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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 and historical emergence 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. 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.[7][8]

Both groups making up the dichotomy of the Lyme disease controversy have compelling empirical evidence to support their points of view and logical arguments. More research into Lyme and its infecting agent, Borrelia burgdorferi, is needed to elucidate the true nature of Lyme disease before definitive treatment guidelines are to be written.

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.[9][10]

Treatment guidelines from the Infectious Diseases Society of America (IDSA), make up the viewpoint of the more conservative party of treatment for Lyme. The ISDA released their most recent version of treatment guidelines in 2006. [11] The guidelines are published by the University of Chicago Press Journal of Clinical Infectious Diseases.

The new guidelines released by the IDSA are more restrictive in their treatment regimens than previously. The IDSA guidelines now require 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.

An opposing group of doctors making up the International Lyme and Associated Disease Society (ILADS) have purported the use of antibiotic treatment beyond four weeks for both early and late Lyme. ILADS supports studies that purport persistent or long term chronic infection with the infecting agent of Lyme, the borrelia spirochete. The ILADS treatment guidelines are available through National Guideline Clearinghouse.

The discourse gap between the standards of care representing the disparate views of the IDSA and ILADS guidelines are juxtaposed in the table below.

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]
Peer-reviewed treatment guidelines ILADS Guidelines[16]

Details of their methods as recorded by the National Guidelines Clearinghouse

IDSA Guidelines[11]

Details of their methods as recorded by the National Guidelines Clearinghouse

EM rash Present less than 50% of the time. Studies that show otherwise are often excluded, as subjects must meet The CDC criteria which prioritize the rash over other disease manifestations. Among those who would be excluded from such studies are seronegative Lyme patients without a rash, seropositive patients without a rash who present with fever, flu-like symptoms, joint and muscle pain, paresthesia and/or encephalopathy, and late-stage patients whose diagnosis was delayed because no rash was present. "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. Lengthy treatment regimens are sometimes required. Persistent Lyme infection is not recognized. Some patients report continuing and/or relapsing non-specific symptoms following an episode of Lyme disease that has been treated with a standard course of antibiotics. 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 A 2-4 week course of antibiotics is not always curative, particularly when diagnosis is delayed and disease is at a later, disseminated stage. Long-term antibiotic therapy is recommended for these symptomatic patients, while acknowledging the lack of published data supporting either long-term or short-term treatment durations. While more research is needed, treatment should not be withheld from patients in the meantime. (See Evidence section for list of published clinical trials.) 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.
Primary concern regarding misdiagnosis The under-diagnosis of Lyme may lead to untreated chronic, persistent infection resulting in severe disability and possibly even death. 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.[17] 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. Long-term antibiotic therapy may be dangerous and lead to drug-resistant superbugs.

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. 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."[18]


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.[19][20]

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 signs of chronic Lyme disease including encephalopathy[21][22][23] (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.[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 Lyme disease#Diagnosis).

Western Blot

There are two 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 kilodalton (KDA) Western Blot 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]

The CDC surveillance criteria were formulated utilizing a cohort of patients who mostly manifested early disease. Moreover, the 'control' group for this study included a large number of patients who, rather than being healthy, had syndromal diagnoses which could have been caused or complicated by late CNS lyme: MS and CFS being prime examples. The 'control' group was further polluted by the inclusion of 25 syphilitic patients, which represented 20% of the control, whereas the incidence of syphilis in the general population is about 3 per 100,000. This selection vastly distorted the meaning of the antibody response at 41 kDa. Subsequent research has demonstrated the Borrelia differentially regulate their outer surface proteins according to stage of infection and even tissue type. Antibodies to numerous proteins important in human infection are not even tested under the current blot standard due to the failure of the authors of these criteria to temperature shift their cultures used for blotting purposes.

For these reasons, experts consider the CDC criteria to be almost worthless in assessing late CNS lyme encephalopathy. Because the antibody response is not consistent in American CSF samples, and PCR while definitive yields only 30% accuracy, the diagnosis of lyme encephalopathy must be made on clinical grounds and should include, in addition to standard serology and intrathecal testing, MRI, SPECT, and neuropsychological assessment, as well as the ruling out of such conditions as syphilis, lupus, brucellosis, and HIV encephalopathy {as examples}.



Testing

The debate over Lyme disease testing remains a heated one, with concern over both false-positives and false-negatives (see Lyme disease#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:

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. 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."[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, 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.[29]

False Negative Tests

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

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 Lyme disease microbiology#Mechanisms of persistence).

  • 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.[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 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. 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 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 Lyme disease microbiology). Several studies have found that this practice can lead to false-negatives[33][34] - another reason some clinicians use tick-borne disease specialty labs, which utilize multiple strains of Borrelia burgdorferi in the preparation of test kits.

False Positive Tests

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[citation needed].
  • 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

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. 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

Klempner et al. (2001)

The study intervention was one month of intravenous ceftriaxone, followed by two months of oral doxycycline or an identical sequence of IV and oral placebo, given to chronic Lyme patients with one or more of the following symptoms: musculoskeletal pain, cognitive impairment, radicular pain, paresthesias or dysesthesias. Two separate analyses were performed, one for Lyme antibody seronegative patients (n=51) and one for Lyme antibody seropositive patients (n=78).[46]

  • No significant benefit was seen in either physical or mental health-related quality of life in either patient group, as assessed with a standardized clinical questionnaire.
  • Physicians writing for the ILADS[5] as well as others[47][48] cited several perceived methodological flaws in the study, including concerns about patient selection criteria, randomization, drug dosing, treatment duration, method of symptom evaluation and analysis, and the accuracy of ancillary diagnostic testing, all of which were suggested to have affected the study's validity and generalizability to other patient populations and long-term antibiotic treatment strategies.

Krupp et al. (2003)

The study intervention was four weeks of intravenous ceftriaxone or placebo, given to previously antibiotic-treated Lyme disease patients with "persistent severe fatigue".[49]

  • Significant improvements were seen in symptoms of fatigue. The treatment effect remained even after adjusting for age, pain, history of psychiatric disorder and depressive symptoms.
  • No improvement was seen in 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) was seen 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 concluded that this data suggests 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)

This trial involved ten weeks of intravenous ceftriaxone or 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.[50] According to an LDA press release, the antibiotic group showed "significant improvement in neurocognitive function," as well as in "other symptoms".[51] Definitive results of this study have not yet been published in a peer-reviewed medical journal as of May 2007.

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.[52][53][54][55][56]

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

Chronic Lyme Disease and Post Lyme Syndrome

Much of the questioning behind continuing antibiotic therapy for patients with ongoing symptoms is whether chronically ill Lyme patients have an 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 persistence of borrelia infection in the central nervous system following some treatment regiments has been discussed in the literature since the 1970's.[57]

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.[58][59]

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,[60] 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

Since October 2006, the Lyme controversy has become more polarized with the release of updated diagnosis and treatment guidelines from the Infectious Diseases Society of America (IDSA).[61] 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[11] 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,[62] 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.[63]

Connecticut State 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."[64]

See Also

References

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