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(October 2007 - November 2010)

October 2007

A Critical Appraisal of “Chronic Lyme Disease”

Henry M. Feder, Jr., M.D., Barbara J.B. Johnson, Ph.D., Susan O'Connell, M.D., Eugene D. Shapiro, M.D., Allen C. Steere, M.D., Gary P. Wormser, M.D., and the Ad Hoc International Lyme Disease Group

N Engl J Med 2007; 357:1422-1430October 4, 2007

The following members of the Ad Hoc International Lyme Disease Group were also authors: Gundersen Lutheran Medical Foundation, La Crosse, WI — W.A. Agger;National Microbiology Laboratory, Health Canada, Winnipeg, MB, Canada — H. Artsob;Johns Hopkins Medical Institutions, Baltimore — P. Auwaerter, J.S. Dumler; St. Luke's Hospital, Duluth, MN — J.S. Bakken; Yale University School of Medicine, New Haven, CT — L.K. Bockenstedt, J. Green; New York Medical College, Valhalla — R.J. Dattwyler, J. Munoz, R.B. Nadelman, I. Schwartz; Danbury Hospital, Danbury, CT — T. Draper; Johns Hopkins Medical Institutions, Crofton, MD — E. McSweegan; Atlantic Neuroscience Institute, Summit, NJ, and the New York University School of Medicine, New York — J.J. Halperin; Boston University School of Medicine and Boston Medical Center, Boston — M.S. Klempner; University of Connecticut School of Medicine and Connecticut Children's Medical Center, Farmington — P.J. Krause; Centers for Disease Control and Prevention, Fort Collins, CO — P. Mead; University of British Columbia, Vancouver, Canada — M. Morshed; University of Medicine and Dentistry of New Jersey– Robert Wood Johnson Medical School, Piscataway — R. Porwancher;University of Connecticut Health Center, Farmington — J.D. Radolf; Maine Medical Center, Portland, ME — R.P. Smith, Jr.; Schneider Children's Hospital at North Shore, Manhasset, NY — S. Sood; Washington Hospital Center and Georgetown University Medical Center, Washington, DC — A. Weinstein; Wadsworth Center, New York State Department of Health, Albany — S.J. Wong; and Connecticut Children's Medical Center, University of Connecticut, Hartford — L. Zemel.

http://www.nejm.org/doi/full/10.1056/NEJMra072023

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November 2010

Scientiﬁc evidence and best patient care practices

should guide the ethics of Lyme disease activism

Paul G Auwaerter,1 Johan S Bakken,2 Raymond J Dattwyler,3 J Stephen Dumler,4

John J Halperin,5,6 Edward McSweegan,7 Robert B Nadelman,8 Susan O’Connell,9

Sunil K Sood,10 Arthur Weinstein,11 Gary P Worms8

Author Affiliations

¹Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
²Section of Infectious Diseases, St Luke''s Hospital, Duluth, Minnesota, USA
³Division of Allergy, Immunology and Rheumatology, Department of Medicine, New York Medical College, Valhalla, New York, USA
⁴Division of Medical Microbiology, Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
⁵Atlantic Neuroscience Institute, Summit, New Jersey, USA
⁶The Mount Sinai School of Medicine, New York, New York, USA
⁷Crofton, Maryland, USA
⁸Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla, New York, USA
⁹Lyme Borreliosis Unit, Health Protection Agency Microbiology Laboratory, Southampton General Hospital, Southampton, UK
¹⁰Division of Pediatric Infectious Diseases, Schneider Children's Hospital at North Shore, Manhasset, New York, USA
¹¹Section of Rheumatology, Department of Medicine, Washington Hospital Center and Georgetown University Medical Center, Washington, DC, USA

Correspondence toDr Gary P Wormser, New York Medical College, Division of Infectious Diseases, Munger Pavilion Room 245, Valhalla, NY 10595, USA; gary_wormser@nymc.edu

Received 28 August 2009
Revised 6 September 2010
Accepted 17 September 2010
Published Online First 21 November 2010

"Competing interests PGA, JSB, RJD, JJH, JSD, RBN, SKS and GPW are members

of the Infectious Diseases Society of America (IDSA) and JSB, RJD, JSD, JJH, RBN

and GPW served on the 2006 IDSA Lyme disease guidelines panel. SOC and AW

served as consultants to the 2006 IDSA panel. EM is a former Lyme disease

programme ofﬁcer at the National Institutes of Health."

http://jme.bmj.com/content/early/2010/11/21/jme.2009.032896.abstract

***

REVIEW ARTICLE

Current Concepts

A Critical Appraisal of “Chronic Lyme Disease”

Henry M. Feder, Jr., M.D., Barbara J.B. Johnson, Ph.D., Susan O'Connell, M.D., Eugene D. Shapiro, M.D., Allen C. Steere, M.D., Gary P. Wormser, M.D., and the Ad Hoc International Lyme Disease Group

N Engl J Med 2007; 357:1422-1430October 4, 2007

Article

References

Citing Articles (19)

Letters

Lyme disease, the most common tick-borne infection in the northern hemisphere, is a serious public health problem. In North America, it is caused exclusively by Borrelia burgdorferi sensu stricto (hereafter referred to as B. burgdorferi), whereas in Europe it is caused by B. afzelii, B. garinii, B. burgdorferi, and occasionally by other species of borrelia.1

This complex infection has a number of objective manifestations, including a characteristic skin lesion called erythema migrans (the most common presentation of early Lyme disease), certain neurologic and cardiac manifestations, and pauciarticular arthritis (the most common presentation of late Lyme disease), all of which usually respond well to conventional antibiotic therapy.2 Despite resolution of the objective manifestations of infection after antibiotic treatment, a minority of patients have fatigue, musculoskeletal pain, difficulties with concentration or short-term memory, or all of these symptoms. In this article, we refer to these usually mild and self-limiting subjective symptoms as “post–Lyme disease symptoms,” and if they last longer than 6 months, we call them “post–Lyme disease syndrome.”

The word “chronic” has been applied to Lyme disease in a wide variety of contexts and is sometimes used interchangeably with the preferred term “late Lyme disease.” For example, in Europe, certain late neurologic manifestations of previously untreated or inadequately treated infection, such as borrelial encephalomyelitis or long-standing meningitis, have been referred to as “chronic neuroborreliosis” (Table 1

TABLE 1

Selected Late or Long-Term Manifestations ofBorrelia burgdorferiInfection.

).1-3 In the United States, reports have described untreated patients with recurrent or persistent arthritis that lasts for up to several years, presumably because of active infection.4 The focus of this review, however, is not the objective manifestations of late Lyme disease but rather the imprecisely defined condition referred to as “chronic Lyme disease.” This term is used by a small number of practitioners (often self-designated as “Lyme-literate physicians”) to describe patients whom they believe have persistent B. burgdorferi infection, a condition they suggest requires long-term antibiotic treatment and may even be incurable.5 Although chronic Lyme disease clearly encompasses post–Lyme disease syndrome, it also includes a broad array of illnesses or symptom complexes for which there is no reproducible or convincing scientific evidence of any relationship to B. burgdorferiinfection. Chronic Lyme disease is used in North America and increasingly in Europe as a diagnosis for patients with persistent pain, neurocognitive symptoms, fatigue, or all of these symptoms, with or without clinical or serologic evidence of previous early or late Lyme disease.

CHRONIC LYME DISEASE

The diagnosis of chronic Lyme disease and its treatment differ substantively from the diagnosis and treatment of recognized infectious diseases. The diagnosis is often based solely on clinical judgment rather than on well-defined clinical criteria and validated laboratory studies, and it is often made regardless of whether patients have been in areas where Lyme disease is endemic.6,7 Although proponents of the chronic Lyme disease diagnosis believe that patients are persistently infected with B. burgdorferi, they do not require objective clinical or laboratory evidence of infection as a diagnostic criterion.5,8-10

Several lines of reasoning are used to provide support for this diagnostic rationale. One is the unproven and very improbable assumption that chronic B. burgdorferi infection can occur in the absence of antibodies against B. burgdorferi in serum (Table 2

TABLE 2

Laboratory Diagnosis of Lyme Disease and Chronic Lyme Disease in North America.

). Negative results of serologic tests are often attributed to previous antibiotic therapy or to the theory that chronic infection with B. burgdorferisuppresses humoral immune responses; neither theory is well supported by scientific data.12-14 When physicians who diagnose chronic Lyme disease obtain laboratory tests to provide support for their diagnoses, they often rely heavily on “Lyme specialty laboratories.” Such laboratories may perform unvalidated in-house tests that are not regulated by the Food and Drug Administration, or they may perform standard serologic tests interpreted with the use of criteria that are not evidence-based.11,12,15-17

Once the diagnosis of chronic Lyme disease is made, patients are commonly treated for months to years with multiple antimicrobial agents, some of which are inactive in vitro against B. burgdorferi.2,5,18-20 Antibiotics may be prescribed either simultaneously or sequentially, and they are often administered parenterally. Occasionally, these patients are treated with unconventional and highly dangerous methods such as bismuth injections or deliberate inoculation of plasmodia to cause malaria.2,21,22 No other spirochetal infection, including the neurologic complications of tertiary syphilis, is managed in an analogous fashion.2,23 The duration of treatment commonly prescribed for chronic Lyme disease often far surpasses even the conventional 6-month course of therapy successfully used for most cases of tuberculosis.

CATEGORIES OF CHRONIC LYME DISEASE

Diagnoses of chronic Lyme disease appear to fall predominantly into one of four categories (Figure 1

FIGURE 1

The Four Predominant Categories of Disease Associated with Chronic Lyme Disease.

).8-10 Patients with category 1 disease do not have objective clinical manifestations or laboratory evidence of B. burgdorferi infection, and they receive a diagnosis on the basis of the presence of nonspecific symptoms such as fatigue, night sweats, sore throat, swollen glands, stiff neck, arthralgia, myalgia, palpitations, abdominal pain, nausea, diarrhea, sleep disturbance, poor concentration, irritability, depression, back pain, headache, and dizziness.5 Nonspecific symptoms such as these are common, and some occur in more than 10% of the general population, regardless of whether Lyme disease is endemic in the area.24,25

Patients with category 2 disease have identifiable illnesses or syndromes other than Lyme disease. Such patients may or may not have a history of Lyme disease. They have received either a misdiagnosis or a diagnosis (e.g., multiple sclerosis) that they are reluctant to accept and have sought an alternative diagnosis from a physician willing to treat them for chronic Lyme disease.

Data from studies of patients who underwent reevaluation at academic medical centers suggest that the majority of patients presumed to have chronic Lyme disease have category 1 or 2 disease.8-10 Since patients in these two categories do not have evidence of active infection with B. burgdorferi, the potential benefit of treating them with antibiotics, beyond a placebo effect, would be attributable to the antiinflammatory or other nonantimicrobial effects of antibiotics.26 Antibiotic therapy in these patients is not warranted.

Patients with category 3 disease do not have a history of objective clinical findings that are consistent with Lyme disease, but their serum samples contain antibodies against B. burgdorferi, as determined by means of standardized assays that were ordered to investigate chronic, subjective symptoms of unknown cause.27 Patients with disease in this category have at most only equivocal evidence of B. burgdorferi infection, since the predictive value of positive serologic results in this setting is low.27,28 Although some clinicians would offer patients with category 3 disease an empirical trial of 2 to 4 weeks of an oral antibiotic, such patients should be told that the diagnosis is uncertain and that a benefit from treatment is unlikely.

Patients with category 4 disease have symptoms associated with post–Lyme disease syndrome.29-31 In prospective studies of patients with erythema migrans, subjective symptoms of unknown cause were present 1 year or more after treatment in 0.5 to 13.1% of patients.31 Whether this prevalence exceeds that of such symptoms in the general population is unknown, since none of these studies included a control group. A meta-analysis suggested that the prevalence of such symptoms exceeded that in control groups without Lyme disease, but this analysis relied on several retrospective studies in which the diagnosis and treatment of Lyme disease often did not meet current standards.30,31

TREATMENT OF POST–LYME DISEASE SYMPTOMS

Controlled treatment trials have been conducted only for patients with category 4 disease. Data from three double-blind, randomized, placebo-controlled trials have shown that there is substantial risk, with little or no benefit, associated with additional antibiotic treatment for patients who have long-standing subjective symptoms after appropriate initial treatment for an episode of Lyme disease.32-34

One of these trials enrolled 78 patients who were seropositive for antibodies against B. burgdorferi at trial entry; a second trial enrolled 51 patients who were seronegative.32 All patients had antecedent objective signs of Lyme disease, most often physician-diagnosed erythema migrans. Patients were treated either with a 1-month course of ceftriaxone administered intravenously, followed by 2 months of doxycycline given orally, or with identical-appearing intravenous and then oral placebos. Patients were assessed at enrollment and 3 months after completion of treatment with the use of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). There were no significant differences in the scores between the patients in the antibiotic and placebo groups.

In a single-center trial conducted by Krupp et al., 55 patients with severe fatigue (as measured by an 11-item questionnaire) after treatment of well-documented Lyme disease underwent randomization to receive ceftriaxone or an identical-appearing placebo for 28 days.33 The investigators reported a reduction in scores for fatigue severity in the ceftriaxone group that exceeded the reduction in the placebo group by 13 percentage points (i.e., a reduction of 22% vs. 9%; P=0.01) but no significant improvement in cognitive function. There was no significant difference between the groups with regard to the degree of improvement in reported health status on the basis of the SF-36 score. Patients in the ceftriaxone group were significantly more likely than those in the placebo group to identify their treatment assignment correctly at the end of therapy, raising a concern that masking was compromised and that a placebo effect may explain the greater improvement in scores for fatigue severity in the treated group.33

Antibiotic therapy can cause considerable harm to patients treated for chronic Lyme disease or post–Lyme disease symptoms.2 Life-threatening anaphylaxis33 and biliary complications requiring cholecystectomy35 have occurred after ceftriaxone administration. Candidemia from infection of an intravenous catheter has resulted in death.36 In an unpublished study in which 37 patients underwent randomization to receive 10 weeks of treatment with either ceftriaxone or placebo, about one fifth of the patients had serious adverse events, the majority of which were related to intravenous catheters.37 In light of the risk of serious adverse events in their study, Krupp et al. concluded that “repeated courses of antibiotic treatment are not indicated for persistent symptoms following Lyme disease, including those related to fatigue and cognitive dysfunction.”33

Eligibility criteria for two controlled trials stipulated that symptoms must be severe enough to interfere with the patient's ability to function.32 Thus, the physical health status of the patients enrolled in these two studies was equivalent to that of patients with congestive heart failure or osteoarthritis.32 This finding was preordained by the study design, but it has been incorrectly interpreted by some to indicate that patients with post–Lyme disease symptoms typically are severely disabled.

The investigators who conducted the controlled treatment trials had great difficulty finding patients who met the criteria for entry, despite intensive efforts that included both the notification and involvement of Lyme disease support groups and associations.32,33 For two of the three studies, additional sites had to be engaged,32 and the enrollment period had to be extended for all three studies.32,33 To enroll 55 patients in one of the studies, investigators had to screen more than 500 people, most of whom were excluded because of the absence of a substantiated history of Lyme disease.33 This difficulty with enrollment appears to reflect the scarcity of persons with well-documented Lyme disease in whom clinically significant problems develop after conventional treatment.

Although anecdotal evidence and findings from uncontrolled studies have been used to provide support for long-term treatment of chronic Lyme disease,18-20 a response to treatment alone is neither a reliable indicator that the diagnosis is accurate nor proof of an antimicrobial effect of treatment. Many patients with intermittent or self-limited symptoms may feel better over time as a result of the natural course of their condition, and controlled trials indicate that nearly 40% of patients with post–Lyme disease symptoms have a positive response to placebo.32 In addition, the assessment of a change in symptoms may be confounded by antiinflammatory and other nonantimicrobial effects of antibiotics.26 Furthermore, the published reports of uncontrolled trials of antibiotic treatment for chronic Lyme disease used poorly standardized case definitions and either undefined criteria for interpreting immunoblots or criteria that have subsequently been found to have very low specificity (approximately 60%).38

PERSISTENT B. BURGDORFERI INFECTION AND POST–LYME DISEASE SYMPTOMS

A report by Phillips and colleagues39 is often cited to provide support for the hypothesis of persistent B. burgdorferi infection. They indicated that they detected B. burgdorferi in blood specimens from 43 of 47 patients who had received or were receiving prolonged antibiotic therapy for chronic Lyme disease (91%). Other investigators have been unable to reproduce these findings in patients with well-documented post–Lyme disease syndrome.32,40-42 Moreover, Phillips and colleagues used a new culture medium that specifically included Detroit tap water; this medium was subsequently shown to be bactericidal for B. burgdorferi.41 In contrast to the findings from their report,39 B. burgdorferi could not be detected in any of 843 specimens of blood or cerebrospinal fluid, tested by means of either culture or polymerase chain reaction (PCR), from the 129 patients enrolled in two of the controlled treatment trials.32,40 Moreover, there was no serologic evidence of tick-borne coinfections in the vast majority of patients.32

In another report, DNA of B. burgdorferi was detected by means of PCR in urine specimens from nearly three quarters of 97 patients who had received the diagnosis of chronic Lyme disease.43 However, the authors did not sequence the amplicons to confirm that the DNA was from B. burgdorferi. Such a high rate of positive results among patients who had been treated extensively with antibiotics is unlikely when one considers that only 1 of 12 urine samples (8%) from untreated patients with erythema migrans was found to be positive in a careful evaluation of this technique's value as a diagnostic test.44 Moreover, detection of bacterial DNA is not necessarily an indicator of either active infection or clinical disease.45 The central question is not whether a few spirochetes might persist after antibiotic treatment, but whether clinical disease can be attributed to their presence.

It is highly unlikely that post–Lyme disease syndrome is a consequence of occult infection of the central nervous system. This conclusion is based on evidence such as the absence of inflammation in the cerebrospinal fluid,32,33 negative results of both cultures and PCR assays for B. burgdorferi in the cerebrospinal fluid,32,40 the absence of structural abnormalities of the brain parenchyma,46 and normal neurologic function, with no effect of antibiotic therapy (as compared with placebo) on cognitive function.33,34

Additional evidence against the hypothesis that chronic symptoms are due to persistent infection is the fact that antibodies against B. burgdorferi in many of these patients are undetectable, which is inconsistent with the well-established immunogenicity of the spirochete's lipoproteins.13,14,20,29,32,47 Patients in whom treatment for most infectious diseases, including syphilis, has failed typically have persistent or rising titers of antibodies because of ongoing B-cell stimulation by microbial antigens.23

The lack of convincing evidence for the persistence of B. burgdorferi in treated patients (Table 3

TABLE 3

Evidence against Active Infection in Patients with Subjective Symptoms Persisting for More Than 6 Months after Antibiotic Treatment for Lyme Disease.

) is not surprising.2,20,23,24,29-33,40,47-49 The failure of treatment for bacterial infections typically occurs as a result of pathogens that either have or acquire resistance to antibiotics, difficulties in achieving sufficient concentrations of antibiotic at sites of infection, or impaired host-defense mechanisms.2 None of these factors are generally applicable to infection with B. burgdorferi. Although B. burgdorferi can develop into cystlike forms in vitro under certain conditions that can be created in the laboratory,50 there is no evidence that this phenomenon has any clinical relevance. B. burgdorferi may penetrate cells in vitro, but there is no evidence that the organism may be sheltered from antibiotics during an intracellular phase and then disseminate and cause clinical relapse.51,52Indeed, the strategies used by B. burgdorferi to adapt to the vertebrate host and evade host defenses indicate an extracellular existence.53

ADVICE TO CLINICIANS

How should clinicians handle the referral of symptomatic patients who are purported to have chronic Lyme disease? The scientific evidence against the concept of chronic Lyme disease should be discussed and the patient should be advised about the risks of unnecessary antibiotic therapy. The patient should be thoroughly evaluated for medical conditions that could explain the symptoms. If a diagnosis for which there is a specific treatment cannot be made, the goal should be to provide emotional support and management of pain, fatigue, or other symptoms as required.54-56 Explaining that there is no medication, such as an antibiotic, to cure the condition is one of the most difficult aspects of caring for such patients. Nevertheless, failure to do so in clear and empathetic language leaves the patient susceptible to those who would offer unproven and potentially dangerous therapies. Additional advice to clinicians is included in theSupplementary Appendix, available with the full text of this article at www.nejm.org.

CHRONIC LYME DISEASE IN THE PUBLIC DOMAIN

Physicians and laypeople who believe in the existence of chronic Lyme disease have formed societies, created charitable foundations, started numerous support groups (even in locations in which B. burgdorferi infection is not endemic), and developed their own management guidelines.5 Scientists who challenge the notion of chronic Lyme disease have been criticized severely.

The attorney general of Connecticut has begun an unprecedented antitrust investigation of the Infectious Diseases Society of America, which issued treatment guidelines for Lyme disease that do not support open-ended antibiotic treatment regimens.2 In some states, legislation has been proposed to require insurance companies to pay for prolonged intravenous therapy to treat chronic Lyme disease. The media frequently disregard complex scientific data in favor of testimonials about patients suffering from purported chronic Lyme disease and may even question the competence of clinicians who are reluctant to diagnose chronic Lyme disease. All these factors have contributed to a great deal of public confusion with little appreciation of the serious harm caused to many patients who have received a misdiagnosis and have been inappropriately treated.

CONCLUSIONS

Chronic Lyme disease is the latest in a series of syndromes that have been postulated in an attempt to attribute medically unexplained symptoms to particular infections. Other examples that have now lost credibility are “chronic candida syndrome” and “chronic Epstein–Barr virus infection.”57,58 The assumption that chronic, subjective symptoms are caused by persistent infection with B. burgdorferi is not supported by carefully conducted laboratory studies or by controlled treatment trials. Chronic Lyme disease, which is equated with chronic B. burgdorferi infection, is a misnomer, and the use of prolonged, dangerous, and expensive antibiotic treatments for it is not warranted.2

The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Dr. Feder reports receiving lecture fees from Merck and serving as an expert witness in medical-malpractice cases related to Lyme disease. Dr. Johnson reports holding patents on diagnostic antigens for Lyme disease. Dr. O'Connell reports serving as an expert witness related to Lyme disease issues in civil and criminal cases in England. Dr. Shapiro reports serving as an expert witness in medical-malpractice cases related to Lyme disease, reviewing claims of disability related to Lyme disease for Metropolitan Life Insurance Company, and receiving speaker's fees from Merck and Sanofi-Aventis. Dr. Steere reports receiving a research grant from Viramed and fees from Novartis. Dr. Wormser reports receiving research grants related to Lyme disease from Immunetics, Bio-Rad, and Biopeptides and education grants from Merck and AstraZeneca to New York Medical College for visiting lecturers for infectious-disease grand rounds, being part owner of Diaspex (a company that is now inactive with no products or services), owning equity in Abbott, serving as an expert witness in a medical-malpractice case, and being retained in other medical-malpractice cases involving Lyme disease. He may become a consultant to Biopeptides. No other potential conflict of interest relevant to this article was reported.

SOURCE INFORMATION

From the Departments of Family Medicine and Pediatrics, Connecticut Children's Medical Center, Hartford, and University of Connecticut Health Center, Farmington (H.M.F.); Microbiology Laboratory, Division of Vector-Borne Infectious Diseases, Centers for Diseases Control and Prevention, Fort Collins, CO (B.J.B.J.); Lyme Borreliosis Unit, Health Protection Agency Microbiology Laboratory, Southampton General Hospital, Southampton, United Kingdom (S.O.); Departments of Pediatrics and Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT (E.D.S.); Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston (A.C.S.); and the Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla (G.P.W.)

Address reprint requests to Dr. Feder at the Departments of Family Medicine and Pediatrics, University of Connecticut Health Center, Farmington, CT 06030, or athfeder@nso2.uchc.edu.

Other members of the Ad Hoc International Lyme Disease Group who were authors are listed in the Appendix.

We thank Alex P. Butensky, Julie Chacko, Rachel Hart, and Lisa Giarratano for assistance.

Appendix

The following members of the Ad Hoc International Lyme Disease Group were also authors: Gundersen Lutheran Medical Foundation, La Crosse, WI — W.A. Agger;National Microbiology Laboratory, Health Canada, Winnipeg, MB, Canada — H. Artsob;Johns Hopkins Medical Institutions, Baltimore — P. Auwaerter, J.S. Dumler; St. Luke's Hospital, Duluth, MN — J.S. Bakken; Yale University School of Medicine, New Haven, CT — L.K. Bockenstedt, J. Green; New York Medical College, Valhalla — R.J. Dattwyler, J. Munoz, R.B. Nadelman, I. Schwartz; Danbury Hospital, Danbury, CT — T. Draper; Johns Hopkins Medical Institutions, Crofton, MD — E. McSweegan; Atlantic Neuroscience Institute, Summit, NJ, and the New York University School of Medicine, New York — J.J. Halperin; Boston University School of Medicine and Boston Medical Center, Boston — M.S. Klempner; University of Connecticut School of Medicine and Connecticut Children's Medical Center, Farmington — P.J. Krause; Centers for Disease Control and Prevention, Fort Collins, CO — P. Mead; University of British Columbia, Vancouver, Canada — M. Morshed; University of Medicine and Dentistry of New Jersey– Robert Wood Johnson Medical School, Piscataway — R. Porwancher;University of Connecticut Health Center, Farmington — J.D. Radolf; Maine Medical Center, Portland, ME — R.P. Smith, Jr.; Schneider Children's Hospital at North Shore, Manhasset, NY — S. Sood; Washington Hospital Center and Georgetown University Medical Center, Washington, DC — A. Weinstein; Wadsworth Center, New York State Department of Health, Albany — S.J. Wong; and Connecticut Children's Medical Center, University of Connecticut, Hartford — L. Zemel.

http://www.nejm.org/doi/full/10.1056/NEJMra072023

***

Scientific evidence and best patient care practices should guide the ethics

of Lyme disease activism

Paul G Auwaerter,1 Johan S Bakken,2 Raymond J Dattwyler,3 J Stephen Dumler,4

John J Halperin,5,6 Edward McSweegan,7 Robert B Nadelman,8 Susan O’Connell,9

Sunil K Sood,10 Arthur Weinstein,11 Gary P Wormser8

ABSTRACT

Johnson and Stricker published an opinion piece in the Journal of Medical Ethics presenting their perspective

on the 2008 agreement between the Infectious Diseases Society of America (IDSA) and the Connecticut

Attorney General with regard to the 2006 IDSA treatment guideline for Lyme disease. Their writings indicate

that these authors hold unconventional views of a relatively common tick-transmitted bacterial infection

caused by the spirochete Borrelia burgdorferi. Therefore, it should come as no surprise that their opinions

would clash with the IDSA’s evidence-based guidelines for the diagnosis and treatment of Lyme disease.

Their allegations of conﬂict of interest against the IDSA resemble those made against the National Institutes

of Health, the Food and Drug Administration and the Centers for Disease Control and Prevention in 2000,

which were found to be baseless. It is the responsibility of all physicians and medical scientists to stand up to

antiscientiﬁc, baseless and unethical attacks on those who support an evidence-based approach to caring

for patients.

Johnson and Stricker1 published an opinion piece in the Journal of Medical Ethics presenting their views on the

2008 agreement between the Infectious Diseases Society of America (IDSA) and the Connecticut Attorney General,

Richard Blumenthal, with regard to the 2006 IDSA treatment guidelines for Lyme disease. They write as if they were disinterested arbiters in what they term ‘the Lyme disease controversy ’, purporting to reveal that the IDSA and its

members have ulterior motives in designing guidelines for the diagnosis and treatment of Lyme disease. Their

arguments, however, are based on numerous distortions and inaccuracies, as well as their own self-interests.

To begin, the title of their opinion piece is wrong. Blumenthal did not ‘force’ the IDSA to withdraw or redo its

2006 Lyme disease guidelines. As a result of the potential legal costs involved in defending against Blumenthal’s

charges and threatened actions, the IDSA agreed to appoint an independent panel to review the 2006 guidelines to

determine if there should be an update or revision.2 3 On 22 April 2010 the new panel concluded that the 2006

Lyme disease guidelines were accurate and appropriate.4 Besides the title, there are numerous other inaccuracies

throughout the opinion piece

(see table 1).1 5e7

Johnson and Stricker1 in their paper focus on two broad themes in their critique of the development of the

IDSA’s Lyme disease guidelines: (1) that the guidelines contribute to centralisation of medical decisions and

thereby limit the doctor ’s ability to use clinical judgement and (2) that conﬂicts of interest affected the outcome

of the process.1 In the material that follows we will demonstrate serious ﬂaws in their analysis.

CENTRALISATION OF MEDICAL DECISIONS

Although Johnson and Stricker1 contend that evidence-based guidelines limit clinical discretion in a way that is

detrimental to patient care, they provide no evidence to substantiate this claim. In addition, the authors fail to

acknowledge that in order to make decisions that are in the best interests of individual patients, ethical physicians

are in fact constrained by the availability of credible scientiﬁc evidence. The purpose of guidelines is to provide

guidance to physicians; guidelines are not intended to supercede a physician’s judgement in the care of an individual

patient. In fact, the IDSA Lyme disease guidelines explicitly stated: ‘It is important to realize that guidelines cannot

always account for individual variation among patients.

They are not intended to supplant physician judgment with respect to particular patients or special clinical situations.

The Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient’s individual

circumstances’.5 To understand the concerns of Johnson and Stricker1 about the application of science-based

practice to the management of patients, it is helpful to appreciate the unorthodox perspectives that exist concerning

Lyme disease.

Lyme disease, post-Lyme disease symptoms and ‘chronic Lyme disease’

Lyme disease is an Ixodes tick-transmitted bacterial infection caused by Borrelia burgdorferi sensu lato. It has been

intensively studied for over 30 years and its natural history is well documented. The most common clinical

manifestation is a characteristic skin lesion called erythema migrans that occurs at the site of the tick bite. Other

clinical manifestations may involve the musculoskeletal system (eg, arthritis of the knee), nervous system (eg,

facial nerve palsy) or the heart (eg, heart conduction disturbances). In addition to such objective clinical

manifestations, patients with Lyme disease may concomitantly have subjective symptoms including fatigue,

arthralgia, myalgia, headache, stiff neck and impaired concentration.

Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore,

Maryland, USA

Section of Infectious Diseases, St Luke’’s Hospital, Duluth, Minnesota, USA

Division of Allergy, Immunology and Rheumatology, Department of Medicine, New York Medical College,

Valhalla, New York, USA

Division of Medical Microbiology, Department of Pathology, The Johns Hopkins Medical Institutions,

Baltimore, Maryland, USA

Atlantic Neuroscience Institute, Summit, New Jersey, USA

The Mount Sinai School of Medicine, New York, New York, USA

Crofton, Maryland, USA

Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla, New York,

USA

Lyme Borreliosis Unit, Health Protection Agency Microbiology Laboratory, Southampton General Hospital,

Southampton, UK

Division of Pediatric Infectious Diseases, Schneider Children’s Hospital at North Shore, Manhasset,

New York, USA

Section of Rheumatology, Department of Medicine, Washington Hospital Center and Georgetown

University Medical Center, Washington, DC, USA

Correspondence to

Dr Gary P Wormser, New York Medical College, Division of Infectious Diseases, Munger Pavilion

Room 245, Valhalla, NY 10595, USA; gary_wormser@nymc.edu

Received 28 August 2009

Revised 6 September 2010

Accepted 17 September 2010

Auwaerter PG, Bakken JS, Dattwyler RJ, et al. J Med Ethics (2010). doi:10.1136/jme.2009.032896 1 of 6

C l i n i c a l e t h i c s

JME Online First, published on November 21, 2010 as 10.1136/jme.2009.032896

Copyright Article author (or their employer) 2010. Produced by BMJ Publishing Group Ltd

under licence.

The vast majority of Lyme disease patients treated with a short course of antibiotic therapy resolve their infections

and become asymptomatic following therapy. A small minority may experience subjective symptoms such as

fatigue or musculoskeletal pain despite resolution of the objective clinical manifestations.5 8 9 Such patients are

referred to as having post-Lyme disease symptoms or post-Lyme disease syndrome, depending on the symptom

duration and severity.5 8 Post-infectious symptoms are not unique to Lyme disease and are not caused by active

infection.10

The term ‘chronic Lyme disease’ has been adopted by certain Lyme disease activists and Lyme disease activist

physicians (the latter group is often referred to as ‘ Lyme literate medical doctors’) as a designation for the presence

of persistent B burgdorferi infection despite previous antibiotic treatment.8 11 Although the term ‘chronic Lyme

disease’ is sometimes applied to patients with post-Lyme disease symptoms, evidence indicates that the majority

of patients with this diagnosis in fact have no convincing clinical or laboratory evidence of ever having had B

burgdorferi infection.8 12 This is not surprising because, to our knowledge, there are no consistent or objective

diagnostic criteria for ‘chronic Lyme disease’. Instead, the diagnosis relies on ‘clinical judgement’, which appears

to mean that if a physician

Table 1 Selected erroneous statements made by Johnson and Stricker1 in their Journal of Medical

Ethics article

Statement or claim Location in article Factually correct statement

Attorney General forces IDSA to redo Lyme guidelines due to ﬂawed development process

Page 283

The IDSA agreed to convene a panel to evaluate whether its guidelines should be updated or revised.

The IDSA did not admit that the process was ﬂawed or that the guidelines are scientiﬁcally incorrect.

Most patients are aware that obtaining a diagnosis and treatment for Lyme disease can be difﬁcult

Page 283

Diagnosis and treatment of active B burgdorferi infection is standard practice and readily available

The IDSA promoted a narrow deﬁnition of Lyme disease in 2000

Page 283

The IDSA did not deﬁne Lyme disease in 2000; however, in 2006 it stipulated that such a deﬁnition

require that it be caused by B burgdorferi infection

The IDSA guidelines excluded most Lyme patients and denied them treatment

Page 283

The IDSA advocated not re-treating patients with post-Lyme syndrome and not treating patients for

Lyme disease who do not have evidence of B burgdorferi infection

The level of disability of patients with Lyme disease is equal to that of congestive heart failure

and Lyme disease may be fatal

Page 283

This level of disability was based on a study of post-Lyme disease syndrome in which functional

disability was a prerequisite. Lyme disease is not fatal. It is usually treated very successfully with

short courses of antibiotics

The IDSA Lyme panel selectively ignored evidence of persistent infection or clinical improvement

with antibiotic treatment in patients with persistent symptoms

Page 283

The IDSA panel carefully evaluated the clinical evidence for persistent infection, as well as the beneﬁt of

prolonged courses of antibiotic therapy; they found the evidence to be unconvincing, as did the newly

appointed panel4

The IDSA intentionally ignored divergent evidence

Page 283

See above and see pages 1114e21 in the IDSA guidelines5

Lyme vaccine was withdrawn because of serious arthritis and neurological

side effects

Page 284

No such effects were found to be vaccine related, based on extensive studies conducted by the FDA.6 7

The vaccine was withdrawn for economic reasons

It is claimed that Abbott makes a Lyme diagnostic test

Page 284

There is no FDA-cleared diagnostic test for Lyme disease made by Abbott

In its previous guidelines, the IDSA summarily tossed out the one panel member who disagreed

with the panel chair

Page 284

One panel member voluntarily withdrew. No one was dismissed

The IDSA guidelines restrict the deﬁnition of the disease and mandate laboratory testing

Page 285

The IDSA restrict the deﬁnition to B burgdorferi infection.

The IDSA recommends against laboratory testing for patients with erythema migrans, which

comprise the majority of cases of Lyme disease5 Guidelines that restrict the disease deﬁnition

are favourable to vaccine manufacturers

Page 285

Even before the IDSA guidelines were developed, trials of vaccines required evidence that the

subjects participating in the trials who are diagnosed with Lyme disease actually had B burgdorferi

infection. A narrow deﬁnition may in fact reduce the potential market for a vaccine. Guidelines that

mandate testing for disease diagnosis promote the interests of those who develop and manufacture diagnostic

tests

Page 285

The IDSA recommended against testing for the majority of patients with Lyme disease, ie, those who have

erythema migrans. The IDSA did not recommend any particular diagnostic kit or test5

Guidelines that deny treatment to patients are favourable to insurance companies and their

consultants

Page 285

The IDSA only recommended against antibiotic treatment of patients who have no evidence of active

infection, who do not require antibiotic treatment and for whom such treatment may be injurious5

With evidence-based guidelines, someone other than the treating doctor will be selecting,

interpreting and making recommendations regarding treatment. There is an obligation to comply

with guidelines as a ‘mandated standard of care’

Page 285

The guidelines state the following: ‘It is important to realize that guidelines cannot always account for

individual variation among patients. They are not intended to supplant physician judgment with respect

to particular patients or special clinical situations. The IDSA considers adherence to these guidelines

to be voluntary, with the ultimate determination regarding their application to be made by the physician

in the light of each patient’s individual circumstances’5

Specialty societies embrace treatment guidelines to expand their sphere of inﬂuence in an

insurance-driven environment

Page 285

The IDSA writes guidelines to assist physicians and to promote quality care for the patients whom they treat

The guidelines published by the IDSA in November 2006 were extremely restrictive and denied

the use of clinical judgement

Page 286

See above

The IDSA restricts treatment to 30 days and offers no suggestions for alternative treatments

Page 286

Incorrect. See page 1106 and pages 1110e13 in the guidelines5

G Wormser, the panel chair, was selected inappropriately and picked a panel without approval

of the IDSA oversight committee

Page 286

None of the panel members or the chair could have served without the approval of the IDSA; 16 other

individuals served as consultants rather than panel members

The IDSA had signiﬁcant ﬁnancial conﬂicts of interest

Page 286

See text for extensive discussion

FDA, US Food and Drug Administration; IDSA, Infectious Diseases Society of America. 2 of 6

Auwaerter PG, Bakken JS, Dattwyler RJ, et al. J Med Ethics (2010). doi:10.1136/jme.2009.032896

thinks that a patient has ‘chronic Lyme disease’, then that is the diagnosis.11 There is certainly no requirement for a

positive laboratory test result to substantiate the diagnosis.8 11 12 Patients who in reality have medically

unexplained symptoms (MUS) or other yet undiagnosed medical conditions, including multiple sclerosis,

Parkinson’s disease, depression or ﬁbromyalgia, among many possibilities, may potentially be labelled as having

‘chronic Lyme disease’.8 12 13 Regrettably, the misdiagnosis of such patients precludes or delays the possibility that

they will have the opportunity to receive appropriate medical treatment for their conditions. Furthermore,

because of the presumption of persistent infection it has been argued that patients with ‘chronic Lyme disease’

may require treatment with antibiotics for months to years.1 8 11 12

In our experience, any response, whether good, bad or indeterminate to antibiotics may be used by practitioners

who believe in‘chronic Lyme disease’ to claim support for the diagnosis. If patients feel better on antibiotic therapy,

this is believed to establish the diagnosis, notwithstanding a well-documented placebo response rate of up to 36%

in treatment studies of post- Lyme disease syndrome,11 14 and the fact that certain antibiotic classes have

well-recognised anti-inﬂammatory and neuroprotective effects independent of their anti-infective actions.15 16

If the patient worsens at any point while on antibiotic therapy, paradoxically, this may also be interpreted to support

the diagnosis, as it is attributed to a JarischeHerxheimer reaction from the effect of massive spirochaetal killing.8

In reality, however, JarischeHerxheimer reactions begin only during the ﬁrst 24 h of initial antibiotic therapy in

spirochaetal infections, and not months to years into sequential antimicrobial therapy.17 An unchanged condition

is also deemed to be consistent with ‘chronic Lyme disease’, as these patients may be regarded as having an

‘incurable’ illness.8 Indeed, we frequently hear patients with ‘chronic Lyme disease’ use terms similar to those

often employed by oncologists for patients with cancer, for example, being ‘in remission’ or having a ‘relapse’.

In their article, Johnson and Stricker1 use the terms ‘ Lyme disease’ and ‘chronic Lyme disease’ interchangeably.

This is misleading insofar as one term has a recognised deﬁnition and one does not. Johnson and Stricker1 also

state that the IDSA guidelines panel ‘selectively ignored evidence of persistent infection.’. This statement is

misleading if it is construed to mean that the subject was not considered by the panel. In fact, eight pages

(w5000 words) of the 2006 IDSA Lyme disease guidelines were devoted to analysing the available scientiﬁc data

on the persistence of infection by B burgdorferi after antibiotic therapy in both humans and animals, and whether

prolonged or repeated courses of antibiotics might beneﬁt patients with chronic post-Lyme disease symptoms.5

Geography of ‘chronic Lyme disease’

The geographical range of B burgdorferi and the tick vectors that spread it are limited. More than 90% of cases of

Lyme disease that meet the Centers for Disease Control and Prevention’s (CDC) surveillance criteria occur in just

10 states located in the mid-Atlantic, northeast and north central regions of the USA.18

‘Chronic Lyme disease’, however, is not conﬁned to regions where tick transmission of B burgdorferi could

possibly occur.19 Indeed, many Lyme disease support groups exist in non-endemic areas, even in areas where

Ixodes scapularis or Ixodes paciﬁcus ticks, the only vectors that transmit Lyme disease in the USA, are not found.

Therefore, it is reasonable to surmise that these Lyme disease support groups may include patients with MUS or

other medical conditions rather than patients with current or past Lyme disease. Patients with MUS are indeed an

important group to consider; however, appropriate advocacy should focus on determining the cause(s) of these

condition(s) and their most effective treatment(s), rather than incorrectly attributing them to B burgdorferi infection.

Evidence-based diagnosis of Lyme disease

The 2006 IDSA Lyme disease guidelines clearly argue for an evidence-based approach for the diagnosis and

treatment of Lyme disease, and dispute the notion of ‘chronic Lyme disease’.5 For example, the IDSA guidelines

recommend laboratory support for the diagnosis except for erythema migrans, which can be reliably identiﬁed based

on the appearance of the skin lesion. The reason that a positive laboratory test result from a reputable laboratory is

necessary to conﬁrm a presumptive diagnosis of the extracutaneous clinical manifestations is that other causes

are actually more common.5 20 For example, in one study only approximately 25% of patients in a high-risk area

of Long Island, New York, with the onset of facial nerve palsy during warm weather months actually had

B burgdorferi infection as the explanation for the palsy.21 Of course, a positive serological test result even

in a patient with a high pretest likelihood of having the disease is not proof positive of a diagnosis of Lyme

disease; it only means that the probability of Lyme disease is higher than it was before the test was done.22

Treatment of Lyme disease

The most troublesome question to both the general physician reader and those with expertise in infectious diseases

is why anyone would rationally promote treatment for what they presume to be B burgdorferi infection (or any other

antibiotic-susceptible bacterial infection) that is open-ended, sometimes involving multiple antibiotics given

simultaneously or sequentially, and often in high doses over a period of many years.8 11 Such unconventional

therapy can be associated with serious adverse events such as hospitalisations for Clostridium difﬁcile colitis or

central venous catheter infection, can promote the emergence of strains of the patients’ normal bacterial ﬂora that

are resistant to antimicrobial agents and is costly. Other ‘therapeutic’ modalities, such as deliberate inoculation

with malaria parasites, or the administration of bismuth injections (which were lethal for one patient), have also

been used.5 8 The IDSA Lyme disease guidelines clearly argue against such treatments.5 As stated in the IDSA

guidelines, the conclusion of the investigators of the three National Institutes of Health-sponsored double-blind,

randomised, placebo controlled treatment trials of patients with post-Lyme disease syndrome was that the

risk/ beneﬁt ratio of additional courses of antibiotic therapy strongly favours non-antibiotic management

approaches.5 14 23 Consistent with these conclusions, there was also no microbiological evidence for the

persistence of B burgdorferi in these studies despite rigorous examination of multiple body ﬂuid samples

using several different assays.5 14

Criteria for enrolment in the aforementioned, randomised treatment trials of patients with post-Lyme disease

syndrome required the presence of functional disability.14 23 Consequently, it is inappropriate to generalise the

severity of illness in these subjects to all patients with subjective complaints after having had Lyme disease, as

Johnson and Stricker have done.1 9 24 In fact, patients with at least 6 months of functionally disabling symptoms

following a well-documented episode of Lyme disease are very uncommon, as demonstrated by the difﬁculty

that the investigators experienced in ﬁnding the desired number of

Auwaerter PG, Bakken JS, Dattwyler RJ, et al. J Med Ethics (2010). doi:10.1136/jme.2009.032896 3 of 6

subjects for the trials.14 23 It is even more misleading to characterise Lyme disease as a fatal infection.1 For

some practitioners such mischaracterisations might serve to justify the prescription of prolonged intravenous courses

of potentially harmful antibiotic therapy, despite the weight of evidence against such an approach, as

discussed above.14 23 25

CIRCUMSTANCES SURROUNDING THE INVOLVEMENT OF THE CONNECTICUT ATTORNEY

GENERAL IN THE IDSA LYME DISEASE GUIDELINES

Supporters of the concept of ‘chronic Lyme disease’ raised objections to the 2006 Lyme disease guidelines

even before they were published. However, it should be noted that the 2006 guidelines, as they pertain to

post-Lyme disease symptoms and the treatment of the objective manifestations of Lyme disease in North

America, are essentially identical to the 2000 IDSA Lyme disease treatment guidelines.26 By 2006, however,

the level of evidence against prolonged and repeated courses of antibiotics had strengthened to level 1

(ie, evidence from randomised, double-blind, placebo controlled treatment trials).

The American Academy of Neurology reached a similar conclusion in its 2007 Lyme disease practice guideline.27

Although the IDSA and the American Academy of Neurology guidelines had three authors in common, between

the two guidelines there were 20 different panelists involved, including the principal investigators of all three

randomised, placebo controlled treatment trials for post-Lyme disease symptoms that had been published by

that time. Both sets of guidelines were extensively peer-reviewed before they were published. In addition, these

guidelines are similar to 14 other sets of guidelines for diagnosis and treatment published by European medical

societies and expert panels.28

According to published reports, three chronic Lyme disease activist groups, the New Jersey-based Lyme Disease

Association, the California Lyme Disease Association and the Connecticut-based Time for Lyme organisation,

registered complaints with several State Attorneys General regarding the IDSA guidelines.29 Of note, Johnson is

Chief Executive Ofﬁcer of the California Lyme Disease Association. Only Richard Blumenthal, the Connecticut

Attorney General, initiated legal action. Notably, he has served on the advisory board of Connecticut Time for Lyme,

helped raise money for the ‘chronic Lyme disease’ movement, helped draft a state law assuring patients in

Connecticut access to prolonged antibiotic therapy for ‘chronic Lyme disease’ and supported a paediatrician

found to have negligently diagnosed and treated children for ‘chronic Lyme disease’ from a non-endemic area

without ever examining them.30 The reason for Blumenthal’s long-time support of the ‘chronic Lyme disease’

movement is unclear. For many advocates, it is based on a personal connection, such as having a family member

diagnosed with‘chronic Lyme disease’, although there is no evidence that Blumenthal falls into this category.

Blumenthal instituted his ‘anti-trust’ investigation in the autumn of 2006 within days after the publication of the

2006 IDSA guidelines. Initiating an anti-trust investigation may seem like an odd approach at ﬁrst glance, because

a 1996 policy statement from the Federal Trade Commission and the Department of Justice states that treatment

guidelines issued by medical societies do not limit competition.31 However, an anti-trust investigation provided

broad authority to conduct an investigation at the expense of Connecticut tax payers.

Blumenthal never provided any evidence of an anti-trust violation by the IDSA, which is in accord with the legal

analysis of the matter by independent attorneys.32 We agree with those who have characterised this action as an

attempt to politicise health policy against the weight of scientiﬁc evidence.30 32 33

CONFLICTS OF INTEREST

Blumenthal concluded that the IDSA guidelines panel was ‘rife with conﬂicts of interest’,29 apparently based

on voluntary disclosures of associations with commercial entities by panel members in different contexts and

at different times. The majority of the panelists had nothing to disclose, and those who had disclosures do not

beneﬁt ﬁnancially from the recommendations made in the IDSA guidelines.

With regard to laboratory diagnosis, the 2006 IDSA Lyme disease guidelines reiterated the CDC recommendations

for two-tier serological testing that has been the standard of care since 1995 and is also the strategy recommended

in Europe and Canada.5 34e38 Although several panel members received research grants to study various new

or novel diagnostic tests for Lyme disease, this was not a conﬂict because no speciﬁc serological tests or test kits

were recommended by the panel. In the past, some panel members had been involved in Lyme disease vaccine

development; however, the guidelines do not recommend any Lyme vaccine, and in fact the sole such commercial

product was withdrawn by the manufacturer in 2002 as a result of poor sales.

It is difﬁcult to discern how IDSA panel members would beneﬁt ﬁnancially by recommending against treating

patients who either do not have Lyme disease or who have had Lyme disease but do not require additional

treatment. For patients with active Lyme disease, the IDSA guidelines recommended 10e28-day antibiotic

regimens using generic antibiotics that are no longer under patent protection.5 Although intended for use in

North America, the recommendations are similar to those widely used in Europe.28 38 39 All guidelines should

strive to recommend cost-effective therapies with treatment restricted to those who require it, and for a duration

limited to that which is safe, effective and required based on scientiﬁc evidence. It is also unclear that insurance

companies would necessarily beneﬁt ﬁnancially from these recommendations, as suggested by Johnson and Stricker.1

In fact, it could actually be less expensive for insurance companies routinely to approve treating patients with MUS

with unnecessary and ineffectual antibiotic therapies, rather than incurring additional healthcare expenditures for

diagnostic procedures to identify the patient’s actual problem and for appropriate treatment, including pain

management and other symptomatic therapies if warranted. The concept of listing holdings in a health insurance

company as a potential conﬂict of interest is not a standard practice. Nevertheless, to the best of our knowledge

none of the 2006 IDSA panelists had a vested interest in any health insurance company.

By contrast, it is possible to imagine the repercussions of the IDSA Lyme disease guidelines on the economic

wellbeing of some healthcare providers who specialise in ‘chronic Lyme disease’ and favour indeﬁnite treatment.

In addition to direct patient care services, these providers also have the opportunity to proﬁt by providing intravenous

treatment or from their associations with intravenous infusion companies.40 It has been reported that several

‘chronic Lyme disease’ healthcare providers were disciplined by their state medical boards for receiving payments

or conspiring with intravenous infusion companies.40

One ‘chronic Lyme disease’ healthcare provider, who practises in a state in which Lyme disease is not endemic,

is reported to have collected, in the year 2005 alone, US$6 million from a single health insurance company.40

The allegations of conﬂicts of interest against the IDSA panel resemble those made against the National Institutes of

4 of 6 Auwaerter PG, Bakken JS, Dattwyler RJ, et al. J Med Ethics (2010). doi:10.1136/jme.2009.032896

Health, the Food and Drug Administration and the CDC by the ‘chronic Lyme disease’ activist groups and their

supporters in 2000. A complete and detailed investigation by the United States General Accounting Ofﬁce found

such allegations to be baseless.41e43

It is noteworthy that Blumenthal did not initiate an investigation of the International Lyme and Associated Diseases

Society (ILADS), a Lyme disease activist organisation that published its own Lyme disease treatment

guidelines.11 Johnson is currently Secretary of ILADS, and Stricker is a past president and co-author of

the ILADS treatment guidelines. These guidelines, which were published in a supplement to a journal,

did not undergo a peer review process by the journal.11 44 45 None of the ILADS guidlines authors disclosed

any potential conﬂicts of interests whatsoever, including the individual who was chief executive of

a laboratory that developed a non-standard diagnostic test for Lyme disease used by many in the ILADS

physician community.34 Stricker is said to be treating approximately 1800 Lyme disease patients in his practice

in San Francisco,46 a number all the more impressive when one considers that over the 10-year period between

1998 and 2007, only 951 cases of Lyme disease in total were reported to the CDC from the entire state of California.

Dr Stricker was previously found by the Ofﬁce of Research Integrity at the National Institutes of Health to have

falsiﬁed research data on the pathogenesis of thrombocytopaenia in HIV-infected patients.47 The paper describing

the spurious results was published in the New England Journal of Medicine, but when the falsiﬁcation was uncovered,

it was retracted by an ofﬁcial from Stricker ’s university (now former university) and by all of its authors except

for Stricker.48

CONCLUSIONS

Assaults on the IDSA and its Lyme disease guidelines panel appear to be the latest strategy to undermine an

evidence-based approach for the diagnosis and treatment of Lyme disease. This is potentially risky for patients,

ethically questionable, and contrary to the scientiﬁc evidence on which medical practice should be based.49

Importantly, treatment recommendations for Lyme disease offered by the IDSA in 2006 are consistent with

those advocated by the American Academy of Pediatrics, the American College of Physicians, the Medical Letter

and the American Academy of Neurology among other organisations, and are similar to those guidelines

independently developed and widely used in Europe.27 28 38 39 In contradistinction, no professional societies

that we are aware of endorse the recommendations that supporters of ‘chronic Lyme disease’ espouse.11

It is the responsibility of all physicians and medical scientists to stand up to antiscientiﬁc, baseless and unethical

attacks on those who support an evidence-based approach to caring for patients.

Acknowledgements The authors would like to thank Diana Olson, Lisa Giarratano and Lenise Banwarie

for their assistance.

Competing interests PGA, JSB, RJD, JJH, JSD, RBN, SKS and GPW are members of the Infectious

Diseases Society of America (IDSA) and JSB, RJD, JSD, JJH, RBN and GPW served on the 2006 IDSA

Lyme disease guidelines panel. SOC and AW served as consultants to the 2006 IDSA panel. EM is a

former Lyme disease programme ofﬁcer at the National Institutes of Health.

Provenance and peer review Not commissioned; externally peer reviewed.

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