal.^[125]

Many patients report a lack of understanding among employers, family, and friends as being the most frustrating aspect of Lyme disease. The fatigue that accompanies it may be perceived as malingering, especially after the disease enters its second and third week of treatment.

Epidemiology

Lyme disease is endemic in Northern Hemisphere temperate regions.^[126][127]

Africa

In northern Africa, B. burgdorferi sensu lato has been identified in Morocco, Algeria, Egypt and Tunisia.^{[128][129][130]}

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.^[131] In East Africa, two cases of Lyme disease have been reported in Kenya.^[132]

Asia

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.^{[133][134][135]} Borrelia has been isolated in Mongolia, as well.^[136]

Australia

In Australia, there is now definitive evidence for the existence of endemic B. burgdorferi infection in a recently published paper titled "Emerging incidence of Lyme borreliosis, babesiosis, bartonellosis and granulocytic ehrlichiosis in Australia" available for download under open access at http://www.dovepress.com/articles.php?article_id=8891. The matter has been controversial for nearly 20 years and has been described as a local lyme-like syndrome and sometimes as Lyme disease.^[137] Cases of neuroborreliosis have been documented in Australia, but are often ascribed to travel to other continents, however it should be noted that the author of the new study states it is entirely a neurological disease in Australia.

Canada

Due 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, Southwest Nova Scotia and parts of the Prairie provinces, as well as British Columbia. Cases have been reported as far east as the island of Newfoundland.^{[138][139][140][141][142]}

Europe

In Europe, Lyme disease is caused by infection with one or more pathogenic European genospecies of the spirochaete B. burgdorferi sensu lato, mainly transmitted by the tick Ixodes ricinus.^[143] 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.^[144][145] Incidence in southern Europe, such as Italy and Portugal, is much lower.

South America

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.^[146] The first reported case of Lyme disease in Brazil was made in 1993 in Sao Paulo.^[147] B. burgdorferi sensu stricto antigens in patients have been identified in Colombia and Bolivia.

United States

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.^[148]

Although Lyme disease has been reported in 49 of 50 states in the U.S, 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).^[149] New 2008 CDC Lyme case definition guidelines are used to determine confirmed CDC surveillance cases.^[150] 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. 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.

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.^[151] Except for one study in Europe,^[152] 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.^{[153][154][155][156]} 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.^[44]

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.

It should be noted that 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.

History

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.^[157] 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."^[158] 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.^[159] 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.^[160] 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.^[161] 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. ^[162]

The early European studies of what is now known as Lyme disease described its skin manifestations. The first study dates to 1883 in Wrocław, Poland (then known as Breslau, Free State of Prussia), where physician Alfred Buchwald described a man who had suffered for 16 years with a degenerative skin disorder now known as acrodermatitis chronica atrophicans. 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.^[163] The skin condition now known as borrelial lymphocytoma was first described in 1911.^[164]

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.^[165] 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.^[166] 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.^[167] 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.^[168][169]

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.^[170]

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.^[171] This was investigated by physicians David Snydman and Allen Steere of the Epidemic Intelligence Service, and by others from Yale University. 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.^[172]

Before 1976, elements of B. burgdorferi sensu lato infection were called or known as tick-borne meningopolyneuritis, Garin-Bujadoux syndrome, Bannwarth syndrome, Afzelius' disease,^[1] Montauk Knee or sheep tick fever. Since 1976 the disease is most often referred to as Lyme disease,^[173][174] Lyme borreliosis or simply borreliosis.

In 1980, Steere, et al., began to test antibiotic regimens in adult patients with Lyme disease.^[175] 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.^[176] In June 1982 he published his findings in Science, and the spirochete was named Borrelia burgdorferi in his honor.^[177]

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.^[178][179] 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.^[180]

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."

—^[181]

Society and culture

Ecology

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.^[182][183] Researchers are investigating possible links between global warming and the spread of vector-borne diseases, including Lyme disease.^[184]

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

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

The risk of acquiring Lyme disease does not depend on the existence of a local deer population, as is commonly assumed. New research suggests eliminating deer from smaller areas (less than 2.5 ha or 6 acres) may in fact lead to an increase in tick density and the rise of "tick-borne disease hotspots".^[185]

Harassment of researchers

In 2001, the New York Times Magazine reported that Allen Steere, chief of immunology and rheumatology at Tufts Medical Center and a codiscoverer and leading expert on Lyme disease, had been harassed, stalked, and threatened by patients and patient advocacy groups angry at his refusal to substantiate their diagnoses of chronic Lyme disease and endorse long-term antibiotic therapy.^[186] Because this intimidation included death threats, Steere was assigned security guards.^[112] Paul G. Auwaerter, director of infectious disease at Johns Hopkins School of Medicine, cited the political controversy and high emotions as contributing to a "poisonous atmosphere" around Lyme disease, which he believes has led to doctors trying to avoid having Lyme patients in their practice.^[187]

Media

A 2004 study in The Pediatric Infectious Disease Journal stated 9 of 19 Internet websites surveyed contained what were described as major inaccuracies. Websites described as providing inaccurate information included several with the word "lyme" in their domain name (e.g. lymenet.org), as well as the website of the International Lyme And Associated Diseases Society.^[188] A 2008 article in the New England Journal of Medicine argued media coverage of chronic Lyme disease ignored scientific evidence in favor of anecdotes and testimonials:

The media frequently disregard complex scientific data in favor of testimonials about patients suffering from purported chronic Lyme disease and may even question the competence of clinicians who are reluctant to diagnose chronic Lyme disease. All these factors have contributed to a great deal of public confusion with little appreciation of the serious harm caused to many patients who have received a misdiagnosis and have been inappropriately treated.

—^[189]

The 2008 documentary film Under Our Skin: The Untold Story of Lyme Disease opened June 19, 2009 in New York City. This documentary, made by a director whose sister contracted the disease, argues that chronic Lyme disease exists.^[190] Lyme disease was also the focus of a major feature in The Times (London) in February 2010^[191] which detailed the impact the disease had had on British author Alex Wade.

Notable cases

• Alex Wade—Author^[191]
• Amy Tan—Author^[192]
• Ben Petrick—Colorado Rockies catcher/outfielder from 1999–2003^[193]
• Ben Stiller—Actor/Director^[194]
• Chuck Schumer—New York Senator^[195]
• Daryl Hall—Musician^[196]
• Diane Varsi—Actress
• John Lurie—Actor, Artist & Musician^[197]
• George W. Bush—former United States President^[198]
• GG Allin-Rock musician
• Ötzi-Austrian Ice Man^[199]
• Parker Posey—Actress^[200]
• Ryan Dunn—Jackass star ^[201]
• Samantha Stosur—Australian tennis player; contracted in 2007 (affected at the French Open, did not play in 2007 after Wimbledon)
• Thalía—Singer
• Trevor Bayne—current NASCAR driver
• Wyatt Sexton—Former Quarterback at Florida State University^[202]
• Kyle Morton-Lead singer of the band Typhoon

Chronic Lyme disease

The term "chronic Lyme disease" or "post-Lyme disease syndrome" is often applied to several different sets of patients. One usage refers to people suffering from the symptoms of untreated and disseminated late-stage Lyme disease: arthritis, peripheral neuropathy and/or encephalomyelitis. The term is also applied to people who have had the disease in the past and some symptoms remain after antibiotic treatment, which is also called post-Lyme disease syndrome. A third and controversial use of the term applies to patients with nonspecific symptoms, such as fatigue, who show no objective evidence they have been infected with Lyme disease in the past, since the standard diagnostic tests for infection are negative.^[6][189]

Up to one third of Lyme disease patients who have completed a course of antibiotic treatment continue to have symptoms, such as severe fatigue, sleep disturbance, unconsiousness, and cognitive difficulties, with these symptoms being severe in about 2% of cases.^[7][203] While it is undisputed these patients can have severe symptoms, the cause and appropriate treatment is controversial. The symptoms may represent "for all intents and purposes" fibromyalgia or chronic fatigue syndrome.^[204] A few doctors attribute these symptoms to persistent infection with Borrelia, or coinfections with other tick-borne infections, such as Ehrlichia and Babesia.^[205][206] Other doctors believe that the initial infection may cause an autoimmune reaction that continues to cause serious symptoms even after the bacteria have been eliminated by antibiotics.^[73]

Four randomized, controlled trials have been performed in patients who have persisting complaints and a history of Borrelia infection. Some of these patients had evidence of an ongoing Borrelia infection, and almost all of them were previously treated with antibiotics. The authors of all four trials concluded their results did not support long-term antibiotic therapy:

• Two studies showed no benefit from 30 days of intravenous ceftriaxone and 60 days of oral doxycycline, concluding "treatment with intravenous and oral antibiotics for 90 days did not improve symptoms more than placebo".^[207][208]
• One study showed an improvement only in fatigue after 28 days of intravenous antibiotics, an effect that was significant only in a group of patients that never had antibiotics previously.^[209] The results may have been compromised by unblinding, and detected a large placebo effect.^[210] This trial also saw several cases of life-threatening side effects, concluding "repeated courses of antibiotic treatment are not indicated for persistent symptoms following Lyme disease including those related to fatigue and cognitive dysfunction, particularly in light of the frequency of serious adverse events."
• One study reported an improvement in fatigue in a subset of patients, and a transient improvement in cognition after 10 weeks of intravenous antibiotics, but concluded the treatment was "not an effective strategy for sustained cognitive improvement."^[211][212] These patients had also been ill for many years and had taken many antibiotic courses. Also, this study performed ad hoc statistical analysis^[213] and its results were questionably significant.^[203]

An advocacy group called the International Lyme And Associated Diseases Society (ILADS)^[214] argues the persistence of B. burgdorferi may be responsible for manifestations of late Lyme disease symptoms.^[215] It has questioned the generalizability and reliability of some of the above trials and the reliability of the current diagnostic tests.^{[206][215][216]} Major US medical authorities, including the Infectious Diseases Society of America, the American Academy of Neurology, and the National Institutes of Health, have stated there is no convincing evidence that Borrelia is involved in the various symptoms classed as chronic Lyme disease, and advise against long-term antibiotic treatment as ineffective and possibly harmful.^{[84][189][217][218]} Prolonged antibiotic therapy presents significant risks and can have dangerous side effects. One death has been reported from complications of a 27-month course of intravenous antibiotics for an unsubstantiated diagnosis of chronic Lyme disease.^[219]

Antibiotic treatment is the central pillar in the management of Lyme disease. However, in the late stages of borreliosis, symptoms may persist despite extensive and repeated antibiotic treatment.^[220] Although these chronic symptoms are possibly due to either autoimmunity or residual bacteria (see immunological studies below), no Borrelia DNA can usually be detected in the joints after antibiotic treatment, which suggests the arthritis may continue, even after the bacteria have been killed.^[73] Lyme arthritis that persists after antibiotic treatment may be treated with hydroxychloroquine or methotrexate.^[221] Corticosteroid injections into the affected joint are not recommended for any stage of Lyme arthritis.^[222]

Patients with chronic neuropathic pain responded well to gabapentin monotherapy with residual pain after intravenous ceftriaxone treatment in a pilot study.^[223] Some antibiotics may have a dual effect on Lyme disease, since minocycline and doxycycline have anti-inflammatory effects in addition to their antibiotic actions, including anti-inflammatory effects specific to the inflammation caused by Lyme disease.^[224][225] Indeed, minocycline is used in other neurodegenerative and inflammatory disorders, such as multiple sclerosis, Parkinson's disease, Huntington's disease, rheumatoid arthritis and ALS.^[226]

Controversy and politics

While there is general agreement on the optimal treatment for early Lyme disease, there is considerable controversy over the existence, prevalence, diagnostic criteria, and treatment of chronic Lyme disease.^[214][227] The mainstream view is exemplified by a 2007 review in the New England Journal of Medicine, which noted the diagnosis of chronic Lyme disease is used by a few physicians despite a lack of "reproducible or convincing scientific evidence", leading the authors to describe this diagnosis as "the latest in a series of syndromes that have been postulated in an attempt to attribute medically unexplained symptoms to particular infections."^[189] Most medical authorities agree with this viewpoint: the IDSA, the American Academy of Neurology, the CDC, and the NIH advise against long-term antibiotic treatment for chronic Lyme disease, given the lack of supporting evidence and the potential toxicities.^{[84][217][218]} A minority view holds that chronic Lyme disease is responsible for a range of unexplained symptoms, sometimes in people without any evidence of past infection.^[227] This viewpoint is promoted by many patient advocates, notably an advocacy organization,^[214] the International Lyme And Associated Diseases Society.^[215] Groups of patients, patient advocates, and the small number of physicians who support the concept of chronic Lyme disease have organized to lobby for recognition of this diagnosis, as well as to argue for insurance coverage of long-term antibiotic therapy, which most insurers deny, as it is at odds with the guidelines of major medical organizations.^[227][228]

In 2006, Richard Blumenthal, the Connecticut Attorney General, opened an antitrust investigation against the IDSA, accusing the IDSA Lyme disease panel of undisclosed conflicts of interest and of unduly dismissing alternative therapies and chronic Lyme disease. The investigation was closed on May 1, 2008 without charges when the IDSA agreed to submit to a review of its guidelines by a panel of independent scientists and physicians which would occur on July 30, 2009.^[187] Views on the motivation and outcome of the investigation varied. Blumenthal's press release described the agreement as a vindication of his investigation and repeated his conflict-of-interest allegations.^[229] The IDSA focused on the fact that the medical validity of the IDSA guidelines was not challenged,^[230] and cited mounting legal costs and the difficulty of presenting scientific arguments in a legal setting as their rationale for accepting the settlement.^[231] A journalist writing in Nature Medicine suggested some IDSA members may not have disclosed potential conflicts of interest,^[227] while a Forbes piece described Blumenthal's investigation as "intimidation" of scientists by an elected official with close ties to Lyme advocacy groups.^[228] The Journal of the American Medical Association described the decision as an example of the "politicization of health policy" that went against the weight of scientific evidence and may have a chilling effect on future decisions by medical associations.^[232]

The state of Connecticut went on to enact a law on June 18, 2009 "to allow a licensed physician to prescribe, administer or dispense long-term antibiotics for a therapeutic purpose to a patient clinically diagnosed with Lyme disease."^[233] The states of Rhode Island^[234] California^[235] Massachusetts^[236] and New Hampshire^[237] have similar laws.^[238] The expert panel's review was published in 2010, with the independent doctors and scientists in the panel unanimously endorsing the guidelines, stating "No changes or revisions to the 2006 Lyme guidelines are necessary at this time," and concluding long-term antibiotic treatments are unproven and potentially dangerous.^[239] The IDSA welcomed the final report, stating that "Our number one concern is the patients we treat, and we’re glad patients and their physicians now have additional reassurance that the guidelines are medically sound."^[240]

Alternative therapies

A number of other alternative therapies have been suggested, though clinical trials have not been conducted, so the therapies are not known to be scientifically sound. For example, the use of hyperbaric oxygen therapy is claimed by CAM enthusiasts as an adjunct to antibiotics for Lyme has been discussed.^[241] Though there are no published data from clinical trials to support its use, preliminary results using a mouse model suggest its effectiveness against B. burgdorferi both in vitro and in vivo.^[242] Anecdotal clinical research has suggested antifungal azole medications, such as fluconazole, could be used in the treatment of Lyme, but the use of these drugs has yet to be tested in a controlled study.^[243]

Alternative medicine approaches include bee venom, because it contains the peptide melittin, which has been shown to exert inhibitory effects on Lyme bacteria in vitro;^[244] however, no clinical trials of this treatment have been carried out. Anecdotally, medical marijuana may aid joint pain, cognitive brain difficulties and other Lyme-associated issues, although clinical trials are lacking.

References

• Jonathan A. Edlow MD, Bull's Eye: Unraveling the Medical Mystery of Lyme Disease, Yale University Press, 2003
• Pamela Weintraub, Cure Unknown: Inside the Lyme Disease Epidemic, May 2008. 400 p. St. Martin's Press, hardcover. ISBN 978-0-312-37812-7.

External links

• Lyme Disease Map Project
• Lyme disease organizations at the Open Directory Project
• Lyme Disease Institute for Good Medicine at the Pennsylvania Medical Society
• Lyme Disease: from the U.S. Centers for Disease Control
• Lyme Disease Information: from the National Institute of Allergy and Infectious Diseases
• Lyme Disease The Merck Manual
• US Army Factsheet on Lyme Disease (CHPPM's Entomological Sciences Program)
• CTV (Canada) W5 Documentary on Lyme Disease in Canada
• International Lyme and Associated Diseases Society