Lorraine Johnson

Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease.

Evidence-based guidelines for the management of patients with Lyme disease were developed by the International Lyme and Associated Diseases Society (ILADS). The guidelines address three clinical questions – the usefulness of antibiotic prophylaxis for known tick bites, the effectiveness of erythema migrans treatment and the role of antibiotic retreatment in patients with persistent manifestations of Lyme disease. Healthcare providers who evaluate and manage patients with Lyme disease are the intended users of the new ILADS guidelines, which replace those issued in 2004 (Exp Rev Anti-infect Ther 2004;2:S1–13). These clinical practice guidelines are intended to assist clinicians by presenting evidence-based treatment recommendations, which follow the Grading of Recommendations Assessment, Development and Evaluation system. ILADS guidelines are not intended to be the sole source of guidance in managing Lyme disease and they should not be viewed as a substitute for clinical judgment nor used to establish treatment protocols.

Lyme disease: the next decade.

Although Lyme disease remains a controversial illness, recent events have created an unprecedented opportunity to make progress against this serious tick-borne infection. Evidence presented during the legally mandated review of the restrictive Lyme guidelines of the Infectious Diseases Society of America (IDSA) has confirmed the potential for persistent infection with the Lyme spirochete, Borrelia burgdorferi, as well as the complicating role of tick-borne coinfections such as Babesia, Anaplasma, Ehrlichia, and Bartonella species associated with failure of short-course antibiotic therapy. Furthermore, renewed interest in the role of cell wall-deficient (CWD) forms in chronic bacterial infection and progress in understanding the molecular mechanisms of biofilms has focused attention on these processes in chronic Lyme disease. Recognition of the importance of CWD forms and biofilms in persistent B. burgdorferi infection should stimulate pharmaceutical research into new antimicrobial agents that target these mechanisms of chronic infection with the Lyme spirochete. Concurrent clinical implementation of proteomic screening offers a chance to correct significant deficiencies in Lyme testing. Advances in these areas have the potential to revolutionize the diagnosis and treatment of Lyme disease in the coming decade.

Treatment of Lyme disease: a medicolegal assessment.

Lyme disease is the most common tick-borne disease in the world today. Despite extensive research into the complex nature of Borrelia burgdorferi, the spirochetal agent of Lyme disease, controversy continues over the diagnosis and treatment of this protean illness. This report will focus on two aspects of the treatment of Lyme disase. First, the medical basis for diagnostic and therapeutic uncertainty in Lyme disease, including variability in clinical presentation, shortcomings in laboratory testing procedures, and design defects in therapeutic trials. Second, the standard of care and legal issues that have resulted from the clinical uncertainty of Lyme disease diagnosis and treatment. Specifically, the divergent therapeutic standards for Lyme disease are addressed, and the difficult process of creating treatment guidelines for this complex infection is explored. Consideration by healthcare providers of the medicolegal issues outlined in this review will support a more rational approach to the diagnosis and treatment of Lyme disease and related tick-borne illnesses.

Healthcare access and burden of care for patients with Lyme disease: A large United States survey

OBJECTIVEnTo evaluate the challenges faced by Lyme disease patients in obtaining adequate healthcare.nnnMETHODSnA web-based survey conducted over nine months was analyzed for the study. The survey focused on medical status, access to healthcare, and burden of illness. For inclusion in the study, survey respondents had to reside in the United States, be more than 10 years old, and have clinically diagnosed Lyme disease with chronic symptoms and positive laboratory testing.nnnRESULTSnResponses from 2424 patients were included in the study. Half of the respondents reported seeing at least seven physicians before the diagnosis of Lyme disease was made. Nearly half had Lyme disease for more than 10 years and traveled over 50 miles to obtain treatment. Most respondents experienced symptoms lasting six months or more despite receiving at least 21 days of antibiotic treatment. A quarter of respondents had been on public support or received disability benefits due to Lyme disease symptoms, and over half had visited an emergency room at least once as a result of these symptoms.nnnCONCLUSIONSnLyme disease patients frequently endure extensive delays in obtaining an initial diagnosis, have poor access to healthcare and suffer a severe burden of illness.

Benefit of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease

Background We have shown previously that extended intravenous antibiotic therapy is associated with low morbidity and no mortality in patients referred for treatment of neurologic Lyme disease. In this study, we evaluated the benefit of extended intravenous antibiotic therapy in patients with symptoms of neurologic Lyme disease. Methods Patients with significant neurologic symptoms and positive testing for Borrelia burgdorferi were treated with intravenous antibiotics, and biweekly evaluation of symptom severity was performed using a six-level ordinal scale. Four symptoms were selected a priori as primary outcome measures in the study, ie, fatigue, cognition, myalgias, and arthralgias. Patients were placed into five groups according to time on treatment (1–4, 5–8, 9–12, 13–24, and 25–52 weeks), and changes in the primary symptoms as a function of time on treatment were analyzed using a mixed-effects proportional odds model. Results Among 158 patients with more than one follow-up visit who were monitored for up to 1 year, there were on average 6.7 visits per person (median 5, range 2–24). The last follow-up day was on average 96 days after enrollment (median 69, range 7–354 days), corresponding to the length of antibiotic therapy. Each primary symptom was significantly improved at one or more time points during the study. For cognition, fatigue, and myalgias, the greatest improvement occurred in patients on the longest courses of treatment (25–52 weeks) with odds ratios (OR) for improvement of 1.97 (P = 0.02), 2.22 (P < 0.01), and 2.08 (P = 0.01), respectively. In contrast, arthralgias were only significantly improved during the initial 1–4 weeks of therapy (OR: 1.57, P = 0.04), and the beneficial effect of longer treatment did not reach statistical significance for this symptom. Conclusion Prolonged intravenous antibiotic therapy is associated with improved cognition, fatigue, and myalgias in patients referred for treatment of neurologic Lyme disease. Treatment for 25–52 weeks may be necessary to obtain symptomatic improvement in these patients.

The Infectious Diseases Society of America Lyme guidelines: a cautionary tale about the development of clinical practice guidelines.

Flawed clinical practice guidelines may compromise patient care. Commercial conflicts of interest on panels that write treatment guidelines are particularly problematic, because panelists may have conflicting agendas that influence guideline recommendations. Historically, there has been no legal remedy for conflicts of interest on guidelines panels. However, in May 2008, the Attorney General of Connecticut concluded a ground-breaking antitrust investigation into the development of Lyme disease treatment guidelines by one of the largest medical societies in the United States, the Infectious Diseases Society of America (IDSA). Although the investigation found significant flaws in the IDSA guidelines development process, the subsequent review of the guidelines mandated by the settlement was compromised by a lack of impartiality at various stages of the IDSA review process. This article will examine the interplay between the recent calls for guidelines reform, the ethical canons of medicine, and due process considerations under antitrust laws as they apply to the formulation of the IDSA Lyme disease treatment guidelines. The article will also discuss pitfalls in the implementation of the IDSA antitrust settlement that should be avoided in the future.

The Pain of Chronic Lyme Disease: Moving the Discourse Backward?

Phillip Baker has taken “Lyme denialism” to new depths (1). According to the Institute of Medicine, there are at least 116 million people living with acute and chronic pain in the United States. According to Baker, not one of those individuals suffers from chronic Lyme disease as a result of persistent infection with the Lyme spirochete, Borrelia burgdorferi. What is the basis for his opinion? Baker claims that “there is no evidence to indicate that chronic Lyme disease is due to a persistent infection” or that “extended antibiotic therapy is beneficial and safe”. This denialist statement about a disease that causes pain and suffering equivalent to that of diabetes or congestive heart failure ignores a growing body of evidence from the peer-reviewed medical literature that contradicts his opinion (2–5). Baker starts by attacking “Lyme-literate” physicians who use a “Lyme disease specialty laboratory” to diagnose tick-borne disease in a manner that is inconsistent with the surveillance case definition established by the Centers for Disease Control and Prevention (CDC). What Baker fails to tell us is that the CDC admits that its surveillance case definition “was developed for national reporting of Lyme disease” and was “not intended to be used in clinical diagnosis” (6). Thus, the diagnostic approach that Baker endorses is inappropriate for diagnosis of Lyme disease. Furthermore, the 46 patented commercial laboratory tests that Baker recommends for Lyme disease diagnosis have a sensitivity of only 46% and appear to yield results that are biased against women (7–9). Consequently, these commercial tests miss more than one-half of the patients with chronic Lyme disease in the United States. In contrast, the maligned “Lyme disease specialty laboratory” uses diagnostic criteria based on evidence from the peerreviewed medical literature (10, 11), and its “genderneutral” testing has a sensitivity and specificity of 90% (12). Clearly, this testing is preferable for the diagnosis of Lyme disease. As for Baker’s pat statement that “there is no evidence to indicate that chronic Lyme disease is due to a persistent infection,” numerous reports of veterinary cases and animal models confirm persistent infection with the Lyme spirochete in gerbils, hamsters, mice, dogs, monkeys, birds, and horses (13– 15). Among these cases, persistent pathology was seen in mice, dogs, and horses after the animals failed short-course treatment for their infection. Furthermore, there are at least 27 reports of persistent symptoms and failure to eradicate B. burgdorferi infection in humans treated with short-course antibiotic therapy for their tick-borne disease (5). Why does Baker deny these reports? He does so because they do not fit his limited view of Lyme disease. Baker also attacks the safety and efficacy of prolonged antibiotic therapy for chronic Lyme disease, stating that “all of the evidence obtained thus far...indicates no significant benefit as well as serious safety problems” with extended antibiotic therapy for these patients. What Baker fails to tell us is that the number of patients in controlled trials of Lyme disease treatment totals a mere 221 highly selected subjects who do not represent the vast majority of patients with chronic Lyme disease (3–5). Further analysis of these studies reveals that they were “of questionable quality”, lacked the power to detect potentially positive treatment effects, and failed to report predefined endpoints (16). Even so, in two of the four controlled trials, a significant benefit was seen in fatigue and cognition with the limited antibiotic regimen that was used, and safety problems were minimal (17, 18). In larger studies of extended antibiotic therapy, the safety of this treatment was shown to be acceptable, and the benefit of extended therapy was significant in terms of cognition, fatigue, and myalgic pain, although it took 6 –12 months of i.v. therapy to achieve this benefit (19, 20). In summary, Baker’s denialist view of the Lyme disease epidemic ignores significant evidence from the peer-reviewed medical literature that contradicts his opinion. It follows that practitioners who subscribe to his narrow view are abandoning the multitude of patients with acute and chronic pain who would benefit from treatment for their persistent spirochetal infection.

Searching for autoimmunity in “antibiotic-refractory” Lyme arthritis

In two recent articles published in Molecular Immunology, Steere and colleagues continue their search for an autoimmune mechanism of arthritis in patients who have failed short-course antibiotic therapy for Borrelia burgdorferi, the spirochetal agent of Lyme disease. As in previous attempts, the authors fail to elucidate a molecular mimicry mechanism for the putative autoimmune process, leading to the conclusion that there is no credible scientific evidence for a post-infectious autoimmune mechanism of arthritis in chronic Lyme disease.

Chronic Lyme disease and the 'Axis of Evil'.

Lyme disease is a controversial illness, and the existence of chronic Lyme disease induced by persistent infection with the Lyme spirochete, Borrelia burgdorferi, is the subject of continued debate. A recent publication defined the Axis of Evil in this controversy as physicians who treat patients with needlessly prolonged courses of antibiotics, specialty laboratories that perform inaccurate Lyme testing and the internet, which promotes Lyme hysteria. We examine the Axis of Evil components in the context of diagnostic and therapeutic challenges for Lyme disease patients and their physicians, and we present an evidence-based refutation to this misguided view. Despite its virulent nature, the Axis of Evil perspective is a useful starting point to resolve the controversy over Lyme disease.

The Infectious Diseases Society of America Lyme guidelines: poster child for guidelines reform.

In the era of managed healthcare, medical specialty societies have gained tremendous power over the practice of medicine. Specialty societies exert their power through clinical practice guidelines that dictate the standard of care for diagnosis and treatment in a given field, and compliance with these guidelines is considered mandatory by insurers, medical boards, government agencies and courts of law. Recent commentaries have highlighted the poor evidence supporting most guideline recommendations and the problems caused by conflicts of interest and bias of guidelines panelists. The article by Susan Ronn in this issue of the SMJ shows how the Lyme disease guidelines published in 2006 by the powerful Infectious Diseases Society of America (IDSA) could serve as a poster child for these problems. IDSA’s monopoly power is undisputed. It is the largest infectious disease specialty society in the world, publishes the two largest medical journals in the field, controls related peer review, acts as a gatekeeper for hospital staff privileges, and provides expert testimony to enforce its guidelines through medical board disciplinary action. The IDSA Lyme guidelines contain a disturbing number of ‘evidence-based’ recommendations (38 of 71) that depend on the weakest Level III evidence, namely ‘expert opinion.’ Consequently, any irregularity in the guidelines panel that provided its ‘expert opinion’ becomes highly significant. These concerns prompted the Connecticut Attorney General to conduct an antitrust investigation into the IDSA guidelines development process. In a settlement with IDSA announced on May 1, 2008, the Attorney General found that IDSA panel members had “commercial interests in drug companies, Lyme disease diagnostic test patents, and consulting arrangements with insurance companies” and that IDSA failed to conduct a conflicts-of-interest review for any of the panelists. IDSA contests the conflicts-of-interest assertion on the grounds that its guidelines do not promote the drugs used to treat Lyme disease. However, conflicts of interest encompass not only drugs used to treat a condition, but also vaccines, diagnostic tests, and insurance consultations. The IDSA Lyme guidelines restrict the definition of the disease and mandate laboratory testing. Guidelines that restrict a disease definition are favorable to vaccine patent holders because they increase the apparent effectiveness of the vaccine. Guidelines that mandate diagnostic testing promote the interests of diagnostic test patent holders. Guidelines that deny treatment to patients are favorable to paid insurance company consultants. The Attorney General found that the IDSA Lyme guidelines panelists had financial conflicts of interest in each of these areas. The investigation by the Attorney General was based on antitrust law, which stipulates that a medical society with monopoly power must ensure a guidelines development process that includes competing points of view and avoids commercial conflicts of interest. IDSA was aware that its opinion about diagnosis and treatment of Lyme disease has been challenged in peer-reviewed publications, and it could have avoided antitrust scrutiny by acknowledging opposing views and running a fair guidelines development process. Instead it relied on a process involving a handpicked guidelines panel with extensive conflicts of interest that suppressed dissent, excluded evidence, and ignored conflicting viewpoints. The IDSA settlement requires that it reconstitute a guidelines panel free of conflicts of interest, consider all submitted scientific evidence, and hold a public hearing aired live over the Internet. Although these measures represent a vast improvement over the IDSA development process for the 2006 Lyme guidelines, even these measures may not go far enough to accomplish the goal of a fair process. While the new panelists are free of traditional monetary conflicts of interests, IDSA has stacked the panel with individuals known to have a bias against alternative treatment options. The panel consists almost entirely of academic researchers while excluding From the International Lyme and Associated Diseases Society, Bethesda, MD.