Lyme disease

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Lyme disease
SpecialtyInfectious diseases, dermatology, neurology, cardiology Edit this on Wikidata

Lyme disease or Lyme borreliosis is an infectious tick-borne disease, caused by the Borrelia spirochete, a gram-negative microorganism.

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 "tick-borne meningopolyneuritis", Garin-Bujadoux syndrome, Bannwarth syndrome or sheep tick fever. It is transmitted to humans by the bite of infected ticks.

History

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 (wood tick) as its vector, and symptoms that included not only the rash but additional ones that affected e.g. the nervous system.

Researchers in the US had been aware of tick infections since the early 1900s. For example, an infection called tick relapsing fever was reported in 1905, and the wood tick, which carries an agent that causes Rocky Mountain spotted fever, was identified soon after. However, the full syndrome now known as Lyme disease, was not identified until a cluster of cases thought to be juvenile rheumatoid arthritis occurred in three towns in southeastern Connecticut, in the United States. 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 honor. Burgdorfer was the partner in the successful effort to culture the spirochete, along with Alan Barbour.

Borrelia burgdorferi has been isolated in skin specimens of white-footed mice in museum specimens as far back as the 1870s in Massachusetts.

Microbiology

The disease is caused by the parasite Borrelia, which has well over three hundred known genomic strains but is usually cultured as Borrelia burgdorferi, Borrelia afzelii or Borrelia garinii. Different Borrelia strains are predominant in Europe and North America.

The disease has been found to be transmitted to humans by the bite of infected Ixodes ticks. Not all ticks carry or can transmit this particular disease.

Borrelia burgdorferi resembles other spirochetes in that it is a highly specialized, motile, two-membrane, spiral-shaped bacterium which lives primarily as an extracellular pathogen. One of the most striking features of Borrelia burgdorferi as compared with other eubacteria is its unusual genome, which includes a linear chromosome approximately one megabase in size and numerous linear and circular plasmids. Genetic exchange, including plasmid transfers, contributes to the pathogenicity of the organism[1].

Long-term culture of Borrelia 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.

Borrelia burgdorferi may persist in humans and animals for months or years following initial infection, despite a robust humoral immune response. Borrelia burgdorferi is susceptible to antibiotics in vitro. However, there are contradictory reports as to the efficacy of antibiotics in vivo. While prompt treatment leads to full recovery in terms of signs and symptoms in the majority of cases, questions have arisen in regard to complete eradication of the bacterium from the host. Numerous studies have demonstrated persistence of infection despite repeated courses of antibiotic therapy. [2] [3] [4] [5] [6] [7] [8]

Transmission

Transmission by ticks

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 (a.k.a. black-legged tick or deer tick) has been identified as the key to the disease's spread.

The number of reported cases of the disease have been increasing, as are endemic regions in the United States. Lyme disease is reported in nearly every state in the U.S., but there are concentrated areas in the northeast, mid-Atlantic states, Wisconsin, Minnesota, and northern California. Lyme disease is endemic to Europe and Asia.

The longer the duration of tick attachment, the greater the risk of disease transmission. Even short-term attachment can result in transmission of the disease. Also, improper tick removal can result in early disease transmission so it is very important to remove a tick properly.

Congenital Lyme disease

Lyme disease can be transmitted from an infected mother to fetus through the placenta during pregnancy, possibly resulting in stillbirth[9][10]. 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 also some anecdotal, largely unconfirmed evidence of sexual transmission.

Symptoms

Lyme disease has many signs and symptoms, but skin signs, arthritis and/or various neurological symptoms are often present. Conventional therapy is with antibiotics.

Acute (early) symptoms that may occur

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

The late symptoms of Lyme disease can appear months from infection. Fatality can occur when the spirochete enters brain fluids and causes meningitis, or due to conductivity defects in the heart.

Lyme disease is sometimes 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. Many of these conditions may also be misdiagnosed as Lyme disease, e.g. due to false-positive Lyme serology. However it should be noted 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 symptomology between Lyme and CFS makes this a crucial point.[13] 

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Diagnosis

The most reliable method of diagnosing Lyme disease is a clinical exam by an experienced practitioner. 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 (often before a sufficient antibody response has been established), it is recommended that tests not be performed when a patient has an EM rash[12][14][15].

The serological laboratory tests available are the Western blot and ELISA. In the two-tiered protocol recommended by the U.S. Centers for Disease Control, 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.

False-positive results for the Western blot IgM are described with varicella-zoster virus[16] [17] , Epstein-Barr virus[18] [19] , cytomegalovirus[18] and herpes simplex type virus 2[20]. However studies show the Western blot IgM has a specificity of 94-96% for patients with symptoms suggestive of Lyme disease[21][22].

False-negative test results have been widely reported in both early and late disease[8] [23] [24] [25] [26].

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.

Prognosis

Prompt treatment is usually curative. The severity and treatment of Lyme disease can 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. The disease is rarely fatal in and of itself.

Prevention

The best prevention involves avoiding areas in which ticks are found and can reduce the probability of contracting Lyme disease.

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. [27]

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 100mg twice a day for three days[28] . Patients should be advised to report any Erythema Migrains 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.

Treatment

Traditional treatment of acute Lyme disease usually consists of a minimum two-week to one-month course of antibiotics. Chronic or late diagnosed lyme is often treated with IV antibiotics, frequently ceftriaxone, for a minimum of four weeks. As it is thought to inhibit the once a month breeding cycle of borrelia burgdorferi, a longer course is recommended.

If the blood/brain barrier has been crossed and the spirochetes have reached the brain, oral antibiotics are not curative; however studies suggest that long-term oral therapy may still be helpful.[29] [30]

Many alternative (or supplemental) therapies have been suggested. Clinical trials of large doses of IV sodium ascorbate (vitamin C) have been shown to kill cancer cells and possibly parasites in the body. Largely due to this, there are many chronic lyme disease sufferers turning to natural therapies, such as those outlined at Lyme Photos.

It should be noted that the most important factor in treating lyme disease is finding a doctor that is familiar with the disease and all of the possible treatments. Some experts, such as Dr. Joseph J. Burrascano recommend both (sometimes long-term) IV treatment and a cocktail of various vitamins.

The Lyme Controversy

Though there is no doubt that Lyme disease exists, there is considerable controversy as to the prevalence of the disease, the proper procedure for diagnosis and treatment, and the likelihood of a chronic, antibiotic-resistant Lyme infection.

On one side are medical practitioners 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 medical practitioners, patients and advocates who believe that Lyme disease is under-diagnosed, that available blood tests are unreliable, and that extended antibiotic treatment is often necessary [31] [32] [33] [34].

The CDC Case Definition

In the United States, confusion over the application of the CDC's case definition for Lyme disease lies at the heart of the controversy. The CDC has explicitly stated that the definition is meant for surveillance purposes only, and is "not intended to be used in clinical diagnosis"[35][36].

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:


A number of well-documented symptoms of chronic Lyme disease including encephalopathy[37] are not part of the CDC case definition. Therefore clinicians using the CDC criteria for diagnostic purposes may miss some patients who have the disease[38]. Additionally, this practice may result in the misdiagnosis of those with false-negative test results, a widely reported phenomenon documented above.

Testing

The debate over testing remains a heated one, with concern over both false-positives and false-negatives (see above). Tests currently rely on indirect methods of detection (i.e. the body's immune system response), because it is very difficult to culture the Lyme 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) misses many patients with the disease, leading to false negatives. A study from the College of American Pathologists concluded that "these tests will not be useful as screening tests until their sensitivity is improved"[39].
  • Inadequate lab standardization. Standardization of testing has been found to be inadequate, with a high degree of interlaboratory variability[39][40][14].
  • No gold standard for evaluation of tests. Without a diagnostic gold standard to identify those with late-stage or chronic Lyme, circular reasoning becomes a problem in studies that evaluate the sensitivity of serologic tests for this population. Selection 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 one of few studies that included late-stage patients with neurological symptoms (a study cited by the CDC to defend the validity of the tests), the authors acknowledge this risk of selection bias[41].
  • Positive test criteria is based on early Lyme. The CDC's criteria for a positive Western blot were developed based upon on a study of patients with early Lyme disease[42]. The serologic response of patients with late-stage 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 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[43]. 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[44]. Several studies have found that this practice can lead to false-negatives [45][46] - another reason some clinicians use tick-borne disease specialty labs, which use multiple strains of Borrelia burgdorferi in the preparation of test kits.
  • Testing positive after treatment. Because the tests measure antibodies to Borrelia burgdorferi and not the organism itself, it is possible to test positive even after 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 who take a broader view of Lyme believe the evidence and clinical picture most likely point to a persisting infection requiring further antibiotic treatment.
  • Concern about false-positives. Many physicians with a conservative view of Lyme believe it is over-diagnosed and over-treated. One of the most widely cited studies concluded that 57% of patients diagnosed with Lyme in an endemic area did not actually have the disease[47]. Critics have responded with the following arguments[48][49]:
    • 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.
    • The authors failed to consider the phenomenon of seronegative Lyme disease (false-negatives)[8][23][24][25][26].
    • 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. This was also taken as evidence that all patients with Lyme respond to treatment - another example of circular reasoning.
    • The authors excluded patients from a Lyme diagnosis if they had psychiatric symptoms, despite the fact that Lyme may cause such symptoms[38][50][51].


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External links

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