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Lyme disease

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

   CAPTION: Lyme disease
   Classifications and external resources

   Nymphal and adult deer ticks can be carriers of Lyme disease. Nymphs
   are about the size of a poppy seed.
     ICD- 10   A 69.2
     ICD- 9    088.81
   DiseasesDB  1531
   MedlinePlus 001319
    eMedicine  med/1346

   Lyme disease or Lyme borreliosis is the most common tick-borne disease
   in North America and Europe, and the second fastest-growing infectious
   disease in the United States after AIDS. It is named after the town of
   Old Lyme, Connecticut where a cluster of cases was identified in 1975,
   although clinical features of the disease had been described in Europe
   as early as 1909. Lyme disease has now been reported in 49 of 50 states
   in the U.S, and on every continent except Antarctica. The cause of Lyme
   disease is a bacterial infection with a spirochete from the species
   complex Borrelia burgdorferi sensu lato, which is most often acquired
   from the bite of an infected Ixodes tick. Borrelia burgdorferi was
   first identified in 1982 by Willy Burgdorfer, a tick-borne disease
   expert at Rocky Mountain Labs in Hamilton, Montana. While Borrelia
   burgdorferi sensu stricto is the predominant cause in the U.S., Lyme
   disease in Europe is more often caused by Borrelia afzelii or Borrelia
   garinii.

   The disease varies widely in its presentation, which may include a rash
   and flu-like symptoms in its initial stage, followed by
   musculoskeletal, arthritic, neurologic, psychiatric and/or cardiac
   manifestations. Early detection and prompt antibiotic treatment most
   often result in an excellent prognosis. However early detection is
   difficult when the characteristic rash is not present, and even those
   who are diagnosed and treated early may remain symptomatic.

   Delayed or inadequate treatment may often lead to a chronic illness
   that is disabling and difficult to treat. Amid great controversy over
   diagnosis, testing and treatment, two different standards of care for
   Lyme disease have emerged.

Symptoms

   Lyme disease has many signs and symptoms, but skin signs, arthritis
   and/or various neurological symptoms are often present. Like syphilis,
   the symptoms frequently seem to resolve, yet the disease progresses.
   Conventional therapy is with antibiotics. People who suspect they have
   been exposed to Lyme disease should consult a doctor with knowledge of
   the disease immediately.

Acute (early) symptoms that may occur

   Bull's-eye-like rash caused by Lyme disease.
   Enlarge
   Bull's-eye-like rash caused by Lyme disease.

   Erythema migrans rash (EM) - Contrary to popular belief, the
   characteristic "bull's-eye" rash with central clearing is not the most
   common form. Rashes that are homogeneously red are seen more
   frequently. Multiple painless EM rashes may occur, indicating
   disseminated infection. The true incidence of the rash is disputed,
   with estimates ranging from less than 50% to over 80% of those
   infected. The symptoms of Lyme disease are fever, malaise, fatigue,
   headache, muscle and joint aches in large joints, sore throat, sinus
   infection

   Other consequences, include facial paralysis - usually associated with
   Lyme meningitis or Rocky Mountain spotted fever, palpitations, kidney
   and intestinal pains.

   The incubation period from infection to the onset of symptoms is
   usually 1–2 weeks, but can be much shorter (a couple of days), or even
   as long as one month.

Chronic (late) symptoms

     * fatigue
     * muscle pain (myalgia)
     * joint pain with or without frank arthritis
     * neuropathy (numbness, tingling, burning, itching, oversensitivity)
     * tremor, muscle twitching
     * Bell's palsy
     * meningitis
     * vision problems (eg. double vision)
     * sensitivity to light, motion
     * hyperacusis (severe sensitivity to sound & vibration)
     * vestibular symptoms (balance; inner/middle ear)
     * seizures
     * severe startle reaction
     * panic attacks
     * depression
     * short-term memory loss
     * sleep disturbance
     * hallucinations
     * cardiac arrhythmias
     * tachycardia (too-rapid heartbeat)
     * nausea or vomiting
     * adrenal disorders
     * immune suppression
     * acrodermatitis chronica atrophicans (ACA)

   The late symptoms of Lyme disease can appear months after infection.

   Lyme disease may be misdiagnosed as multiple sclerosis, rheumatoid
   arthritis, fibromyalgia, chronic fatigue syndrome (CFS), or other
   (mainly autoimmune and neurological) diseases, which leaves the
   infection untreated and allows it to further penetrate the organism.
   Some of these conditions may be misdiagnosed as Lyme disease, although
   this is thought to be a rare occurrence. False positive Lyme diagnosis
   is most commonly due to false positive serology in a subset of patients
   who may suffer from syphillis, rheumatologic diseases, or infectious
   mononucleosis. More confounding is that patients may present with Lyme
   Disease and a related disease such as MS. This makes diagnosis
   exceptionally difficult. It should be noted that this kind of
   misdiagnosis is the exception rather than the rule as it is widely held
   that Lyme Disease is underdiagnosed and underreported ranging from
   factors of 10 to upwards of 40. It is important to remember that
   chronic fatigue syndrome (CFS) is by definition a diagnosis of
   exclusion, meaning it would be inaccurate to say that a patient does
   not have Lyme because he or she has CFS. The substantial overlap in
   symptomatology between Lyme and CFS makes this a crucial point.

Transmission

Transmission by ticks

   Hard-bodied (Ixodes) ticks are the primary Lyme disease vectors. In
   Europe, Ixodes ricinus, known commonly as the sheep tick, castor bean
   tick, or European castor bean tick is the transmitter. In North
   America, Ixodes scapularis ( black-legged tick or deer tick) has been
   identified as the key to the disease's spread on the east coast, while
   on the west coast the primary vector is Ixodes pacificus (Western
   black-legged tick). Another possible vector is Amblyomma americanum
   (Lone Star tick), which is found throughout the southeastern U.S. as
   far west as Texas, and increasingly in northeastern states as well.

   The longer the duration of tick attachment, the greater the risk of
   disease transmission, but, typically, for the spirochete to be
   transferred, the tick must be attached for a minimum of 12 hours,
   although, only the first part of this statement can be said to be
   strictly correct. (see Proper Removal of Ticks). Unfortunately only 20%
   of persons infected with Lyme by the deer tick are aware of any tick
   bite, making early detection difficult in the absence of a rash. Tick
   bites usually go unnoticed due to 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. New research suggests that
   transmission can occur within a few hours of tick attachment, and that
   the rate of transmission by infected ticks may be much higher than
   previously assumed.

Congenital Lyme disease

   Lyme disease can be transmitted from an infected mother to fetus
   through the placenta during pregnancy, possibly resulting in
   stillbirth. The risk of transmission is minimized if the mother
   receives prompt antibiotic treatment, though physicians disagree as to
   the duration of treatment required.

Other modes of transmission

   There is at least one case report of transmission by a biting fly. Lyme
   spirochetes have been found in biting flies as well as mosquitos. Some
   researchers believe biting insects do not feed long enough to transmit
   the infection, while others including Borrelia burgdorferi discoverer
   Willy Burgdorfer believe more research is needed. There is also some
   anecdotal, largely unconfirmed evidence of sexual transmission. Lyme
   spirochetes have been found in semen and breast milk, though
   transmission by these routes has yet to be proven.

Microbiology

Strains

   Lyme disease is caused by spirochetal bacteria from the genus Borrelia,
   which has well over three hundred known genomic strains. The Borrelia
   species known to cause Lyme disease are collectively known as Borrelia
   burgdorferi sensu lato, and have been found to have greater strain
   diversity than previously estimated. Until recently it was thought that
   only three genospecies caused Lyme disease: B. burgdorferi sensu
   stricto (predominant in North America, but also in Europe), B. afzelii,
   and B. garinii (both predominant in Eurasia). However, newly discovered
   genospecies have also been found to cause disease in humans: B.
   lusitaniae in Europe (especially Portugal), North Africa and Asia, B.
   bissettii in the U.S. and Europe, and B. spielmanii in Europe.
   Additional B. burgdorferi sensu lato genospecies suspected of causing
   illness, but not confirmed by culture, include B. valaisiana ( Eurasia,
   especially England, Switzerland and the Netherlands); B. japonica, B.
   tanukii and B. turdae (Japan); B. sinica (China); and B. andersonii (
   U.S.). Some of these species are carried by ticks not currently
   recognized as carriers of Lyme disease. Note: At present, diagnostic
   tests are based only on B. burgdorferi sensu stricto (the only species
   used in the U.S.), B. afzelii and B. garinii.

   Apart from this group of closely related genospecies, additional
   Borrelia species of interest include B. lonestari, a spirochete
   recently detected in the Amblyomma americanum tick (Lone Star tick) in
   the U.S. B. lonestari is suspected of causing STARI (Southern
   Tick-Associated Rash Illness), also known as Masters disease in honour
   of its discoverer. The illness follows a Lone Star tick bite and
   clinically resembles Lyme disease, but sufferers usually test negative
   for Lyme. There is currently no diagnostic test available for
   STARI/Masters, and no official treatment protocol, though antibiotics
   are generally prescribed. The B. miyamotoi spirochete, related to the
   relapsing fever group of spirochetes, is also suspected of causing
   illness in Japan. Spirochetes similar to B. miyamotoi have recently
   been found in both I. ricinus ticks in Sweden and I. scapularis ticks
   in the U.S.

Genomic characteristics

   One of the most striking features of B. burgdorferi as compared with
   other eubacteria is its unusual genome, which is far more complex than
   that of its spirochetal cousin Treponema pallidum, the agent of
   syphilis. The genome of B. burgdorferi includes a linear chromosome
   approximately one megabase in size, with 21 plasmids (12 linear and 9
   circular) - by far the largest number of plasmids found in any known
   bacterium. Genetic exchange, including plasmid transfers, contributes
   to the pathogenicity of the organism. Long-term culture of B.
   burgdorferi results in a loss of some plasmids and changes in expressed
   protein profiles. Associated with the loss of plasmids is a loss in the
   ability of the organism to infect laboratory animals, suggesting that
   the plasmids encode key genes involved in virulence.

Structure and growth

   B. burgdorferi is a highly specialized, motile, two-membrane,
   spiral-shaped spirochete ranging from about 9 to 32 micrometers in
   length. It is often described as gram-negative and has an outer
   membrane with LPS, though it stains only weakly in the Gram stain. B.
   burgdorferi is a microaerophilic organism, requiring little oxygen to
   survive. It lives primarily as an extracellular pathogen, although it
   can also hide intracellularly (see Mechanisms of persistence section).

   Like other spirochetes such as T. pallidum (the agent of syphilis), B.
   burgdorferi has an axial filament composed of flagella which run
   lengthways between its cell wall and outer membrane. This structure
   allows the spirochete to move efficiently in corkscrew fashion through
   viscous media, such as connective tissue. As a result, B. burgdorferi
   can disseminate throughout the body within days to weeks of infection,
   penetrating deeply into tissue where the immune system and antibiotics
   may not be able to eradicate the infection.

   B. burgdorferi is very slow growing, with a doubling time of 12-24
   hours (in contrast to pathogens such as Streptococcus and
   Staphylococcus, which have a doubling time of 20-30 minutes). Since
   most antibiotics kill bacteria only when they are dividing, this longer
   doubling time necessitates the use of relatively longer treatment
   courses for Lyme disease. Antibiotics are most effective during the
   growth phase, which for B. burgdorferi occurs in four-week cycles. Some
   clinicians have observed that chronic Lyme patients commonly experience
   a worsening of symptoms every four weeks; these periodic flare-ups are
   thought to correspond to the growth phase of B. burgdorferi.

Mechanisms of persistence

   While B. burgdorferi is susceptible to a number of antibiotics in
   vitro, there are contradictory reports as to the efficacy of
   antibiotics in vivo. B. burgdorferi may persist in humans and animals
   for months or years despite a robust immune response and standard
   antibiotic treatment, particularly when treatment is delayed and
   dissemination widespread. Numerous studies have demonstrated
   persistence of infection despite antibiotic therapy.

   Various survival strategies of B. burgdorferi have been posited to
   explain this phenomenon, including the following:
     * Physical sequestration of B. burgdorferi in sites that are
       inaccessible to the immune system and antibiotics, such as the
       brain and central nervous system. New evidence suggests that B.
       burgdorferi may use the host's fibrinolytic system to penetrate the
       blood-brain barrier.

     * Intracellular invasion. B. burgdorferi has been shown to invade a
       variety of cells, including endothelium, fibroblasts, lymphocytes,
       macrophages, keratinocytes, synovium, and most recently neuronal
       and glial cells. By 'hiding' inside these cells, B. burgdorferi is
       able to evade the immune system and is protected to varying degrees
       against antibiotics, allowing the infection to persist in a chronic
       state. Paradoxically, many of these scientific studies were
       performed and published by critics of persistent Borrelia
       infection.

     * Altered morphological forms, i.e. spheroplasts (cysts, granules).
          + The existence of B. burgdorferi spheroplasts, which lack a
            cell wall, has been well documented in vitro, in vivo, and in
            an ex vivo model.The fact that energy is required for the
            spiral bacterium to convert to the cystic form suggests that
            these altered forms have a survival function, and are not
            merely end stage degeneration products. The spheroplasts are
            indeed virulent and infectious, able to survive under adverse
            environmental conditions, and have been shown to revert back
            to the spiral form in vitro, once conditions are more
            favorable.
          + A number of other factors make B. burgdorferi spheroplasts a
            key factor in the relapsing, chronic nature of Lyme disease.
            Compared to the spiral form, spheroplasts have dramatically
            reduced surface area for immune surveillance. They also
            express different surface proteins - another reason for
            seronegative disease (i.e. false-negative antibody tests), as
            current tests only look for antibodies to surface proteins of
            the spiral form. In addition, B. burgdorferi spheroplasts are
            generally not susceptible to the antibiotics traditionally
            used for Lyme disease. They have instead shown sensitivity in
            vitro to antiparasitic drugs such as metronidazole,
            tinidazole, and hydroxychloroquine, to which the spiral form
            of B. burgdorferi is not sensitive.

     * Antigenic variation. Like the Borrelia that cause relapsing fever,
       B. burgdorferi has the ability to vary its surface proteins in
       response to immune attack. This ability is related to the genomic
       complexity of B. burgdorferi, and is another way B. burgdorferi
       evades the immune system to establish a chronic infection.

     * Immune system suppression. Complement inhibition, induction of
       anti-inflammatory cytokines such as IL-10, and the formation of
       immune complexes have all been documented in B. burgdorferi
       infection. Furthermore, the existence of immune complexes provides
       another explanation for seronegative disease (i.e. false-negative
       antibody tests of blood and cerebrospinal fluid), as studies have
       shown that substantial numbers of seronegative Lyme patients have
       antibodies bound up in these complexes.

Diagnosis

   The most reliable method of diagnosing Lyme disease is a clinical exam
   by an experienced practitioner, taking into account symptoms, history,
   and possible exposure to ticks in an endemic area. Clinicians who
   diagnose strictly based on the U.S. Centers for Disease Control (CDC)
   Case Definition for Lyme are in error, as the CDC explicitly states
   that this definition is intended for surveillance purposes only, and is
   "not intended to be used in clinical diagnosis."

   The EM rash, which does not occur in all cases, is considered
   sufficient to make a diagnosis of Lyme disease and prompt treatment
   without further testing. In fact because of the undisputed high rate of
   false negatives during the early stage of the disease (before a
   sufficient antibody response has been established), it is recommended
   that tests not be performed when a patient has an EM rash.

   The serological laboratory tests available are the Western blot and
   ELISA. In the two-tiered protocol recommended by the CDC according to
   their case definition, the ELISA is performed first, and if it is
   positive or equivocal, a Western blot is then performed to support the
   diagnosis. The reliability of testing in diagnosis remains
   controversial (see The Lyme controversy--Testing).

   False-positive results for the Western blot IgM are described with
   varicella-zoster virus, Epstein-Barr virus, cytomegalovirus. and herpes
   simplex type virus 2. However studies show the Western blot IgM has a
   specificity of 94-96% for patients with symptoms suggestive of Lyme
   disease.

   False-negative test results have been widely reported in both early and
   late disease.

   Polymerase chain reaction (PCR) tests for Lyme disease may also be
   available to the patient. A PCR test attempts to detect the genetic
   material (DNA) of the Lyme disease spirochete, whereas the Western blot
   and ELISA tests look for antibodies to the organism. PCR tests are
   rarely susceptible to false-positive results but can often show
   false-negative results.

   Given the testing difficulties described above, some patients are
   employing a vitamin D metabolites test as an alternative indicator. A
   finding of a low 25-hydroxyvitamin D level coupled with a high
   1,25-dihydroxyvitamin D level can be associated with an infection by B.
   burgdorferi or other spirochetal bacteria. Since such abnormal vitamin
   D levels can also be caused by other disease processes, further
   evaluation is warranted to rule those out before initiating treatment.

Prognosis

   For early cases, prompt treatment is usually, but not always, curative.
   However, the severity and treatment of Lyme disease may be complicated
   due to late diagnosis, failure of antibiotic treatment, simultaneous
   infection with other tick-borne diseases including ehrlichiosis,
   babesiosis, and bartonella, and immune suppression in the patient
   (sometimes resulting from inappropriate treatment with steroids).

   A meta-analysis published in 2005 found that some patients with Lyme
   disease have fatigue, joint and/or muscle pain, and neurocognitive
   symptoms persisting for years despite antibiotic treatment. Patients
   with chronic Lyme disease have been shown to experience a level of
   physical disability equivalent to that seen in congestive heart
   failure. The disease is rarely fatal in and of itself, although deaths
   have been reported.

Treatment

   Persons who remove attached ticks should be monitored closely for signs
   and symptoms of tick-borne diseases for up to 30 days. Single-dose
   doxycycline therapy may be considered for deer tick bites when the tick
   has been on the person for at least 36 hours.

   Traditional treatment of acute Lyme disease usually consists of a
   minimum two-week to one-month course of antibiotics. In later stages,
   the bacteria disseminate throughout the body and may cross the
   blood-brain barrier, making the infection more difficult to treat.
   Chronic or late diagnosed Lyme is treated with oral or IV antibiotics,
   frequently ceftriaxone, for a minimum of four weeks.

   With little research conducted specifically on chronic Lyme disease,
   treatment remains controversial. Currently there are two sets of
   peer-reviewed published guidelines; the International Lyme and
   Associated Diseases Society (ILADS) advocates extended courses of
   antibiotics for chronic Lyme patients, while the Infectious Diseases
   Society of America does not recognize chronic infection and recommends
   no treatment for persistent symptoms following infection (see The Lyme
   controversy--Two standards of care). Double-blind, placebo-controlled
   trials of long-term antibiotics for chronic Lyme have produced mixed
   results (see The Lyme controversy--Long-term antibiotic therapy).

   A number of alternative therapies have been suggested, though clinical
   trials have not been conducted. For example, the use of hyperbaric
   oxygen therapy (which is used conventionally to treat a number of other
   conditions), as an adjunct to antibiotics for Lyme has been discussed.
   Though there is no published data from clinical trials to support its
   use, preliminary results using a murine model suggest its effectiveness
   against Borrelia burgdorferi both in vitro and in vivo. Alternative
   medicine approaches include bee venom because it contains the peptide
   melittin, which has been shown to exert profound inhibitory effects on
   lyme bacteria in vitro. The herb andrographis, though not specifically
   studied for Borrelia species, has been found to have both antimalarial
   and antibacterial properties against a wide range of organisms in vitro
   and in vivo, leading some herbalists to recommend it for Lyme. Other
   alternative practitioners recommend large doses of salt combined with
   vitamin C, based on the theory that this protocol kills bacteria by
   enhancing the activity of elastase and possibly by other mechanisms,
   though the safety and efficacy of this approach remains unproven.

The Lyme controversy

   Although there is no doubt that Lyme disease exists, and most
   clinicians agree on the treatment of early Lyme disease, there is
   considerable controversy as to the prevalence of the disease, the
   proper procedure for diagnosis and treatment of later stages, and the
   likelihood of a chronic, antibiotic-resistant Lyme infection. On one
   side are those who believe that Lyme disease is relatively rare, easily
   diagnosed with available blood tests, and easily treated with two to
   four weeks of antibiotics. On the other side are those who believe that
   Lyme disease is under-diagnosed, that available blood tests are
   unreliable, and that extended antibiotic treatment is often necessary.

   The majority of public health agencies such as the U.S. Centers for
   Disease Control maintain the former position. While this narrower
   position is sometimes described as the "mainstream" view of Lyme
   disease, published studies involving non-randomized surveys of
   physicians in endemic areas found physicians evenly split in their
   views, with the majority recognizing seronegative Lyme disease, and
   roughly half prescribing extended courses of antibiotics for chronic
   Lyme disease.

   Since October 2006, the Lyme controversy has heated up dramatically
   beginning with the release of updated diagnosis and treatment
   guidelines from the Infectious Diseases Society of America (IDSA). The
   new IDSA recommendations are even more restrictive than before,
   requiring either an EM rash or positive laboratory tests for diagnosis.
   Seronegative Lyme disease is no longer acknowledged, except in early
   Lyme. The authors of the guidelines maintain that chronic Lyme disease
   does not result from persistent infection, and therefore treatment
   beyond 2-4 weeks is not recommended by the IDSA, even in late stage
   cases.

   The 2006 IDSA guidelines have come under fire from a variety of
   corners. The International Lyme and Associated Diseases Society
   (ILADS), a professional medical society, formally requested retraction
   of the IDSA guidelines, arguing that the authors ignored all published
   data that conflicted with their opinions, and refused input from
   physicians and patients with differing views. The all-volunteer Lyme
   Disease Association, which is the largest Lyme advocacy group in the
   U.S., expressed concerns that the guidelines do not allow for
   physicians' clinical discretion, and that with more cases going
   undiagnosed and untreated by the stricter guidelines, more patients
   than ever will develop disabling, late-stage Lyme disease.

   In an unprecedented move, Connecticut Attorney General Richard
   Blumenthal initiated a formal investigation into the development of the
   IDSA guidelines in November 2006. The Attorney General's office is
   considering whether the IDSA violated antitrust laws through
   exclusionary conduct and monopolization in the development of the
   guidelines. "These guidelines were set by a panel that essentially
   locked out competing points of view," Blumenthal said. "Presumably, the
   IDSA is a non-profit making organization, but such organizations can
   still be used for anti-competitive purposes."

Two standards of care

   Because the legal standard of care is defined by the consensus of
   treating physicians (rather than published guidelines), two standards
   of care for Lyme disease are now recognized in the U.S., a situation
   with significant legal implications for both patients and clinicians.
   ILADS (The International Lyme and Associated Diseases Society)
   ILADS Mission Statement IDSA (The Infectious Diseases Society of
   America)
   IDSA Mission Statement
   Peer-reviewed treatment guidelines ILADS Guidelines IDSA Guidelines
   Public statements "A small group of scientists...deny the existence of
   chronic Lyme disease," wrote ILADS president Raphael Stricker, M.D.,
   referring in part to the IDSA. "Fearing 'over-diagnosis,' they publish
   guidelines endorsing an insensitive testing program that misses half
   the patients with the tick-borne illness. Fearing 'over-treatment,'
   they recommend antibiotic therapy barely adequate for acute infection
   and wholly inadequate for chronic Lyme disease. Soon they will publish
   the latest version of an already restrictive set of guidelines that
   will further pressure the Centers for Disease Control and Prevention
   and academic institutions to ignore chronic Lyme disease. The
   guidelines will encourage insurance companies to embrace up-front cost
   savings inherent in shorter treatment and deny payment for longer
   treatment, even if the Lyme patient is still sick but showing signs of
   improvement. Although the Lyme denialists claim support from mainstream
   medical groups, the reality is that the handful of them have managed to
   dictate policy to larger health care organizations through a closed
   process that rejects dissenting views." The IDSA has attacked ILADS as
   a "special interest group... which represents a few physicians who
   advocate unconventional treatments based on testimonials rather than
   scientifically sound clinical trials." (See Clinical Trials). “Nearly
   all people – more than 95 percent – who do get sick with Lyme disease
   and are treated with the recommended course of antibiotics get better
   and go on with their lives,” said Gary Wormser, M.D., lead author of
   IDSA’s 2006 guidelines on Lyme disease.
   EM rash Present less than 50% of the time. Studies that show otherwise
   are flawed because they rely on circular logic, as subjects must meet
   CDC criteria which prioritize the rash over other disease
   manifestations. Among those who would be excluded from such studies
   are: 1) seronegative Lyme patients without a rash (even if there is
   definitive evidence of infection such as a positive PCR), 2)
   seropositive patients without a rash who present with fever, flu-like
   symptoms, joint and muscle pain, paresthesias and/or encephalopathy
   (symptoms not included in the restrictive CDC case definition), and 3)
   late-stage patients whose diagnosis was delayed because no rash was
   present. The exclusion of these groups leads to an artificially high
   estimate of the incidence of EM rash among those infected with Lyme.
   "The great majority of Lyme patients" present with an EM rash,
   according to studies of patients with early Lyme disease diagnosed by
   CDC criteria.
   Testing Not reliable, particularly for late cases; used to support a
   clinical diagnosis (see Testing section for discussion). Nearly always
   reliable after the first few weeks of infection.
   Chronic Lyme disease Persistent Lyme infection exists due to various
   mechanisms of antibiotic resistance, particularly when diagnosis and
   treatment are delayed, as numerous studies have demonstrated (see
   Mechanisms of persistence section). Lengthy treatment regimens are
   sometimes required. Persistent Lyme infection is not recognized. Some
   patients report continuing and/or relapsing non-specific symptoms such
   as generalized pain, joint pain or fatigue following an episode of Lyme
   disease that has been treated with a standard course of antibiotics.
   “These patients with symptoms that persist for weeks, months or longer
   appear to be a heterogeneous group, and they report non-specific
   symptoms that also are associated with a number of other medical
   diseases, both infectious and noninfectious,” according to Gary
   Wormser, M.D., lead author of the IDSA guidelines. Post-treatment
   symptoms are termed "Post-Lyme disease syndrome" and are often
   attributed to an unspecified autoimmune process and/or the development
   of fibromyalgia or chronic fatigue syndrome, psychiatric disorders such
   as somatization, or simply stress.
   Long-term antibiotic treatment ILADS maintains that a 2-4 week course
   of antibiotics is not always curative, particularly when diagnosis is
   delayed and disease is at a later, disseminated stage. ILADS recommends
   long-term antibiotic therapy for these symptomatic patients, while
   acknowledging the lack of published data supporting either long-term or
   short-term treatment durations. The medical literature provides a
   compelling rationale for the use of longer regimens for some patients.
   While more research is needed, treatment should not be withheld from
   patients in the meantime. (See Evidence section for list of published
   clinical trials.) According to the IDSA, virtually all patients are
   cured of infection with a single course of 14-28 days of antibiotics,
   regardless of the stage of their illness. Rarely, a second course of
   treatment is recommended, but long-term antibiotic therapy is not
   recommended according to IDSA guidelines. Lead author Dr. Gary Wormser
   cautioned that “there are no convincing published data showing such
   [long-term] treatment to be effective.” (See Evidence section for list
   of published clinical trials.)
   Primary concern regarding misdiagnosis The under-diagnosis of Lyme may
   lead to untreated chronic, persistent infection resulting in severe
   disability and possibly even death (see #Prognosis). The over-diagnosis
   of Lyme may lead to the unnecessary use of antibiotics resulting in
   side effects (most commonly nausea). Where intravenous therapy is used,
   there are more serious risks including central line infection, which
   has resulted in the death of one patient being treated for chronic Lyme
   disease. There are also concerns about the cost of antibiotic
   treatment.
   Risk-benefit analysis The potential harm in letting a persistent Lyme
   infection go untreated far outweighs the potential side-effects of
   long-term antibiotic use. If long-term oral antibiotic therapy is
   considered safe enough for acne patients, its use is certainly
   justified for chronic Lyme patients. Intravenous therapy is justified
   for serious, refractory cases or those with clear central nervous
   system involvement. Risks are minimized by skilled clinicians who take
   appropriate precautions. Since chronic Lyme infection is presumed not
   to exist, any potential adverse effects of long-term antibiotic therapy
   (both oral and intravenous) outweigh the (non-existent) benefits.
   According to Gary Wormser, M.D., lead author of the IDSA guidelines,
   long-term antibiotic therapy may be dangerous and lead to
   drug-resistant superbugs.

The CDC case definition

   Confusion about the significance of the U.S. Centers for Disease
   Control Case Definition for Lyme disease lies at the heart of the
   controversy over diagnosis. The CDC has explicitly stated that the
   following definition is meant to be used for surveillance purposes, not
   diagnostic purposes.

   CDC Case Definition for Lyme disease

    1. Erythema migrans rash (at least 5 cm in diameter)

                - OR -

    2. Positive blood tests (ELISA followed by Western blot) AND one or
       more of the following manifestations:
          + Recurrent arthritis
          + Bell's Palsy or other cranial neuritis, radiculoneuropathy,
            lymphocytic meningitis, encephalomyelitis, or positive Lyme
            titer in CSF
          + 2nd or 3rd degree heart block

   A number of well-documented signs of chronic Lyme disease including
   encephalopathy (manifested by memory loss, mood changes and sleep
   disturbance) are not part of the CDC case definition. Therefore
   clinicians using the CDC criteria for diagnostic purposes will
   misdiagnose patients who have the disease. Additionally, reliance on
   the CDC case definition for clinical purposes would result in the
   misdiagnosis of those with false-negative test results, a widely
   reported phenomenon (see Diagnosis).

Testing

   The debate over Lyme disease testing remains a heated one, with concern
   over both false-positives and false-negatives (see Diagnosis). Tests
   currently rely on indirect methods of detection (i.e. the body's immune
   system response), because it is very difficult to culture the bacteria
   directly from patients. Specific issues with regard to the testing
   controversy include the following:
     * Sensitivity of the CDC's testing protocol. Critics argue that the
       CDC's 2-tiered testing protocol ( ELISA test, followed by
       confirmatory Western blot test if positive or equivocal) misses
       many patients who are infected. This criticism is not without
       merit. Several studies have examined this question and found that
       as many as 50 percent of definite Lyme Disease as defined by the
       presence of Borrelial DNA or Borrelial culture were negative when
       tested against the CDC's recommendations. It is important to note
       that such studies have included both early and late stage Lyme
       Disease patients. A study from the College of American Pathologists
       concluded that "these tests will not be useful as screening tests
       until their sensitivity is improved."

     * Inadequate lab standardization. Standardization of testing has been
       found to be inadequate, with a high degree of interlaboratory
       variability.

     * No diagnostic gold standard to determine sensitivity of tests in
       late disease. Without a diagnostic gold standard to identify those
       with chronic Lyme disease, circular reasoning becomes a problem in
       studies that evaluate the sensitivity of serologic tests for this
       population. Bias is unavoidable if subjects are selected by CDC
       criteria, since late-stage patients must have tested positive
       previously in order to qualify for a study. In a study cited by the
       CDC to defend the tests' validity, the authors acknowledge this
       risk of selection bias.

     * False negative test results due to the following, particularly in
       late and chronic Lyme disease:
          + Immune system evasion by Borrelia burgdorferi. Intracellular
            sequestration, antigen variation, immune suppression, the
            formation of immune complexes, and predominance of cystic
            forms have all been cited as reasons for seronegativity in
            late and chronic Lyme disease (see Mechanisms of persistence
            section).
          + Positive test criteria is based on early Lyme disease. The
            CDC's criteria for a positive Western blot were developed
            based upon on a study of patients with early Lyme disease. The
            serologic response of patients with late-stage Lyme disease
            was not analyzed and incorporated, despite that fact that such
            cases require a positive Western blot for diagnosis by CDC
            standards.
          + Specific markers for late-stage Lyme disease left out. Several
            highly specific antibody bands for Lyme (31-kDa and 34-kDa,
            corresponding to outer surface proteins A and B) were not
            included in the CDC criteria for a positive Western blot
            because they only appear late in the disease. It is important
            to note that these bands which have not been included on the
            CDC Western Blot are so specific to Borrelia Burgdorferri that
            they are being used/studied for the development of a Lyme
            Disease vaccine. As a result, the vast majority of
            laboratories do not report these bands, even if they are
            positive. This is one reason some clinicians use laboratories
            that specialize in tick-borne disease, as they usually report
            all antibody bands.
          + Tests based on only one strain. Current tests at most
            laboratories are based on only one strain of Borrelia
            burgdorferi (the B31 strain is used in the U.S.) despite the
            fact that there are over three hundred strains worldwide and
            over one hundred in North America (see #Strains). Several
            studies have found that this practice can lead to
            false-negatives - another reason some clinicians use
            tick-borne disease specialty labs, which utilize multiple
            strains of Borrelia burgdorferi in the preparation of test
            kits.

     * Concern about false-positives. Many physicians with a conservative
       view of Lyme disease believe it is over-diagnosed and over-treated.
       One of the most widely cited studies from critics of Lyme Disease
       was written by Allan Steere. His study, published in JAMA concluded
       that 57% of patients diagnosed with Chronic Lyme in an endemic area
       did not actually have the disease. Critics have responded with the
       following arguments:
          + 45% of those considered "misdiagnosed" in the study received
            positive results from another laboratory, and negative results
            from the authors' laboratory. However there was no independent
            evaluation, and no reason to assume that the authors'
            laboratory was superior. In a separate study funded by the
            NIH, the laboratory used by Allan Steere was sent definite
            Lyme Disease serology in a blinded fashion in an attempt to
            discover the reliability of testing at major academic centers.
            The study concluded that the rate of true positives for this
            laboratory was significanly less than 100 percenent.
          + The authors failed to consider the phenomenon of seronegative
            Lyme disease ( false-negatives).
          + Rather than consider the possibility of persistent infection,
            the authors considered treatment failure to be evidence of
            misdiagnosis, i.e. patients could not possibly have Lyme if
            they were not cured by a standard course of antibiotics even
            though the authors had previously published that treatment
            failures were common. However, despite this fact, the authors
            concluded that all patients with Lyme respond to treatment -
            another example of circular reasoning.
          + The authors excluded patients from a diagnosis of Lyme disease
            if they had psychiatric symptoms, despite the fact that Lyme
            can cause such symptoms.

     * Testing positive after treatment. Because the tests measure
       antibodies to Borrelia burgdorferi and not the organism itself, it
       is theoretically possible to test positive even if the organism has
       been eradicated. All agree that no treatment is required in
       asymptomatic patients regardless of test results; however,
       controversy arises when a patient continues to have symptoms after
       a course of treatment. In this scenario, those who hold a
       conservative view believe the infection must have been eradicated
       by the treatment, and the positive test no longer indicates active
       infection but rather a persisting antibody response, regardless of
       the clinical picture. Those with a broader view of Lyme believe the
       evidence and clinical picture in this case most likely point to a
       persisting infection requiring further antibiotic treatment.

Long-term antibiotic therapy

   There is little concrete evidence either for or against the use of
   antibiotics for chronic Lyme disease, because only three such
   double-blind, placebo-controlled clinical trials have been funded to
   date by the U.S. National Institutes of Health, with conflicting
   results.

Evidence from controlled studies

   1) Klempner et al. (2001). One month of intravenous ceftriaxone
   followed by two months of low-dose oral doxycycline or placebo given to
   chronic Lyme patients with one or more of the following symptoms:
   musculoskeletal pain, cognitive impairment, radicular pain,
   paresthesias or dysesthesias.
     * No significant benefit found in physical or mental health. However
       critics maintain that the study contains serious methodological
       flaws including the following:
          + The dose of doxycycline used in the study (200 mg daily) is
            too low to penetrate the central nervous system; failure was
            to be expected at this dose.
          + This was not in actuality a "long-term" trial as described,
            but rather a short-term trial of ceftriaxone, because of the
            sequential use of two antibiotics with different modes of
            action (and with the second antibiotic inadequately dosed).
            Since patients had failed similar treatment previously, it was
            unlikely that this regimen would produce any benefit.
          + Cognitive status was measured only subjectively using patient
            surveys (the SF-36), making it impossible to assess changes in
            executive functioning often seen in chronic Lyme patients.
            Objective neuropsychiatric testing results were not reported.
          + The authors’ statement that not a single one of 1800 patients
            screened were PCR positive for Lyme is puzzling in light of
            numerous studies documenting persisting infection in patients
            who remain symptomatic after treatment.Either selection bias
            resulted in a study population that was not representative of
            chronic Lyme patients (and thus the study is not
            generalizable), or the accuracy of the authors’ PCR methods is
            in doubt. In either scenario, the authors' conclusion that
            chronic Lyme patients do not suffer from persistent infection
            is invalid.
          + The external validity of the study has been questioned on the
            grounds that the study population was not representative of
            the general population of chronic Lyme patients - an issue
            that Klempner et al. did not address in their discussion. The
            average subject had been ill for 4.7 years and had already
            failed three courses of treatment. Thus it is argued that the
            data are not generalizable to all patients with chronic Lyme
            disease, meaning one can not conclude, as Klempner et al. did,
            that long-term antibiotic therapy is unhelpful for all chronic
            Lyme patients.

   2) Krupp et al. (2003). Four weeks of intravenous ceftriaxone or
   placebo given to chronic Lyme patients with "persistent severe
   fatigue".
     * Significant improvement in fatigue. The treatment effect remained
       even after adjusting for age, pain, history of psychiatric disorder
       and depressive symptoms.
     * No improvement in cognitive symptoms. However the only symptom
       criteria for entrance into the study was severe fatigue. The
       authors acknowledge that the patients’ cognitive deficits at
       baseline were mild, which may explain the lack of treatment effect
       on cognition.

   3) Fallon et al. (not yet published). Results presented on October 22,
   2004 at the Columbia University/Lyme Disease Association Conference in
   Rye, NY . Ten weeks of intravenous ceftriaxone or placebo given to
   chronic Lyme patients with ongoing memory impairment.
     * Significant improvement in both physical and cognitive symptoms.
       Physical improvement was maintained at 12 weeks followup. Patients
       relapsed on cognitive measures at followup, suggesting longer
       regimens may be required.
     * Improvements in cognitive functioning correlated with changes in
       blood flow to the brain as measured by SPECT scans.

   It is important to note that Fallon et al's study is the only
   biological examination of chronic Lyme Disease to date. In the two
   other studies, results were interpreted using questionnaires, often
   administered over the phone.

   Fallon's study had several blinds. This level of methodology has never
   before been attempted in a study of chronic Lyme Disease. One of the
   reasons that many levels of blind were used in Fallon's study has to do
   with the controversy surrounding Lyme Disease. The aim of this study
   was to include people for whom there was little disagreement in terms
   of a correct Lyme Disease diagnosis. Secondly, the strict methodology,
   though tedious, was required because scientific rigor of a very high
   degree was necessary given the political nature of Lyme Disease. In
   this study, patients with chronic Lyme Disease were given SPECT scans
   before and after treatment. A SPECT scan of the brain qualitatively or
   quantitatively (depending on the sophistication of the equipment)
   measures metabolic and blood flow activity within the brain. This is a
   physical marker that can scientifically examine cause and effect as
   opposed to questionnaires which are open to the opinions of the
   participant and influence of the examiner. Patients were also
   administered purely quantitative examinations aimed at assessing
   disability, ie: neuropsychological testing. Lastly, as in other
   studies, patients were asked how they felt after treatment. All of
   these tests included several degrees of blind, ie: radiologist blind to
   diagnosis, neuropsychiatrists blind to diagnosis, patient blind to
   treatment, etc..

Evidence from uncontrolled studies

   While the results of placebo-controlled studies are mixed, several
   uncontrolled studies suggest that longer durations of antibiotic
   treatment may be beneficial for chronic Lyme disease.

Implications for treatment

   The widely publicized results of the Klempner study have led some to
   proclaim that long-term antibiotics are unhelpful for patients with
   chronic Lyme disease, warning patients and clinicians that the evidence
   does not support their use. Others see this as an abuse of the concept
   of evidence-based medicine. They argue that treatment failure in one
   questionably designed clinical trial does not justify such warnings in
   light of other evidence, and that withholding antibiotic treatment is
   unethical in the face of patient suffering. Since the optimal choice of
   antibiotic(s) and treatment duration is unknown and may vary by strain,
   many believe additional research on chronic Lyme disease is needed
   before strict treatment recommendations can be issued.

Prevention

   The best prevention involves avoiding areas in which ticks are found
   and can reduce the probability of contracting Lyme disease. Other good
   prevention practices include wearing clothing that covers the entire
   body when in a wooded area; using mosquito/tick repellent; after
   exposure to wooded areas, check all parts of the body (including hair)
   for ticks.

   A method of protecting your whole property - Damminix - is also cited.
   It consists of biodegradable cardboard tubes stuffed with
   permethrin-treated cotton and works in the following way: Mice collect
   the cotton for lining their nests. The pesticide on the cotton kills
   any immature ticks that are feeding on the mice. It is important to put
   the tubes where mice will find them, such as in dense, dark brush or at
   the base of a log; mice are unlikely to gather the cotton from an open
   lawn. Best results are obtained with regular applications early in the
   spring and again in late summer. The more neighbors who also use
   Damminix, the better. Damminix appears to help control tick
   populations, particularly in the year following initial use. Note that
   it is not effective on the West Coast.

   A potential alternative to Damminix, the Maxforce Tick Management
   system, is based on plastic baitboxes that attract rodents. Rodents
   entering these baitboxes would then be painted with fipronil. This
   product requires professional installation. As of June 2006, this
   product is no longer available. The reason appears to have been that in
   2005, there were selective reports of grey squirrels "chewing" into
   some Maxforce TMS boxes in areas of the northeastern United States,
   compromising the child resistant box. Due to this problem, the Federal
   Environmental Protection Agency (EPA) has asked that all similarly
   designed TMS boxes applied in 2006 be covered with a protective shroud
   capable of preventing squirrel damage.

   An unusual, organic approach to control of ticks and prevention of Lyme
   disease involves the use of domesticated guineafowl. Guinea Fowl are
   voracious consumers of insects and have a particular fondness for
   ticks. They may reduce dependence on chemical pest-control methods..
   Many victims of ticks and others with concern often turn to the Guinea
   Fowl Breeders Association found at Guinea Fowl Breeders Association for
   advice on this topic.

   A vaccine against a North American strain of the spirochetal bacteria
   was available between 1998 and 2002. When taking it off the market, the
   manufacturer cited poor sales, though some people believe that the
   actual reason was that the vaccine was not safe or effective at all.

   The advice of the UK's Hospital for Tropical Diseases is that
   significant exposure (an attached mite for more than twelve hours)
   should be managed, as in America & Germany, with Doxycycline 100 mg
   twice a day for three days. Patients should be advised to report any
   Erythema migrans over the subsequent two to six weeks. If there should
   be suspicion of disease, then a course of Doxycycline should be
   immediately given for ten days; without awaiting serology tests which
   only yield positive results after an interval of one to two months.

Proper Removal of Ticks

   There are many urban legends about the proper and effective method to
   remove a tick. One legend states that something hot (cigarette; burnt
   match) should be applied to the back of the tick, which causes the tick
   to remove its head from the victim. It further states that ticks
   "screw" their heads into their victims; therefore, one must "unscrew"
   the head. These legends are incorrect and potentially dangerous. Proper
   removal of a tick: use a pair of tweezers, grab the head of the tick
   near the mouth, and pull it out. The area should then be disinfected
   with rubbing alcohol or hydrogen peroxide. If the head is not
   completely removed, local infection of the person/animal bitten may
   result, and a doctor should be consulted (or a veterinarian if the tick
   was removed from a pet).

Ecology

   Urbanization and other anthropogenic factors can be implicated in the
   spread of the Lyme disease into the human population. In many areas,
   expansion of suburban neighborhoods has led to the gradual
   deforestation of surrounding wooded areas and increasing "border"
   contact between humans and tick-dense areas. Human expansion has also
   resulted in a gradual reduction of the predators that normally 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 to Lyme
   residents has greatly increased. Researchers are also investigating
   possible links between global warming and the spread of vector-borne
   diseases including Lyme disease.

   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. (Note: At
   this stage, it is proposed that tick infestation may be controlled
   using acaricides ( miticide). A commercial method is to provide nesting
   material soaked in permethrin ( Damminix).) The infected larvae molt
   into nymphs. These infected nymphs transmit the majority of Lyme
   infection to humans, feeding on humans and small animals from spring
   through summer. The nymphs then molt into adults, which feed on larger
   animals such as deer in the fall and early spring. Adult ticks may also
   transmit disease to humans. After feeding, female adult ticks lay their
   eggs on the ground, and the cycle is complete. Note: on the west coast,
   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 necessarily depend on the
   existence of a local deer population, as is commonly assumed. New
   research suggests that eliminating deer from smaller areas (less than
   2.5 ha or 6.2 acres) may in fact lead to an increase in tick density
   and the rise of "tick-borne disease hotspots".

Epidemiology

   The number of reported cases of the disease have been increasing, as
   are endemic regions in North America. For example, it had previously
   been accepted that Borrelia burgdorferri couldn't be maintained in an
   enzootic cycle in the Southern United States because it was assumed the
   large lizard population would dilute the prevalence of Borrelia
   burgdorferri in local tick poplations. The reason this assumption was
   made was based upon a study which found that lizard blood from certain
   species was lethal to Borrelia burgdorferri. Secondly, in areas where
   lizards are abundant, they are often used as blood meals by
   sequestering ticks. However, when this theory has been examined it has
   failed to be as promising in the real world as it had been in previous
   lab experiments. This suggests that the enzootic cycle in areas of the
   country other than New England are highly complex and the study needed
   to identify risk factors will be a difficult epidemiological task. For
   example, in recent studies from Clark, results have shown that the
   prevalence of Borrelia burgdorferri has been very high, even among
   lizards. The author speculated that the enzootic cycle in nature for
   Borrelia burgdorferri in the South was quite different from that found
   in New England. For instance, in repeated studies from Clark, a high
   prevalence of Borrelia burgdorferri sensu lato was found in her study
   of Southern enzootic cycles of Borrelia burgdorferri, whereas in New
   England, enzootic cycles are almost entirely Borrelia burgdorferri
   sensu stricto. Lyme disease is reported in nearly every state in the
   U.S., but there are concentrated areas in the north-east, mid-Atlantic
   states, Wisconsin, Minnesota, and northern California. Lyme disease is
   also endemic to Europe and Asia.

History

   Lyme disease is named after a cluster of cases that occurred in and
   around Old Lyme and Lyme, Connecticut in 1975. Before 1975, elements of
   Borrelia infection were also known as Tickborne meningopolyneuritis,
   Garin-Bujadoux syndrome, Bannwarth syndrome or sheep tick fever.

   The disease was first documented as a skin rash in Europe in 1883. Over
   the years, researchers there identified additional features of the
   disease, including an unidentified pathogen, its response to
   penicillin, the role of the Ixodes tick (black legged tick) as its
   vector, and other symptoms including those affecting the central
   nervous system.

   In the U.S., Borrelia burgdorferi has been isolated in the skin of
   white-footed mice in museum specimens that date back to the 1870s in
   Massachusetts, but researchers were unaware of the organism's existence
   until the 1970s. Interest in tick-borne infections in the U.S. began
   with the first report of tick-borne relapsing fever in 1905, and the
   discovery of the wood tick's role as a vector of Rocky Mountain spotted
   fever the following year. However, 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 1977. Two of these towns, Lyme and Old
   Lyme, gave the disease its popular name.

   In 1982 a novel spirochete was isolated and cultured from the midgut of
   Ixodes ticks, and subsequently from patients with Lyme disease. The
   infecting agent was first identified by Jorge Benach, and soon after
   isolated by Willy Burgdorfer, a scientist at the National Institutes of
   Health, who specialized in the study of spirochete microorganisms. The
   spirochete was named Borrelia burgdorferi in his honour. Burgdorfer was
   the partner in the successful effort to culture the spirochete, along
   with Alan Barbour.

   In Europe, the earliest known cases of Lyme disease date back about 30
   years. However, the disease was not thoroughly recognized before 1998.
   Patients entering doctor's offices with vague symptoms such as chronic
   exhaustion and joint pains where often wrongly diagnosed. Fortunately,
   more knowledge of the disease and its treatment is available now, and
   many patients are treated with antibiotics on time to prevent serious
   infection. However, many people in countries such as The Netherlands
   and France were diagnosed too late and still suffer from the disease in
   spite of regular antibiotics treatment.
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