The Lyme Wars - time to listen 1. Introduction 2. Assertions and comments 3. Expert opinion and conclusion Raphael B Stricker† & Andrew Lautin †Department of Medicine, California Pacific Medical Center, San Francisco, CA, USA Lyme disease represents a public health threat of major proportions. The murky science and acrimonious politics of Lyme disease have created barriers to reliable diagnosis and effective treatment of this protean illness. Two major clinical problems with the disease are the absence of a therapeutic end point in treating Borrelia burgdorferi, the spirochetal agent of Lyme disease, and the presence of tick-borne co-infections such as Babesiosis, Anaplasmosis and Bartonellosis that may complicate the course of the illness. From a pathophysiological standpoint, the affinity of B. burgdorferi for multiple cell types and the presence of non-replicating forms of the spirochete have contributed to persistent infection and failure of simple antibiotic regimens. Newer approaches to the treatment of Lyme disease should take into account its clinical complexity in co-infected patients and the possible need for prolonged combination therapy in patients with persistent symptoms of this potentially debilitating illness. The risk and prevention of human transmission of Lyme disease merit further study. Keywords: Anaplasma, Babesia, Bartonella, Borrelia, co-infections, Lyme disease Expert Opin. Investig. Drugs (2003) 12(10) 1. Introduction Virtually from the moment of its discovery in 1975, Lyme disease has been a controversial illness [1,2]. The controversy is grounded in the murky nature of the disease, from its protean manifestations and inconsistent diagnostic parameters to its uncertain treatment. In addition to these scientific inconsistencies, the politics surrounding Lyme disease rivals the worst medical defamation in history, from syphilis (always the ‘other country’s venereal disease’) to AIDS (the ‘scourge of alternative lifestyles’). Perhaps the political apogee of Lyme disease came in 1993, when Joseph Burrascano testified before the US Congress that Lyme disease was not "hard to catch and easy to cure", as others had reassured the government. Rather, the disease was an underreported and growing menace that would exact a huge toll on the healthcare system if policy did not change [3,4]. For his efforts, Burrascano was prosecuted by his state medical board and the ‘Lyme Wars’ have become even more acrimonious. What sustains this controversy? It is important to recognise that the science of Lyme disease suffers from two major problems. First, there is no test currently available that proves the eradication of Borrelia burgdorferi, the spirochetal agent of Lyme disease, from the human body [5,6]. Conversely, there is growing evidence for longterm persistence of the Lyme disease spirochete in animal models [7-11] and humans [12-14] despite alleged adequate treatment for the disease. The second problem is that Lyme disease likes company, and over the past 20 years we have seen compelling evidence for co-infections transmitted by ticks (which have been called ‘sewers of infectious disease’) along with the Lyme disease spirochete [15-21]. Thus, the term ‘Lyme disease’ often signifies a poorly characterised polymicrobial infection with no fixed end point. This nebulous infectious disease presents a nightmare scenario for both the victim of Lyme disease and any rational healthcare provider who must deal with the complex implications of the tick-borne illness. A corollary to this nightmare is the growing recognition of possible spread of the Lyme disease spirochete by human contact [22,23]. With this background, the article by Charles Pavia  on current and novel therapies for Lyme disease is yet another trivialising treatise that presents inaccurate or incorrect information about this potential nightmare. In our view, the banality of the article reflects an entrenched and growing ignorance and neglect of the severity of Lyme disease, while its victims continue to suffer. Below is a partial rundown of points presented in the article with which we strongly take issue. We have listed these points in their order of appearance and appended our corresponding commentary. 2. Assertions and comments Assertion (1): B. burgdorferi can be readily cultivated in vitro using special culture medium. Comment (1): B. burgdorferi is difficult to culture by routine methods, and virtually no clinical laboratory can perform this basic infectious disease test [25,26]. This clinical drawback has severely limited the diagnosis of Lyme disease. A similar problem is seen with syphilis, an illness caused by the spirochete Treponema pallidum. Since this organism cannot be cultured in vitro, the diagnosis of syphilis (like Lyme disease) is supported by serological testing, prompting the observation that ‘any infection for which diagnosis and assessment of treatment response depend on serologic testing is one in which clinical certainty is elusive’ . Assertion (2): About 20 – 25% of Lyme disease patients do not remember developing a characteristic ‘bullseye’ erythema migrans (EM) rash. Comment (2): According to recent health department statistics from Texas, Connecticut and California, the EM rash fails to appear in 41 – 65% of Lyme disease patients, and recognition of the rash may be even lower depending on the location of the tick-bite and the awareness of the person who was bitten [28,101]. The published incidence of the EM rash also reflects a type of circular reasoning that pervades Lyme disease research: since the presence of an EM rash is the best evidence for Lyme disease, it has become the most common criterion for admission into Lyme disease studies. Since most patients in these studies have an EM rash, the incidence of the rash becomes inflated in the medical literature. The literature then perpetuates the myth that the vast majority of Lyme disease patients have an EM rash [4,22]. Assertion (3): The Lyme enzyme-linked immunosorbent assay (ELISA) is the preferred method to diagnose Lyme disease due to its sensitivity, adaptability to automation and ease of quantitation. Comment (3): The Lyme ELISA misses at least 50% of Lyme disease cases due to the assay’s insensitivity and variability with antibiotic treatment . It follows that the two-tiered testing system endorsed by the US Centers for Disease Control and Prevention (CDC), which includes an ELISA screening test followed by a confirmatory Western blot, will also miss 50% of Lyme disease cases because a positive ELISA result is required to proceed to the confirmatory Western blot test [28,101]. Parenthetically, the CDC criteria were developed for surveillance of Lyme disease, not for diagnostic purposes. This is an important distinction because it is inappropriate to apply surveillance criteria to symptomatic patients whose clinical picture already suggests the presence of Lyme disease. Thus, there is currently no sanctioned, standardised, consistent serological test for Lyme disease in the US [28,101]. Assertion (4): Only motile forms (of B. burgdorferi) are considered to be viable and capable of replicating. Comment (4): B. burgdorferi assumes different forms in different hosts [29-35]. The most troublesome is the so-called cyst form that may lie dormant in the human host, thus evading antibiotic therapy that targets replicating bacteria [29-33]. The non-replicating cyst form is undoubtedly the key to persistence of infection with the Lyme disease spirochete, and any antibiotic approach to Lyme disease that fails to recognise this pathogenic entity is doomed to failure [34,35]. Assertion (5): The Lyme disease vaccine was withdrawn due to lack of public interest. Comment (5): The GlaxoSmithKline Lyme vaccine (LYMErix™) was withdrawn in the face of a class action lawsuit involving > 300 patients who claim that they developed a ‘Lyme-like’ illness after receiving the vaccine. Assertion (6): Early Lyme disease is readily treatable with a 2 – 3 week course of antibiotics. Comment (6): This statement is misleading for several reasons. First, ‘early Lyme disease’ often goes undetected due to lack of awareness of a tick-bite and absence of an EM rash . Second, recent studies have shown that tick saliva carries immunosuppressive substances that allow tick-borne agents to invade tissues while paralysing the local immune response [36,37]. Thus, the Lyme disease spirochete may rapidly disseminate and become entrenched and resistant early in the disease (see below) [38-40]. Third, co-infections may alter the course of ‘early Lyme disease’, and these co-infections may make the Lyme disease patient more difficult to treat (see below). Assertion (7): To date, there is no evidence for the existence of any antibiotic-resistant strains of B. burgdorferi’. Comment (7): A serious understatement. B. burgdorferi is an extremely complex organism. The Lyme disease spirochete contains at least 132 functioning genes, in contrast to T. pallidum, the spirochete that causes syphilis, which contains only 22 such genes . Although B. burgdorferi may not be ‘resistant’ to antibiotics by conventional laboratory methods, we know that the spirochete can enter cells such as fibroblasts, synovial cells, endothelial cells and macrophages [42-47]. In these cells, B. burgdorferi becomes functionally resistant to treatment, partly due to ‘camouflage’ proteins produced by the organism or adsorbed from the cell and partly due to the altered morphology and replication of the spirochetal cyst form (see above) [34,40,43]. This functional resistance leads to persistent infection despite supposedly adequate treatment for Lyme disease. The immune evasion strategy of B. burgdorferi is reminiscent of mycobacterial infections such as tuberculosis or leprosy [38-40]. Assertion (8): It is unclear whether a concurrent Anaplasma or Babesia infection can influence the outcome of a standard course of treatment for Lyme disease. Comment (8): Animal models of co-infection with B. burgdorferi and either Babesia microti or Anaplasma phagocytophila (the agent of human granulocytic ehrlichiosis) have demonstrated an altered immune response and clinically worse disease in these animals [48-50]. Similar exacerbation of clinical symptoms and resistance to treatment has been observed in humans [16,51]. Assertion (9): A single dose of doxycycline given within 72 h after a recognisable tick-bite was highly effective in preventing early Lyme disease. Comment (9): The study that showed the alleged benefit of prophylactic single-dose doxycycline had inadequate follow up to prove the absence of clinical infection following this simple treatment . Furthermore, the authors used development of an EM rash as an end point in the study. Since 41 – 65% of Lyme disease patients do not develop an EM rash, the study may have missed more than half the patients who eventually came down with Lyme disease after this theoretically inadequate prophylaxis. The use of single-dose doxycycline also raises concern about antibiotic resistance following this microbiologically unsound therapy. Assertion (10): Healthcare providers who deal with Lyme disease can be divided into two groups: ‘specialists’ who are often affiliated with ‘large academic institutions’, versus ‘community-based’ providers in ‘private (family) practice’. The former group tends to adhere to the guidelines of the CDC and the Infectious Disease Society of America (IDSA) in diagnosing and treating Lyme disease. In contrast, the latter group tends to rely on ‘anecdotal reports citing an alarming number of Lyme disease patients who are supposedly co-infected with one or more of the following: Anaplasma, Bartonella or Babesia. Such an unlikely scenario of multiple infections arouses suspicion on the authenticity of these cases and those willing to make such diagnoses’. Comment (10): We feel that this is a very politically charged statement, featuring two issues that define the Lyme Wars. The first issue concerns the lofty ‘academic specialists’ who follow the CDC and IDSA guidelines in diagnosing and treating Lyme disease. We have seen that the CDC guidelines give a poor diagnostic yield for Lyme disease, since they were meant for surveillance purposes and not for diagnosis [22,101]. The IDSA guidelines were written by a panel of 12 Lyme disease ‘experts’, 11 of whom were research scientists with minimal clinical experience in treating Lyme disease. These guidelines have doomed thousands of suffering Lyme disease patients to a lack of therapy based on the opinions of a handful of researchers. With this knowledge, is it any wonder that ‘communitybased’ providers who deal with the clinical nightmare of Lyme disease have rejected the CDC/IDSA guidelines and formulated their own diagnostic and therapeutic parameters [53-55]? Pavia raises the second issue based on this clinical dichotomy, stating that Lyme disease treatment outside the CDC/IDSA guidelines represents a provider-driven policy that impugns the integrity of the provider. The reality is that suffering patients seek out ‘Lyme-literate ’ providers because the ‘academic’ researchers have abandoned them. These researchers and their followers offer nothing in the way of treatment for the suffering of Lyme disease patients other than pseudopsychiatric semantics [4,22] or meaningless labels such as chronic fatigue syndrome or fibromyalgia, which are often manifestations of chronic, poorly treated Lyme disease [56,57]. Pavia also refers to the alarming number of Lyme disease patients who are supposedly co-infected with other tick-borne organisms. Since this number is now ~ 20% or more of all Lyme disease cases [18,20,29], the alarm should have sounded long ago. Assertion (11): The Pavia paper praises the ‘highly significant’ results of the study by Klempner et al.  that examined retreatment of Lyme disease patients who had persistent symptoms of the disease. The study claimed that it is unlikely that prolonged antibiotic treatment will offer any major benefit to symptomatic patients who are no longer infectious. Comment (11): The study by Klempner et al.  has been analysed in detail elsewhere [55,102]. At the beginning of this article, we noted that one of the main problems with Lyme disease is the lack of a test that proves the eradication of spirochetal infection. Thus, we feel that the design of the study by Klempner et al. was basically flawed, since the culture and molecular techniques used in the study were insufficient to prove that patients were ‘no longer infectious’ . Furthermore, the choice of ‘prolonged’ antibiotic therapy for patients with neurological disease (1 month of intravenous ceftriaxone followed by 2 months of low-dose oral doxycycline) was irrational and doomed to failure [55,102]. Consequently, the study simply shows that inadequate retreatment of chronic Lyme disease leads to inadequate results . Unfortunately, because of the widespread publicity given to this article and its prestigious publisher, the flawed data has been widely used to deny care for symptomatic subjects. Assertion (12): Pavia focuses on hyperbaric oxygen therapy (HBOT), shorter course treatment with antibiotics and evernimicin therapy as future treatment options for Lyme disease. Comment (12): HBOT is currently being used as adjunctive treatment for chronic Lyme disease . Although in theory it is effective in creating a more hostile environment for the Lyme disease spirochete, HBOT is a cumbersome procedure that probably will never be available to the majority of patients with chronic infection. The cost of multiple treatments is also prohibitive. The Pavia paper fails to address the hepatic toxicity of evernimicin, and it is doubtful that this toxic antibiotic will ever be marketed for Lyme disease. Shorter course antibiotic therapy was the subject of a recent study , and this minimalist approach promises to yield more inadequately treated Lyme disease sufferers. In contrast to these impractical or potentially toxic treatment options, current and future Lyme disease therapy should focus on combinations of antibiotics that are readily available and administered in a rational manner, with monitoring of clinical and immunological parameters [53,60-62]. In this regard, it is important to remember that the current World Health Organization (WHO) recommendation for treating infection with Mycobacterium tuberculosis is a combination of two antimicrobial agents administered for 18 months, while the WHO-sanctioned treatment for leprosy is a combination of three antimicrobial agents administered for 2 years [63-65]. For a spirochete as complex and crafty as B. burgdorferi, these guidelines are probably closer to what is needed for the eradication of chronic spirochetal infection in Lyme disease. As stated previously, recognition and evaluation of human transmission of Lyme disease will also play a role in developing effective treatment strategies [22,23]. 3. Expert opinion and conclusion In conclusion, Lyme disease remains a public health threat of major proportions. Continued trivialisation of this complex spirochetal illness only serves to augment the threat by legitimising ignorance of Lyme disease and neglect of Lyme disease patients. Until this trend is reversed, we will continue to see thousands of patients suffering at the hands of the medical establishment and desperately seeking care from the few providers who will listen. As modern medicine rockets into the 21st Century, this ostracism of suffering patients and persecution of dissenting healthcare providers can no longer be tolerated. For their part, Lyme disease patients and their providers must learn from the AIDS experience, where activism brought change when it was perceived that nobody was listening. And as more people listen, the ‘Lyme Wars’ may finally reach an end. Acknowledgements The authors thank Robert Bransfield, Joseph Burrascano, Kathleen Dickson, David Dorward, Brian Fallon, Andrea Gaito, Julie Gerberding, Nick Harris, William Harvey, Barbara Johnson, Anne Kjemtrup, Robert Lane, Kenneth Liegner, Robert Lull, Daniel Moore, Scott Morrow, Steven Phillips, Walter Prehn, Lynn Shepler, Virginia Sherr, Harold Smith, Gerald Sugarman and Edward Winger for helpful discussion. We also thank Pat Smith of the Lyme Disease Association, Phyllis Mervine, Lee Lull, Peggy Leonard and Barb Barsocchini of the California Lyme Disease Resource Center and Karen Forschner of the Lyme Disease Foundation for continuing support. This article is dedicated to the memory of Paul Lavoie. Bibliography Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1. STEERE AC, TAYLOR E, MCHUGH GL, LOGIGIAN EL: The overdiagnosis of Lyme disease. JAMA (1993) 269:1812-1816. 2. 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STRICKER RB, BURRASCANO J, WINGER EE: Longterm decrease in the CD57 lymphocyte subset in a patient with chronic Lyme disease. Ann. Agric. Environ. Med. (2002) 9:111-113. 62. STRICKER RB, WINGER EE: Normalization of the CD57 natural killer cell subset associated with prolonged antibiotic therapy in patients with chronic Lyme disease. Clin. Immunol. (2002) 103:S117-S118. 63. SMALL PM, FUJIWARA PI: Management of tuberculosis in the United States. N. Engl. J. Med. (2001) 345:189-200. 64. SHAW IN, NATRAJAN MM, RAO GS, JESUDASAN K, CHRISTIAN M, KAVITHA M: Long-term follow up of multibacillary leprosy patients with high BI treated with WHO/MDT regimen for a fixed duration of two years. Int. J. Lepr. Other Mycobact. Dis. (2000) 68:405-409. 65. GOTO M: Chemotherapy of leprosy: theoretical basis of new guideline in Japan. Nihon Hansenbyo Gakkai Zasshi (2001) 70:151-155. Websites 101. http://www.geocities.com/HotSprings/Oasis/6455/lyme-links.html Lots of links on Lyme disease - over 12,000 categorised links on Lyme disease (2001). •• The most extensive collection of Lyme disease references in existence. 102. http://www.ilads.org/stricker.htm PHILLIPS SE, BRANSFIELD R, SHERR VT et al.: Evaluation of antibiotic treatment in patients with persistent symptoms of Lyme disease: an ILADS position paper (2003). •• A comprehensive critique of , the flawed study of ‘long-term’ antibiotic therapy for Lyme disease. Affiliation Raphael B Stricker MD1† & Andrew Lautin2 †Author for correspondence 1†Department of Medicine, California Pacific Medical Center, 450 Sutter Street, Suite 1504, San Francisco, CA, USA Tel: +1 415 399 1035; Fax: +1 415 399 1057; E-mail: firstname.lastname@example.org 2Department of Psychiatry, New York University School of Medicine, New York, NY, USA Top Contents of this Web Site are for the purpose of information and education only, and not a guide to diagnosis or treatment of a particular disorder or its symptoms.