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Lyme disease controversy

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While there is no doubt that Lyme disease exists, and most clinicians agree on the treatment of early Lyme disease,[1] 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.[2] 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.[3][4][5][6]

The majority of public health agencies such as the U.S. Wikipedia: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 Wikipedia:seronegative Lyme disease, and roughly half prescribing extended courses of antibiotics for chronic Lyme disease.[7][8]

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Two standards of care[edit]

Because the legal Wikipedia: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.[9][10]

ILADS (The International Lyme and Associated Diseases Society)[11]
ILADS Mission Statement[12] 		IDSA (The Infectious Diseases Society of America)[13]
IDSA Mission Statement[14]
Peer-reviewed treatment guidelines ILADS Guidelines[15]

Details of their methods as recorded by the National Guidelines Clearinghouse

IDSA Guidelines[16]

Details of their methods as recorded by the National Guidelines Clearinghouse

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."[17] 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 Wikipedia: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) Wikipedia: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, Wikipedia:paresthesias and/or Wikipedia: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 Wikipedia:Lyme disease microbiology#mechanisms of persistence). 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 Wikipedia:fibromyalgia or Wikipedia: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 Wikipedia:Lyme disease#Prognosis). The over-diagnosis of Lyme may lead to the unnecessary use of antibiotics resulting in side effects (most commonly Wikipedia:nausea). Where Wikipedia: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.[18] There are also concerns about the cost of antibiotic treatment.
Wikipedia: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[edit]

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.[19][20]

CDC Case Definition for Lyme disease
  1. Wikipedia: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 signs of chronic Lyme disease including Wikipedia:encephalopathy[21][22][23] (manifested by Wikipedia:memory loss, mood changes and Wikipedia: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.[24] 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 Wikipedia:Lyme disease#Diagnosis).

Western Blot[edit]

There are two Wikipedia:Western blot tests for borrelia species. IgG and IgM.

  • IgM is a sign of a current infection.
  • IgG is a sign of a current infection, or of a past exposure to or past infection by the organism.

There are nine known Borrelia burgdorferi genus specie specific Wikipedia:kilodalton (KDA) Western Blot Wikipedia:antibodies (bands): 18, 23, 30, 31, 34, 37, 39, 83, and 93.

CDC Western Blot IgG surveillance criteria includes 18, 23, 30, 37, 39, and 93 and excludes bands 31, 34, and 83, making positive diagnosis for borrelia more problematic.

Under the CDC criteria Western Blot IgG must have at least five of ten specific serologic bands to positive. 18, (22-25), 28, 30, 39, 41, 45, 58, 66 and 93. Western Blot IgM must have two of the three following bands to be considered positive (22-25), 39, and 41.[25]

Testing[edit]

The debate over Lyme disease testing remains a heated one, with concern over both false-positives and false-negatives (see Wikipedia:Lyme disease#Diagnosis). Tests currently rely on indirect methods of detection (i.e. the body's Wikipedia: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:

Critics argue that the CDC's 2-tiered testing protocol (Wikipedia:ELISA test, followed by confirmatory Wikipedia: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. Such studies have included both early and late stage Lyme Disease patients. A study from the Wikipedia:College of American Pathologists concluded that "these tests will not be useful as screening tests until their sensitivity is improved."[26]

  • Inadequate lab standardization.

Standardization of testing has been found to be inadequate, with a high degree of interlaboratory variability.[27][26][28]

Without a diagnostic gold standard to identify those with chronic Lyme disease, Wikipedia: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 Wikipedia:selection bias.[29]

False Negative Tests[edit]

False negative test results due to the following, particularly in late and chronic Lyme disease:

Wikipedia:Intracellular sequestration, Wikipedia: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 Wikipedia:Lyme disease microbiology#Mechanisms of persistence).

  • Positive test criteria is based on early Lyme disease.

The CDC's criteria for a positive Wikipedia:Western blot were developed based upon on a study of patients with early Lyme disease.[30] 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 Wikipedia: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 Wikipedia:Western blot because they only appear late in the disease. 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.[31] 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 Wikipedia: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[32] (see Wikipedia:Lyme disease microbiology). Several studies have found that this practice can lead to false-negatives[33][34] - another reason some clinicians use Wikipedia:tick-borne disease specialty labs, which utilize multiple strains of Borrelia burgdorferi in the preparation of test kits.

False Positive Tests[edit]

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.[35] Critics have responded with the following arguments:[36][37]

  • 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 significantly less than 100 percent[unverified].
  • 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. This assumption is supported by Borrelia burgdorferi not being resistant to the antibiotics used in its treatment. However, this assumption does not consider the possibility that symptoms may be due to abnormal host immunological response[43]. This type of response might be similar to the arthritides associated with gastrointestinal diseases.
  • The authors excluded patients from a diagnosis of Lyme disease if they had psychiatric symptoms, despite the fact that Lyme can cause such symptoms.[24][44][45]

Testing positive after treatment[edit]

Because the tests measure Wikipedia: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[edit]

There is little concrete evidence either for or against the use of antibiotics for chronic Lyme disease, because only three such Wikipedia:double-blind, placebo-controlled Wikipedia:clinical trials have been funded to date by the U.S. Wikipedia:National Institutes of Health, with conflicting results. More randomized studies with long-term follow-up are warranted to determine the most successful regimens and adequate durations of antibiotic treatments for disseminated Lyme borreliosis.

Evidence from controlled studies[edit]

Klempner et al. (2001)[edit]

One month of intravenous Wikipedia:ceftriaxone followed by two months of low-dose oral Wikipedia:doxycycline or Wikipedia:placebo given to chronic Lyme patients with one or more of the following symptoms: musculoskeletal pain, cognitive impairment, Wikipedia:radicular pain, Wikipedia:paresthesias or dysesthesias.[46]

  • No significant benefit found in physical or mental health. However critics maintain that the study contains serious methodological flaws including the following:[5][47][48]
    • The dose of doxycycline used in the study (200 mg daily) is too low to penetrate the Wikipedia: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.
    • The primary measure reported post-treatment, the SF-36, is a general health questionnaire commonly recognized as insufficient to evaluate a specific disease. The study's authors did not report the eight scores the questionnaire generates, only controversial summary scores. These summary scores were further generalized before data analysis making any treatment effect highly unlikely to be detectable.
    • Cognitive status was measured only obliquely and subjectively using a mental health summary score in the patient survey (the SF-36), making it impossible to assess changes in Wikipedia: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[49] is puzzling in light of numerous studies documenting persisting infection in patients who remain symptomatic after treatment.[50][51][52][53][54][55][56][57][58]Either Wikipedia: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 Wikipedia: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.[59]

Krupp et al. (2003)[edit]

Four weeks of intravenous Wikipedia:ceftriaxone or Wikipedia:placebo given to chronic Lyme patients with "persistent severe fatigue".[60]

  • Significant improvement in fatigue. The treatment effect remained even after adjusting for age, pain, history of psychiatric disorder and depressive symptoms.
  • No improvement in Wikipedia:cognitive symptoms. The authors caution, "although the patients with Lyme disease showed cognitive slowing compared to healthy controls, these deficits were relatively mild, which may have contributed to the lack of a treatment effect on cognition."
  • A 7% incidence of severe adverse events (requiring hospitalization) between the two groups, with three episodes of IV sepsis (in the IV placebo group) and one episode of anaphylaxis (in the ceftriaxone group).
  • The authors concuded that this data suggsts that "repeated courses of antibiotic treatment are not indicated for persistent symptoms following Lyme disease including those related to fatigue and cognitive dysfunction, particularly in light of the frequency of serious adverse events."

Fallon et al. (not yet published)[edit]

This trial involved ten weeks of intravenous Wikipedia:ceftriaxone or Wikipedia:placebo given to chronic Lyme patients with ongoing memory impairment. Advanced neuroimaging techniques were used to study the patients' response to treatment. Preliminary results were orally presented on October 22, 2004 at the Columbia University / Lyme Disease Association Conference in Rye, NY.[61] According to an LDA press release, the antibiotic group showed "significant improvement in neurocognitive function," as well as in "other symptoms".[62] Definitive results of this study have not yet been published in a peer-reviewed medical journal as of May 2007.

Google Scholar search: Fallon Lyme disease

Evidence from uncontrolled studies[edit]

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.[54][63][64][65][66][67]

Implications for treatment[edit]

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 Wikipedia: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. More randomized studies are needed to elucidate proper use and duration of antibiotics in treatment protocol.

Chronic Lyme Disease and Post Lyme Syndrome[edit]

Much of the questioning behind continuing antibiotic therapy for patients with ongoing symptoms is whether chronically ill Lyme patients have an Wikipedia:autoimmune reaction in the patient via immunologic mechanisms triggered by the initial borrelia infection, or have an ongoing (chronic) borrelia infection. There is viable evidence for both theories.

The new IDSA guidelines reject the term "chronic Lyme disease" in favor of "post-Lyme syndrome" because they argue the infection does not persist after treatment, although the same authors have used the term "chronic Lyme disease" in previously published work.

Patients with "post-Lyme syndrome" may or may not have serologic evidence of continuing spirochete infection. Previous antibiotic treatment may reduce or completely clear the borrelia infection in these patients but the inflammatory response persists. Inadequate serology testing does not help define if infection has been cleared or not. A patient may continue with symptoms after antibiotic treatment but have a negative serology, or they may be asymptomatic but have a positive serology. Further antibiotic treatments are not ameliorating of symptoms in these patients.[68][69]

There is currently no consensus on whether ongoing symptoms result from the various hypotheses put forth by the IDSA in their discussion of "post-Lyme syndrome" including autoimmune hypersensitivity, or cell-mediated proinflammatory process,[70] or if they sometimes result from persistent infection. IDSA argues that there is no convincing evidence of persistent infection. ILADS and others argue that the IDSA ignored evidence that Lyme infection sometimes persists despite a standard course of antibiotics.

The distinction has treatment implications: the IDSA recommends no specific treatment for "post-Lyme syndrome," and never recommends long-term antibiotic therapy, while ILADS and others recommend longer courses of antibiotics for "chronic Lyme disease" if it is believed that the patient has an ongoing infection. The term "chronic Lyme disease" definitively suggests persistent infection by viable bacteria, when an autoimmune reaction to the initial infection may be the cause of continuing symptoms. This has yet to be unequivocally defined, and may be a case by case scenario.

Further investigation to the nature of borrelia burgdoferi senso latu is warranted, both in the laboratory and in the clinical setting, for optimal treatment in patients with continuing symptoms of borrelia infection who may be antibiotic refractory in the late course of disease. Since the optimal choice of antibiotic(s) and treatment duration is unknown and may vary by strain, additional research is needed before strict treatment recommendations can be issued.

Both ILADS and ISDA guidelines are meant to guide the physician and neither are the final word on treatment for Lyme disease. Ultimately physicians should make their choices based upon the available science and best interest of their patients taking into account benefits and risks of any treatment.

Recent Developments[edit]

Since Wikipedia:October 2006, the Lyme controversy has become more polarized with the release of updated diagnosis and treatment guidelines from the Wikipedia:Infectious Diseases Society of America (IDSA).[71] The new IDSA recommendations are even more restrictive than previous ISDA guidelines, 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[16] 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,[72] 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.[73]

Wikipedia:Connecticut State Attorney General Wikipedia:Richard Blumenthal initiated a formal investigation into the development of the IDSA guidelines in Wikipedia:November 2006. The Attorney General's office is considering whether the IDSA violated Wikipedia: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."[74]


References[edit]

  1. ↑ Murray T, Feder H, (2001). "Management of tick bites and early Lyme disease: a survey of Connecticut physicians.," Pediatrics, 108, 1367-70.
  2. ↑ Wormser G, (2006). "Clinical practice. Early Lyme disease.," N Engl J Med, 354, 2794-801.
  3. ↑ Stricker RB, Lautin A, Burrascano JJ, (2006). "Lyme Disease: The Quest for Magic Bullets," Chemotherapy, 52, 53-59.
  4. ↑ Phillips SE, Harris NS, Horowitz R, Johnson L, Stricker RB, (2005). "Lyme disease: scratching the surface," Lancet, 366, 1771.
  5. ↑ 5.0 5.1 Phillips S, Bransfield R, Sherr V, Brand S, Smith H, Dickson K, and Stricker R (2003). Evaluation of antibiotic treatment in patients with persistent symptoms of Lyme disease: an ILADS position paper. (PDF) International Lyme and Associated Diseases Society. URL accessed on 2006-03-15.
  6. ↑ Harvey WT, Salvato P, (2003). "'Lyme disease': ancient engine of an unrecognized borreliosis pandemic?," Med Hypotheses, 60, 742-59.
  7. ↑ Ziska MH, Donta ST, Demarest FC, (1996). "Physician preferences in the diagnosis and treatment of Lyme disease in the United States," Infection, 24, 182-6.
  8. ↑ Eppes SC, Klein JD, Caputo GM, Rose CD, (1994). "Physician beliefs, attitudes, and approaches toward Lyme disease in an endemic area," Clin Pediatr (Phila), 33, 130-4.
  9. ↑ Johnson, Lorraine Lyme disease: two standards of care. International Lyme and Associated Diseases Society. URL accessed on 2006-11-17.
  10. ↑ Johnson L, Stricker R, (2004). "Treatment of Lyme disease: a medicolegal assessment.," Expert Rev Anti Infect Ther, 2, 533-57.
  11. ↑ ILADS (The International Lyme and Associated Diseases Society)
  12. ↑ ILADS Mission Statement
  13. ↑ IDSA (The Infectious Diseases Society of America)
  14. ↑ IDSA Mission Statement
  15. ↑ Cameron D, Gaito A, Narris N, Bach G, Bellovin S, Bock K, Bock S, Burrascano J, Dickey C, Horowitz R, Phillips S, Meer-Scherrer L, Raxlen B, Sherr V, Smith H, Smith P, Stricker R; ILADS Working Group, (2004). "Evidence-based guidelines for the management of Lyme disease," Expert Rev Anti Infect Ther, 2, S1-13.
  16. ↑ 16.0 16.1 Wormser G, Dattwyler R, Shapiro E, Halperin J, Steere A, Klempner M, Krause P, Bakken J, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler J, Nadelman R, (2006). "The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America.," Clin Infect Dis, 43, 1089-134.
  17. ↑ Stricker, Raphael B. (2006-07-31). "Medical Revisionists Threaten Effective Lyme Treatment". Hartford Courant. p. A7. http://www.ilads.org/stricker_07_2006.html. </li>
  18. ↑ Patel R, Grogg K, Edwards W, Wright A, Schwenk N, (2000). "Death from inappropriate therapy for Lyme disease.," Clin Infect Dis, 31, 1107-9.
  19. ↑ Lyme Disease (Borrelia burgdorferi): 1996 Case Definition. CDC Case Definitions for Infectious Conditions under Public Health Surveillance. URL accessed on 2006-03-15.
  20. ↑ CDC Testimony before the Connecticut Department of Health and Attorney General's Office. CDC's Lyme Prevention and Control Activities. URL accessed on 2006-03-15.
  21. ↑ Fallon BA, Keilp J, Prohovnik I, Heertum RV, Mann JJ, (2003). "Regional cerebral blood flow and cognitive deficits in chronic lyme disease," J Neuropsychiatry Clin Neurosci, 15, 326-32.
  22. ↑ Kaplan RF, Meadows ME, Vincent LC, Logigian EL, Steere AC, (1992). "Memory impairment and depression in patients with Lyme encephalopathy: comparison with fibromyalgia and nonpsychotically depressed patients," Neurology, 42, 1263-7.
  23. ↑ Logigian EL, Kaplan RF, Steere AC, (1990). "Chronic neurologic manifestations of Lyme disease," N Engl J Med, 323, 1438-44.
  24. ↑ 24.0 24.1 Fallon BA, Kochevar JM, Gaito A, Nields JA, (1998). "The underdiagnosis of neuropsychiatric Lyme disease in children and adults," Psychiatr Clin North Am, 21, 693-703, viii.
  25. ↑ Morbidity and Mortality Weekly Report Centers for Disease Control and Prevention: Notice to Readers Recommendations for Test Performance and Interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease
  26. ↑ 26.0 26.1 Bakken LL, Callister SM, Wand PJ, Schell RF, (1997). "Interlaboratory comparison of test results for detection of Lyme disease by 516 participants in the Wisconsin State Laboratory of Hygiene/College of American Pathologists Proficiency Testing Program," J Clin Microbiol, 35, 537-43.
  27. ↑ Brown SL, Hansen SL, Langone JJ, (1999). "Role of serology in the diagnosis of Lyme disease," JAMA, 282, 62-6.
  28. ↑ Bakken LL, Case KL, Callister SM, Bourdeau NJ, Schell RF, (1992). "Performance of 45 laboratories participating in a proficiency testing program for Lyme disease serology," JAMA, 268, 891-5.
  29. ↑ Bacon RM, Biggerstaff BJ, Schriefer ME, Gilmore RD Jr, Philipp MT, Steere AC, Wormser GP, Marques AR, Johnson BJ, (2003). "Serodiagnosis of Lyme disease by kinetic enzyme-linked immunosorbent assay using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi compared with 2-tiered testing using whole-cell lysates," J Infect Dis, 187, 1187-99.
  30. ↑ Dressler F, Whalen JA, Reinhardt BN, Steere AC, (1993). "Western blotting in the serodiagnosis of Lyme disease," J Infect Dis, 167, 392-400.
  31. ↑ Ma B, Christen B, Leung D, Vigo-Pelfrey C, (1992). "Serodiagnosis of Lyme borreliosis by western immunoblot: reactivity of various significant antibodies against Borrelia burgdorferi," J Clin Microbiol, 30, 370-6.
  32. ↑ List of 321 Borrelia burgdorferi (Bb) strains from NIH/NLM/NCBI database as of 22 June 2001. Art Doherty's Lots of Links on Lyme disease. URL accessed on 2006-03-18.
  33. ↑ Kaiser R, (2000). "False-negative serology in patients with neuroborreliosis and the value of employing of different borrelial strains in serological assays," J Med Microbiol, 49, 911-5.
  34. ↑ Hauser U, Wilske B, (1997). "Enzyme-linked immunosorbent assays with recombinant internal flagellin fragments derived from different species of Borrelia burgdorferi sensu lato for the serodiagnosis of Lyme neuroborreliosis," Med Microbiol Immunol (Berl), 186, 145-51.
  35. ↑ Steere AC, Taylor E, McHugh GL, Logigian EL, (1993). "The overdiagnosis of Lyme disease," JAMA, 269, 1812-6. Full text at OVID (subscription required)
  36. ↑ Burrascano JJ, (1993). "The overdiagnosis of Lyme disease [Comment]," JAMA, 270, 2682.
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