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Nymphal and adult deer ticks can be carriers of Lyme disease. Nymphs are about the size of a poppy seed.
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Lyme disease, Lyme borreliosis is an infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. Borrelia burgdorferi sensu stricto is the main cause of Lyme disease in North America, whereas Borrelia afzelii and Borrelia garinii cause most European cases. The disease is named after the towns of Lyme and Old 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"). Early symptoms may include fever, headache, fatigue, depression, and a characteristic circular skin rash called erythema migrans (EM). 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. Delayed or inadequate treatment can lead to more serious symptoms, which can be disabling and difficult to treat.
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. Asymptomatic infection exists, but occurs in less than 7% of infected individuals in the United States. Asymptomatic infection may be much more common among those infected in Europe.
Early localized infection is where the Lyme disease has not yet spread throughout the body. The only area affected is where the infection has first come into contact with the skin. 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. 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 bullseye. However, partial clearing is uncommon, and the bullseye pattern more often involves central redness.
The erythema migrans rash associated with early infection is found in approximately 80% of patients and can have a range of appearances including the classic target bull's-eye lesion and nontarget appearing lesions. The 20% without the erythema migrans and the nontarget lesions can often cause mis-identification of Lyme disease.
EM is thought to occur in about 80% of infected patients. Patients can also experience flu-like symptoms, such as headache, muscle soreness, fever, and malaise. Lyme disease can progress to later stages even in patients who do not develop a rash.
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. Another skin condition that 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. Other discrete symptoms include migrating pain in muscles, joints, tendons, heart palpitations and dizziness caused by changes in heartbeat.
Various acute neurological problems, termed neuroborreliosis, appear in 10–15% of untreated patients. 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.
The disease may also have cardiac manifestations such as AV block.
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 paraparesis in extreme cases. The associated nerve pain radiating out from the spine is termed Bannwarth syndrome.
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. 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. 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.
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.
Lyme arthritis usually affects the knees. 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. 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.
Lyme disease is caused by spirochetal bacteria from the genus Borrelia. Spirochetes are surrounded by peptidoglycan and flagella and are composed of about 40% of DNA. Because of their double-membrane envelope, Borrelia are often mistakenly described as Gram negative despite the considerable differences in their envelope components with Gram-negative bacteria. The Borrelia species that are Lyme-related are collectively known as Borrelia burgdorferi sensu lato, and show a great deal of genetic diversity.
Borrelia 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). 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.
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. Hard-bodied ticks of the genus Ixodes are the main vectors of Lyme disease (also the vector for Babesia). Most infections are caused by ticks in the nymphal stage, as they are very small and may feed for long periods of time undetected. Larval ticks are very rarely infected.
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 downregulate OspA and upregulate OspC, another surface protein. After the borrelia 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. Successful infection of the mammalian host depends on bacterial expression of OspC.
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 and as quickly as within 4 hours.
In Europe, the vector is Ixodes ricinus, which is also called the sheep tick or castor bean tick. In China, Ixodes persulcatus (the taiga tick) is probably the most important vector. In North America, the black-legged tick or deer tick (Ixodes scapularis) is the main vector on the east coast.
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, though it may be implicated in a related syndrome called southern tick-associated rash illness, which resembles a mild form of Lyme disease.
On the West Coast of the United States, the main vector is the western black-legged tick (Ixodes pacificus). 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.
While Lyme spirochetes have been found in insects as well as ticks, reports of actual infectious transmission appear to be rare. Lyme spirochete DNA has been found in semen and breast milk, but transmission has not been known to take place through sexual contact. According to the CDC live spirochetes have not been found in breast milk, urine, or semen.
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.
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.
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. Among early Lyme disease patients, depending on their location, 2–12% will also have HGA and 2–40% will have babesiosis. Ticks in certain regions, including the landscapes along the eastern Baltic Sea, also transmit tick-borne encephalitis.
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.
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. Many of the signs and symptoms of Lyme disease are a consequence of the immune response to the spirochete in those tissues.
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. 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. 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.
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.
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. 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.
In the brain, B. burgdorferi may induce astrocytes to undergo astrogliosis (proliferation followed by apoptosis), which may contribute to neurodysfunction. 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. Both microglia and astrocytes secrete IL-6 and TNF-alpha in the presence of the spirochete. This cytokine response may contribute to cognitive impairment.
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.
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.
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. Researchers are investigating if this neurohormone secretion is the cause of neuropsychiatric disorders developing in some patients with borreliosis.
Exposure to the Borrelia bacterium during Lyme disease possibly causes a long-lived and damaging inflammatory response, a form of pathogen-induced autoimmune disease. 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.
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.
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, i.e., 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.
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. 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. Serological testing can be used to support a clinically suspected case, but is not diagnostic by itself.
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." 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.
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. Serologic tests for Lyme disease are of limited use in people lacking objective signs of Lyme disease because of false positive results and cost.
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 (CDC): the sensitive ELISA test is performed first, and if it is positive or equivocal, then the more specific Western blot is run. The reliability of testing in diagnosis remains controversial. Studies show the Western blot IgM has a specificity of 94–96% for patients with clinical symptoms of early Lyme disease. 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.
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, as well as herpes simplex virus. 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.
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. Even when properly performed, PCR often shows false negative results with blood and cerebrospinal fluid (CSF) specimens. 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.
With the exception of culture or 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.
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.
New techniques for clinical testing of Borrelia infection have been developed, such as LTT-MELISA, although the results of studies are contradictory, and there is no study assessing the diagnostic sensitivity and specificity of the test. Others, such as focus floating microscopy, are under investigation. New research indicates chemokine CXCL13 may also be a possible marker for neuroborreliosis.
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".
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.
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.
Permethrin sprayed on clothing kills ticks on contact, and is sold for this purpose.
Attached ticks should be removed promptly, as removal within 36 hours can reduce transmission rates. 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.
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.
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.
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 and Mumford Cove, Connecticut. 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. 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, more recent research has shown that the risk of acquiring Lyme disease does not depend on the existence of a local deer population, as is commonly assumed. This research suggests eliminating deer from smaller areas 2.5 hectares (6.2 acres) may in fact lead to an increase in tick density and the rise of "tick-borne disease hotspots".
Action can be taken to avoid getting bitten by ticks by using insect repellants, for example those that contain DEET (N,N-Diethyl-meta-toluamide). DEET-containing repellants are thought to be moderately effective in the prevention of tick bites.
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. 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. 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.
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, in the setting of negative media coverage and fears of vaccine side effects. The fate of LYMErix was described in the medical literature as a "cautionary tale"; 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." 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."
New vaccines are being researched using outer surface protein C (OspC) and glycolipoprotein as methods of immunization. Vaccines have been formulated and approved for prevention of Lyme disease in dogs. There are currently three Lyme disease vaccines available. The first is LymeVax, formulated by Fort Dodge Laboratories. This vaccine contains intact dead spirochetes which expose the host to the organism. The second vaccine is Galaxy Lyme, or Intervet-Schering-Plough's vaccine. This formula targets proteins OspC and OspA. The OspC antibodies kill any of the bacteria that has not been killed by the OspA antibodies. The third vaccine, Canine Recombinant Lyme, formulated by Merial, generates antibodies against the OspA protein so that 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.
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 tick's body. 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.
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 of all, for dog owners who live near or who often frequent tick-infested areas, routine vaccinations for their dogs is an important step.
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). These acaricides target primarily the adult stages of Lyme-carrying ticks and reduce the number of reproductively active ticks in the environment. Formulations of these ingredients are available in a variety of topical forms, including spot-ons, sprays, powders, impregnated collars, solutions, and shampoos.
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.
Antibiotics are the primary treatment for Lyme disease; the most appropriate antibiotic treatment depends upon the patient and the stage of the disease. 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. If Lyme arthritis symptoms fail to respond to a 30-day antibiotic regimen, some recommend an additional 30 days of antibiotics. Alternative choices are cefuroxime and cefotaxime. Treatment of pregnant women is similar, but doxycycline should not be used.
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.
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.
For early cases, prompt treatment is usually curative. 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. Patients with late stage Lyme disease have been shown to experience a level of physical disability equivalent to that seen in congestive heart failure.
In dogs, a serious long-term prognosis may result in glomerular disease, which is a category of kidney damage that may cause chronic kidney disease. 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. In rare cases, Lyme disease can be fatal to both humans and dogs.
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.
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. In East Africa, two cases of Lyme disease have been reported in Kenya.
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. Borrelia has also been isolated in Mongolia.
In Australia, there is definitive evidence for the existence of endemic B. burgdorferi infection. The matter has been controversial for nearly 20 years and has been described as a local lyme-like syndrome and sometimes as Lyme disease. Cases of neuroborreliosis have been documented in Australia, but are often ascribed to travel to other continents. Of note the author of the new study states it is entirely a neurological disease in Australia.
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, Southwest Nova Scotia and limited parts of Saskatchewan and Alberta, as well as British Columbia. Cases have been reported as far east as the island of Newfoundland. 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.
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. 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. Incidence in southern Europe, such as Italy and Portugal, is much lower.
In the United Kingdom the number of laboratory confirmed cases of Lyme disease has been rising steadily since voluntary reporting was introduced in 1986 when 68 cases were recorded in the UK and Republic of Ireland combined. In the UK there were 23 confirmed cases in 1988 and 19 in 1990, but 973 in 2009 and 953 in 2010. Provisional figures for the first 3 quarters of 2011 show a 26% increase on the same period in 2010.
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, (with an average of around 15% of the infections acquired overseas), 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."
Despite Lyme disease (Borrelia burgdorferi infection) being a notifiable disease in Scotland since January 1990, which should therefore be reported on the basis of clinical suspicion, it is believed that many GPs are unaware of the requirement. Mandatory reporting, limited to laboratory test results only, was introduced throughout the UK in October 2010, under the Health Protection (Notification) Regulations 2010.
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 and the West coast and islands of Scotland infected ticks are widespread, and can even be found in the parks of London. 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.
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. 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.
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. The first reported case of Lyme disease in Brazil was made in 1993 in Sao Paulo. B. burgdorferi sensu stricto antigens in patients have been identified in Colombia and Bolivia.
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.
Although Lyme disease has been reported in all states except Montana, 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). New 2011 CDC Lyme case definition guidelines are used to determine confirmed CDC surveillance cases.
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.
Except for one study in Europe, 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. 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.
While B. burgdorferi is most associated with ticks hosted by white-tailed deer and white-footed mice, Borrelia afzelii is most frequently detected in rodent-feeding vector ticks, and Borrelia garinii and Borrelia valaisiana appear to be associated with birds. Both rodents and birds are competent reservoir hosts for B. burgdorferi sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative complement pathway of various host species may determine its reservoir host association.
Several similar but apparently distinct conditions may exist, caused by various species or subspecies of Borrelia in North America. A regionally restricted condition that may be related to Borrelia infection is southern tick-associated rash illness (STARI), also known as Masters' disease. Amblyomma americanum, known commonly as the lone-star tick, is recognized as the primary vector for STARI. In some parts of the geographical distribution of STARI, Lyme disease is quite rare (e.g., Arkansas), so 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.
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.
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.
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.
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."
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.
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. 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. 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.
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.
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. The skin condition now known as borrelial lymphocytoma was first described in 1911.
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. 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. 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. 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.
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.
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. 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.
Before 1976, elements of B. burgdorferi sensu lato infection were called or known as tick-borne meningopolyneuritis, Garin-Bujadoux syndrome, Bannwarth syndrome, Afzelius' disease, Montauk Knee or sheep tick fever. Since 1976 the disease is most often referred to as Lyme disease, Lyme borreliosis or simply borreliosis.
In 1980, Steere, et al., began to test antibiotic regimens in adult patients with Lyme disease. 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. In June 1982, he published his findings in Science, and the spirochete was named Borrelia burgdorferi in his honor.
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. 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.
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."
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. Researchers are investigating possible links between global warming and the spread of vector-borne diseases, including Lyme disease.
The term "chronic Lyme disease" is not recognized in the medical literature. and most medical authorities advise against long-term antibiotic treatment for chronic Lyme disease, 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 that should be classified as having post-Lyme disease syndrome, 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.
The Centers for Disease Control states that "approximately 10 to 20% of patients treated for Lyme disease with a recommended 2-4 week course of antibiotics will have lingering symptoms of fatigue, pain, or joint and muscle aches. In some cases, these can last for more than 6 months. Although often called 'chronic Lyme disease,' this condition is properly known as 'Post-treatment Lyme disease Syndrome' (PTLDS)". The term 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.
Up to one third of Lyme disease patients who have completed a course of antibiotic treatment continue to have symptoms, often termed "post-Lyme syndrome", such as severe fatigue, sleep disturbance, unconsciousness, and cognitive difficulties, with these symptoms being severe in about 2% of cases. 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. A few doctors attribute these symptoms to persistent infection with Borrelia, or coinfections with other tick-borne infections, such as Ehrlichia and Babesia. 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.
A review looked at several animal studies that found persistence of live but disabled spirochetes following treatment of B. burgdorferi infection with antibiotics. The authors noted that none of the lingering spirochetes were associated with inflamed tissues and criticized the studies for not considering adequately the different pharmacodynamics and pharmacokinetics of the antibiotics used to treat the animals in the trials versus what would be expected to be used to treat humans. The authors concluded, "There is no scientific evidence to support the hypothesis that such spirochetes, should they exist in humans, are the cause of post-Lyme disease syndrome."
An advocacy group called the International Lyme And Associated Diseases Society (ILADS) argues the persistence of B. burgdorferi may be responsible for manifestations of late Lyme disease symptoms. It has questioned the generalizability and reliability of some of the above trials and the reliability of the current diagnostic tests. 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. Prolonged antibiotic therapy presents significant risks and can have dangerous side effects. One death has been reported from an infected catheter as a complication of a 27-month course of intravenous antibiotics for an unsubstantiated diagnosis of chronic Lyme disease. Randomized placebo-controlled studies have shown that antibiotics offer no sustained benefit in "chronic Lyme" patients, a review notes evidence of both placebo effects and significant adverse effects from such treatment.
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. 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. Lyme arthritis that persists after antibiotic treatment may be treated with hydroxychloroquine or methotrexate. Corticosteroid injections into the affected joint are not recommended for any stage of Lyme arthritis.
Patients with chronic neuropathic pain responded well to gabapentin monotherapy with residual pain after intravenous ceftriaxone treatment in a pilot study. 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. Indeed, minocycline has been suggested for other neurodegenerative and inflammatory disorders, such as multiple sclerosis, Parkinson's disease, Huntington's disease, rheumatoid arthritis and ALS.
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. The evidence-based perspective 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." Most medical authorities agree with this viewpoint: the IDSA, the American Academy of Neurology, the Centers for Disease Control and Prevention (CDC), and the NIH advise against long-term antibiotic treatment for chronic Lyme disease, given the lack of supporting evidence and the potential toxicities.
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. This viewpoint is promoted by many patient advocates, notably an advocacy organization, the International Lyme And Associated Diseases Society. 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.
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. 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.
The IDSA focused on the fact that the medical validity of the IDSA guidelines was not challenged, and cited mounting legal costs and the difficulty of presenting scientific arguments in a legal setting as their rationale for accepting the settlement. A journalist writing in Nature Medicine suggested some IDSA members may not have disclosed potential conflicts of interest, while a Forbes piece described Blumenthal's investigation as "intimidation" of scientists by an elected official with close ties to Lyme advocacy groups. 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.
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." The states of Rhode Island California Massachusetts and New Hampshire have similar laws.
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. 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."
In 2001, The New York Times Magazine reported that Allen Steere, chief of immunology and rheumatology at Tufts Medical Center and a co-discoverer 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. Because this intimidation included death threats, Steere was assigned security guards. 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 practices.
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. 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 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. Lyme disease was also the focus of a major feature in The Times in February 2010 that detailed the impact the disease had had on British author Alex Wade.
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