The American Journal of Medicine
Volume 121, Issue 7 , Pages 562-564, July 2008

Perspectives on “Chronic Lyme Disease”

  • Phillip J. Baker, PhD

      Affiliations

    • Corresponding Author InformationRequests for reprints should be addressed to Phillip J. Baker, PhD, Post Office Box 466, Lyme, CT 06371.

American Lyme Disease Foundation, Lyme, Connecticut.

Article Outline

Abstract 

There is much controversy about the treatment of Lyme disease with respect to 2 poorly defined entities: “chronic Lyme disease” and “posttreatment Lyme disease syndrome.” In the absence of direct evidence that these conditions are the result of a persistent infection, some mistakenly advocate extended antibiotic therapy (≥6 months), which can do great harm and has resulted in at least 1 death. The purpose of this brief report is to review what is known from clinical research about these conditions to assist both practicing physicians and lawmakers in making sound and safe decisions with respect to treatment.

Keywords: Adverse effects of extended antibiotic therapy, Antibiotic therapy, Borrelia burgdorferi, Chronic Lyme disease, Extended antibiotic treatment, Lyme disease, Neuroprotective effects of antibiotics, Posttreatment Lyme disease syndrome

 

During the 2007 session of the Maryland House of Delegates, legislation was proposed that would have compelled health insurance companies to pay for extended antibiotic therapy for the treatment of “chronic Lyme disease” and prohibited local medical boards from disciplining physicians who administered such therapy. Similar legislation was proposed in Pennsylvania, Connecticut, Massachusetts, and New York, where Lyme disease is endemic. This is all part of an orchestrated campaign by some who mistakenly believe that “chronic Lyme disease” is the result of a persistent infection requiring 6 months or more of antibiotic therapy to cure. The purpose of this document is to review what is known about “chronic Lyme disease” and examine the impact of such therapy on the public health.

Clinical Significance

 


•There is much confusion and controversy about the treatment of “chronic Lyme disease” and “posttreatment Lyme disease syndrome,” which have not yet been defined as distinct clinical entities.

•Although there is no direct evidence of a persistent infection, some advocate extended antibiotic therapy.

•The purpose of this brief review is to provide relevant information on this issue to assist practicing physicians in making sound and safe judgments in that regard.

Lyme disease is easy to cure with a short course of oral antibiotics, such as doxycycline or amoxicillin. What is less well recognized is that late manifestations also are responsive to 3 to 4 weeks of treatment with doxycycline, amoxicillin, or ceftriaxone. Despite the proven efficacy of these regimens, there still is much controversy about the treatment of 2 poorly defined entities, “chronic Lyme disease” and “posttreatment Lyme disease syndrome,” which occur in a small percentage (<5%) of individuals previously treated for correctly diagnosed early Lyme disease. To address this issue, the National Institutes of Health (NIH) funded 3 placebo-controlled clinical trials on the efficacy of prolonged antibiotic therapy for these conditions; the results obtained were published in major scientific journals and thus were subjected to rigorous peer review. Two large studies provided no evidence that prolonged antibiotic treatment is beneficial.1 In the third study, the score for severity of fatigue improved in both the antibiotic-treated and the placebo groups;2 however, the improvement was greater by 13% in those who received antibiotic treatment (22% vs 9%). No significant benefit was found for other symptoms, and unblinding may have occurred. Because of the high frequency of serious adverse effects noted, the investigators concluded that “repeated courses of antibiotic treatment are not indicated for persistent symptoms following Lyme disease, including those related to fatigue and cognitive dysfunction….”2

Several key factors were considered in the design of these clinical trials. They included the following:

•the susceptibility of Borrelia burgdorferi, the causative agent of Lyme disease, to the antibiotics used;

•the ability of the antibiotics used to access the central nervous system and to persist at effective levels during the course of therapy;

•the ability of the antibiotics used to penetrate mammalian cells, even though there is much evidence to indicate that Borrelia are extracellular, rather than intracellular, pathogens;

•the possibility that various co-infecting agents could influence the expression and severity of symptoms;

•the safety of patients enrolled in the trials.

Because the experimental protocols used addressed all of these issues, there is no reason to believe that different results would be obtained using other antibiotics, given singly or in combination by different routes, for longer periods of time. The results obtained are consistent with the findings of more than 20 years of basic research on the pathogenesis and treatment of Lyme disease supported by the NIH and the Centers for Disease Control and Prevention.

Despite the convincing results obtained, some continue to claim—in the absence of relevant peer-reviewed experimental data—that “chronic Lyme disease/posttreatment Lyme disease syndrome” is the result of a persistent infection with Borrelia burgdorferi requiring several months of antibiotic therapy to cure. Such a regimen, which is unprecedented for a disease that is not life threatening, is harmful and exposes patients to great risks that may result in the following:

•death from fulminating fungal infections;3

•obstruction of the gall bladder, often requiring its removal;4

•outbreaks of severe Clostridium difficile infections with significant mortality;5

•and the generation of new antibiotic-resistant strains of bacterial pathogens that are an increasing and serious public health problem.6

Obviously, extended antibiotic therapy for the treatment of “chronic Lyme disease/posttreatment Lyme disease syndrome” is not warranted unless there is clear evidence of a persistent infection, which proponents of this view have yet to provide.

To be accepted by the medical and scientific community, the validity of any therapeutic regimen proposed must be supported by the results of carefully designed and critically reviewed clinical trials. This has always been the norm and is the foundation of sound evidenced-based medical practice where the burden of proof is on those recommending a particular therapeutic approach. They must provide unequivocal evidence that their approach is justified, effective, and safe. In this context, those advocating extended antibiotic therapy for the treatment of “chronic Lyme disease/posttreatment Lyme disease syndrome” have failed to address the following key issues:

•“Chronic Lyme disease/posttreatment Lyme disease syndrome” must be defined in terms of well-established diagnostic criteria so that it can be distinguished from other noninfectious medical conditions with similar symptoms, for example, fibromyalgia and chronic fatigue syndrome. This issue was a matter of great concern in developing the criteria for enrollment in the aforementioned NIH-supported clinical trials to ensure that those enrolled had a high probability of having this condition; otherwise, the results obtained would have been inconclusive. In the trials conducted at the New England Medical Center, more than 1500 individuals claiming to have chronic Lyme disease were screened to obtain the 129 subjects (8.6%) enrolled.1 An enrollment rate of approximately 5% was noted in another treatment study.2 This indicates that “chronic Lyme disease/posttreatment Lyme disease syndrome” is not common. Several peer-reviewed publications from Lyme disease referral centers indicate that “most patients unresponsive to antibiotics never had Lyme disease, do not have it, or were cured of B. burgdorferi infection.”7

•Direct evidence must be provided that “chronic Lyme disease/posttreatment Lyme disease syndrome” is caused by a persistent bacterial infection in patients being considered for treatment. Without such evidence, prolonged antibiotic therapy is not justified, can result in great harm, and contributes to the emergence of new strains of antibiotic-resistant bacterial pathogens.

•Evidence must be provided, from the results of placebo-controlled studies, that prolonged antibiotic therapy is beneficial and safe. Testimonial observations and anecdotal reports are not reliable because a placebo effect of 40% was noted in the published studies cited above,1 and other investigators have noted periodic improvements in the symptoms of patients given only placebo during the course of their studies.

•Adjustments must be made in the experimental design to compensate for the unanticipated beneficial effects of antibiotics that are unrelated to their antimicrobial properties. The anti-inflammatory properties of macrolides, doxycycline, and other tetracyclines are well known; however, these, as well as several other beta-lactam and cephalosporin antibiotics, including ceftriaxone, which is often used to treat “chronic Lyme disease/posttreatment Lyme disease syndrome,” have profound neuroprotective properties that might ameliorate neurologic symptoms.8, 9, 10 Such pharmacologic effects, rather than the elimination of a presumed persisting infection per se, might account for the short-lived beneficial effects sometimes seen. In the absence of evidence for a persisting infection, some have suggested treatment with gabapentin to alleviate symptoms associated with “chronic Lyme disease/posttreatment Lyme disease syndrome.” Although promising results were obtained in 1 small clinical trial,11 this approach requires more study. The Food and Drug Administration recently approved the use of pregabalin for the treatment of fibromyalgia, a condition with symptoms similar to those ascribed to “chronic Lyme disease/posttreatment Lyme disease syndrome.”

The results of NIH-supported studies acknowledge that some patients with “chronic Lyme disease/posttreatment Lyme disease syndrome” indeed have deficits with respect to their physical health status.1 No doubt such patients experience significant pain and therefore require appropriate medical attention and care. However, because there is no evidence to indicate that their symptoms are caused by a persistent Borrelia burgdorferi infection, other options must be considered to determine their cause and how such patients might be treated to relieve their symptoms. Without direct evidence for a persistent infection, it is clear that extended antibiotic therapy is not the answer; it remains an unproven and unsafe therapeutic approach that is neither justified nor in the best interest of the public health. This is in accord with the views expressed by many outstanding experts in infectious disease.12, 13, 14

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References 

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  9. Rothstein JD, Patel S, Regan MR, et al. β-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005;433:73–77
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  11. Weissenbacher S, Ring J, Hofman H. Gabapentin for the symptomatic treatment of chronic neuropathic pain in patients with late-stage Lyme borreliosis: a pilot study. Dermatology. 2005;211:123–127
  12. Wormser GP, Dattwyler RJ, Shapiro ED, et al. 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. 2006;43:1089–1134
  13. Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review). Neurology. 2007;69:91–102
  14. Feder HM, Johnson BJB, O'Connell S, et al. A critical appraisal of “chronic Lyme disease.”. N Engl J Med. 2007;357:1422–1430

PII: S0002-9343(08)00181-2

doi:10.1016/j.amjmed.2008.02.013

The American Journal of Medicine
Volume 121, Issue 7 , Pages 562-564, July 2008

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