posted
Sorry for the problems earlier. This copy should work just fine.
Patti
Chemotherapy 933 DOI: 10.1159/0000XXXXX
Received: September 22, 2004 Accepted after revision: June 20, 2005 Published online: $ $ $
Lyme Disease: The Quest for Magic Bullets
Raphael B. Strickera Andrew Lautinb Joseph J. Burrascanoc
a California Pacific Medical Center, San Francisco, Calif. , b New York University School of Medicine, New York , and c East End Medical Associates, East Hampton, N.Y. , USA
Lyme disease represents a growing public health threat. Recent molecular and genetic studies have confirmed that Borrelia burgdorferi, the spirochetal agent of Lyme disease, is one of the most complex bacteria known to man. Affinity for multiple cell types and the presence of non-replicating forms of B. burgdorferi have contributed to persistent infection and failure of simple antibiotic regimens. The controversial clinical science of Lyme disease has impeded reliable diagnosis and effective treatment of this protean illness. Two major clinical hurdles are the absence of a therapeutic endpoint in treating Lyme disease and the presence of tick-borne coinfections that may complicate the course of the illness. New strategies for the diagnosis, treatment and prevention of Lyme disease are urgently needed.
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 to its inconsistent diagnostic parameters to its uncertain treatment. As a result of these scientific inconsistencies, Lyme disease has become one of the most politically charged diseases in history, rivalling syphilis (always the `other country's venereal disease') and AIDS (the `scourge of alternative life-styles'). The political battle over Lyme disease features two polarized medical camps: the dominant camp adheres to the philosophy that the disease is `hard to catch and easy to cure', and that chronic infection with Borrelia burgdorferi, the spirochetal agent of Lyme disease, is extremely rare or nonexistent. The opposing camp views Lyme disease as an underreported and growing menace that often fails to respond to standard antibiotic therapy, resulting in a chronic debilitating infection that requires prolonged antibiotic treatment [3, 4]. This festering controversy has resulted in systematic denial of treatment for patients with chronic Lyme disease and prosecution of healthcare providers who treat these patients, and over the past decade the `Lyme Wars' have become progressively more acrimonious.
What sustains this controversy? It is important to recognize that the science of Lyme disease suffers from two major problems. First, there is no test currently available that proves the eradication of B. burgdorferi from the human body [5, 6] . Conversely, there is growing evidence for long-term persistence of the Lyme disease spirochete in animal models [7-11] and humans [12-14] despite `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 coinfections transmitted by ticks (which have been called `sewers of infectious disease') along with the Lyme disease spirochete [15-23] . Thus the term `Lyme disease' often connotes a poorly characterized polymicrobial infection with no fixed endpoint [15] . 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 complications of tick-borne illness. A corollary to this nightmare is the growing recognition of possible spread of the Lyme disease spirochete by a variety of tick species, including the American dog tick and Pacific coast tick [23] . Furthermore, studies in mice have demonstrated direct transmission of B. burgdorferi without a tick vector [24, 25], and recent epidemiologic and immunologic evidence suggests that transmission of the Lyme disease spirochete may occur by direct human contact [26, 27].
Despite the complexity of tick-borne diseases, numerous articles that address Lyme disease diagnosis and treatment provide a banal assessment of the Lyme disease nightmare [1, 4, 28, 29] . These articles generally present the gamut of half-truths about the disease, from misinformation about diagnosis to simplistic concepts of disease pathogenesis and politically charged views about the treatment of Lyme disease and its coinfections. Sadly, the banality of the articles reflects an entrenched and growing ignorance and neglect of the severity of Lyme disease, while its victims continue to suffer.
Drawing from Lyme disease articles published over the past decade [1, 4, 28, 29], we have selected representative excerpts that illustrate many misconceptions about tick-borne diseases, accompanied by appropriate commentary:
Fiction: `About 70-80%' of Lyme disease patients presence of Lyme disease. In fact, the clinical case rate present with a characteristic `bullseye' erythema migrans for Lyme disease may be as much as 40 times greater than (EM) rash.
Fact: According to recent health department statistics from Texas, Connecticut and California, only 35-59% of Lyme disease patients present with an EM rash, and the rate may be even lower depending on the location of the tick bite and the awareness of the person who was bitten [29, 30] . 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, 26]
Fiction: `Early Lyme disease is readily treatable with a 2- to 3-week course of antibiotics.'
Fact: 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 [30]. Second, recent studies have shown that tick saliva carries immunosuppressive substances that allow tickborne agents to invade tissues while paralyzing the local immune response [31, 32] . Thus the Lyme disease spirochete may rapidly disseminate and become entrenched and resistant early in the disease (see below) [33-35]. Third, coinfections may alter the course of `early Lyme disease', and these coinfections may make the Lyme disease patient more difficult to treat (see below).
Fiction: The Lyme enzyme-linked immunosorbent as say (ELISA) is the `preferred method' to diagnose Lyme disease due to its `sensitivity, adaptability to automation and ease of quantitation'.
Fact: The Lyme ELISA consistently misses at least 50% of Lyme disease cases due to the insensitivity of the assay and variability with antibiotic treatment [5, 6, 29, 36]. It follows that the `two-tiered' testing system endorsed by the 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 [29, 30]. 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 symptom-atic patients whose clinical picture already suggests the the CDC surveillance case rate [37]. Thus, in contrast to standardized blood testing for human immunodeficiency virus, there is currently no sanctioned, standardized, con- sistent serologic test for Lyme disease in the United States [5, 6, 29, 30].
Fiction: B. burgdorferi can be `readily cultivated in vitro' using special culture medium.
Fact: This statement is also misleading. Although B. burgdorferi is easy to grow in vitro using laboratory strains, the organism is extremely difficult to culture from human blood or tissues, and virtually no clinical laboratory can perform this basic infectious disease test [38, 39] . 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. Because this organism cannot be grown in vitro, the diagnosis of syphilis (like Lyme disease) is supported by serologic 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' [40].
Fiction: Only motile forms of B. burgdorferi are `considered to be viable and capable of replicating'.
Fact: B. burgdorferi assumes different forms in different hosts [41-47]. 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 [41-45]. 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 recognize this pathogenic entity may fail to eradicate the infection, leading to chronic disease [46, 47].
Fiction: `To date, there is no evidence for the existence sound therapy. A more recent study of ultrashort course of any antibiotic-resistant strains of B. burgdorferi.'
Fact: Another misleading statement. B. burgdorferi is an extremely complex organism. With more than 1,500 gene sequences, the Lyme disease spirochete contains at least 132 functioning genes, in contrast to T. pallidum, the spirochete that causes syphilis, which contains only con22 such genes [48, 49]. Furthermore, the Lyme disease spirochete contains 21 plasmids (9 circular and 12 linear) [49]. This is by far the largest number of plasmids found in any known bacterium, and one of the plasmids is known to produce a functional complement resistance protein [49, 50]. Recent studies have shown that B. burgdorferi adapts to diverse environments in the tick and mammalian host by selective gene expression, and that several plasmid genes play a `critical role' in immune evasion [50-52] . The combination of intracellular localization, genetic complexity, immune evasion and autoregulation makes the Lyme disease spirochete a formidable infectious agent [53].
Fiction: `It is unclear whether a concurrent Anaplasma or Babesia infection can influence the outcome of a standard course of treatment for Lyme disease.'
Fact: Animal models of coinfection 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 [54-56]. Similar exacerbation of clinical symptoms and resistance to treatment has been observed in humans [17, 57, 58] . Although Babesia, Anaplasma and Bartonella species were originally thought to produce only acute infection in their hosts, recent studies have demonstrated chronic infection with these organisms in both animals and humans [59-63]. It follows that persistent coinfection with tick-borne agents may enhance the chronicity of B. burgdorferi infection.
Fiction: A single dose of doxycycline given within 72 h after a recognizable tick bite was `highly effective in preventing early Lyme disease' .
Fact: The study that showed the alleged benefit of prophylactic single-dose doxycycline had inadequate follow-up (6 weeks) to prove the absence of clinical infection following this simple treatment [64]. Furthermore, the authors used development of an EM rash as an endpoint 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 receiving single-dose prophylaxis. The use of single-dose doxycycline also raises concern about antibiotic resistance following this microbiologically unsound therapy. A more recent study of ultrashort course doxycycline therapy (10 days) for early Lyme disease had signifi cant design flaws and showed efficacy in less than 50% of patients [65, 66].
Fiction: A `highly significant' study by Klempner et al. [67] examined retreatment of Lyme disease patients who had persistent symptoms of the disease. The study cluded that `it is unlikely that prolonged antibiotic treatment will offer any major benefit to symptomatic patients who are no longer infectious'.
Fact: The highly flawed study by Klempner et al. [67] has been analyzed in detail elsewhere [68, 69] . 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 the design of the study by Klempner et al. was basically flawed because the culture and molecular techniques used in the study were insufficient to prove that patients were `no longer infectious' [69] . Furthermore, the choice of `pro longed' antibiotic therapy for patients with neurologic disease (1 month of intravenous ceftriaxone followed by 2 months of low-dose oral doxycycline) was irrational and doomed to failure [68, 69] . Consequently, the study simply showed that inadequate retreatment of chronic Lyme disease leads to inadequate results [69]. Unfortunately, because of the widespread publicity given to this article and its prestigious publisher, the flawed data have been widely used to deny care for symptomatic patients with chronic Lyme disease. As mentioned previously, numerous studies have found evidence of persistent spirochetal infection in animals and humans with chronic Lyme disease [7-14, 70, 71].
Fiction: 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 coinfected 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'.
Fact: This politically charged statement features two issues that define the `Lyme Wars'. The first issue concerns the `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 [26, 29]. Many of the IDSA recommendations for diagnosis and treatment of Lyme disease are contingent on the weakest Category III evidence, which derives `from opinions of respected authorities that is based on clinical experience, descriptive studies, or reports of expert committees' [72]. These guidelines do not conform to minimal standards of evidence-based medicine, and they have doomed thousands of suffering Lyme disease patients to lack of therapy based on the opinions of a handful of `academic specialists'. With this background, it is logical that `community-based' providers who deal with the clinical nightmare of Lyme disease have rejected the CDC/IDSA guidelines and formulated their own diagnostic and therapeutic parameters [69, 73-75].
The second politically charged issue is reflected in statement that Lyme disease treatment outside the CDC/ Organization 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 suffering Lyme disease patients other than pseudopsychiatric semantics [4, 26] or meaningless labels such as `chronic fatigue syndrome' or `fi bromyalgia', which are often manifestations of chronic, poorly treated Lyme disease [76, 77]. As for the `alarming' number of Lyme disease patients who are `supposedly' coinfected with other tick-borne organisms, studies have shown coinfection in 20% or more of Lyme disease cases [19, 21, 29, 30], confirming the risk of polymicrobial infection in chronic Lyme disease.
Fiction: The Lyme disease vaccine was withdrawn due to `lack of public interest'.
Fact: The GlaxoSmithKline Lyme vaccine (Lymerix�) was withdrawn in the face of a class action lawsuit involving over 300 patients who claim that they developed a `Lyme-like' illness after receiving the parenteral vaccine [78]. A more attractive immunization strategy is based on a mucosal vaccine that targets B. burgdorferi antigens or associated tick salivary proteins [78, 79]. This form of prophylactic therapy has yet to be tested in clinical trials.
Fiction: `Future treatment options' for Lyme disease include hyperbaric oxygen therapy (HBOT), shorter course treatment with antibiotics, and evernimicin therapy [28].
Fact: HBOT is currently being used as adjunctive treatment for chronic Lyme disease [29]. 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 hepatic toxic- ity of evernimicin makes it doubtful that this risky antibiotic will ever be marketed for Lyme disease. Shorter course antibiotic therapy was the subject of a recent study 65], and this minimalist approach promises to yield more inadequately treated Lyme disease sufferers [66]. In contrast to these impractical or dangerous treatment options, current and future Lyme disease therapy should focus on combinations of antibiotics that are effective against spirochetes, readily available and administered in a rational manner, with monitoring of clinical and immunologic parameters [69, 80-86] . In this regard, the it is important to remember that the current World Health (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 [87-89] . For disseminated infection with nontuberculous mycobacteria such as M. chelonae, treatment may involve a combination of oral and intravenous antibiotics administered for 6-12 months [90] . In the case of Q fever endocarditis caused by another tick-borne infectious agent, Coxiella burnetii, the recommended treatment is a combination of two antibiotics administered for 3 years; even with prolonged antimicrobial therapy, the relapse rate in this disease is approximately 15% [91] . For a spirochete as complex and crafty as B. burgdorferi, these therapeutic guidelines are probably closer to what is needed for the eradication of chronic spirochetal infection in Lyme disease [75, 92] . As stated previously, recognition and evaluation of human transmission of Lyme disease will also play a role in developing effective treatment strategies for the disease [26, 27].
In conclusion, Lyme disease remains a public health threat of major proportions. The trivialization of spirochetal illness by various authors only serves to augment this threat by legitimizing 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 from a medicolegal standpoint [92]. 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.
Acknowledgments
The authors thank Drs. Robert Bransfi eld, Kathleen Dickson, David Dorward, Brian Fallon, Andrea Gaito, Julie Gerberding,
References
1 Steere AC, Taylor E, McHugh GL, Logigian EL: The overdiagnosis of Lyme disease. JAMA 1993;269:1812-1816.
2 Burrascano JJ: The overdiagnosis of Lyme dis ease. JAMA 1993;270:2682.
3 Meek JI, Roberts CL, Smith EV, Cartter ML: Underreporting of Lyme disease by Connecti cut physicians, 1992. J Public Health Manag Pract 1996;2:61-65.
4 Lautin A, McNeil EL, Liegner KB, Stricker RB; Sigal LH: Lyme disease controversy: use and misuse of language. Ann Intern Med 2002; 137:775-777.
5 Bakken LK, Case KL, Callister SM, Bourdeau NJ, Schell RF: Performance of 45 laboratories participating in a proficiency testing program for Lyme disease serology. JAMA 1992;268: 891-895.
6 Brown SL, Hanson SL, Langone JJ: Role of serology in the diagnosis of Lyme disease. JAMA 1999;282:62-66.
7 Montgomery RR, Nathanson MH, Malawista SE: The fate of Borrelia burgdorferi, the agent for Lyme disease, in mouse macrophages. De struction, survival, recovery. J Immunol 1993; 150:909-915.
8 Bockenstedt LK, Mao J, Hodzic E, Barthold SW, Fish D: Detection of attenuated, noninfec tious spirochetes in Borrelia burgdorferi-infect ed mice after antibiotic treatment. J Infect Dis 2002;186:1430-1437.
Lyme Disease
Nick Harris, William Harvey, Barbara Johnson, Anne Kjemtrup, Robert Lane, Kenneth Liegner, Robert Lull, Daniel Moore, Scott Morrow, Steven Phillips, Walter Prehn, Ginger Savely, 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, Lorraine Johnson, Lee Lull, Peggy Leonard and Barb Barsocchini of the California Lyme Disease Association, and Karen Forschner of the Lyme Disease Foundation for continuing support. This article is dedicated to the memory of Dr. Paul Lavoie.
9 Straubinger RK, Summers BA, Chang YF, Ap-15 Stricker RB: Lyme disease: A potential polymipel MJ: Persistence of Borrelia burgdorferi in crobial infection. ASM News 2003;69:265. experimentally infected dogs after antibiotic 16 Benach JL, Coleman JL, Habicht GS, Mac- treatment. J Clin Microbiol 1997;35:111- Donald A, Grunwaldt E, Giron JA: Serological
116. evidence for simultaneous occurrences of 10 Straubinger RK: PCR-based quantifi cation of Lyme disease and babesiosis. J Infect Dis 1985; Borrelia burgdorferi organisms in canine tis-152:473-477. sues over a 500-day postinfection period. J 17 Marcus LC, Steere AC, Duray PH, Anderson Clin Microbiol 2000;38:2191-2199. AE, Mahoney EB: Fatal pancarditis in a pa
11 Cadavid D, O'Neill T, Schaefer H, Pachner tient with coexistent Lyme disease and babe- AR: Localization of Borrelia burgdorferi in the siosis. Demonstration of spirochetes in the nervous system and other organs in a nonhu-myocardium. Ann Intern Med 1985;103:374- man primate model of Lyme disease. Lab In-376. vest 2000;80:1043-1054. 18 Nadelman RB, Horowitz HW, Hsieh TC, Wu
12 Preac-Mursic V, Weber K, Pfister HW, Wilske JM, Aguero-Rosenfeld ME, Schwartz I, Nowa- B, Gross B, Baumann A, Prokop J: Survival of kowski J, Varde S, Wormser GP: Simultaneous Borrelia burgdorferi in antibiotically treated human granulocytic ehrlichiosis and Lyme patients with Lyme borreliosis. Infection 1989; borreliosis. N Engl J Med 1997;337:27-30. 17:355-359. 19 DeMartino SJ, Carlyon JA, Fikrig E: Coinfec
13 Frey M, Jaulhac B, Piemont Y, Marcellin L, tions with Borrelia burgdorferi and the agent of Boohs PM, Vautravers P, Jesel M, Kuntz JL, human granulocytic ehrlichiosis. N Engl J Med Monteil H, Sibilia J: Detection of Borrelia 2001;345:150-151. burgdorferi DNA in muscle of patients with 20 Krause PJ, McKay K, Thompson CA, Sikand chronic myalgia related to Lyme disease. Am J VK, Lentz R, Lepore T, Closter L, Christian- Med 1998;104:591-594. son D, Telford SR, Persing D, Radolf JD,
14 Oksi J, Marjamaki M, Nikoskelainen J, et al: Spielman A: Disease-specific diagnosis of coin- Borrelia burgdorferi detected by culture and fecting tickborne zoonoses: babesiosis, human PCR in clinical relapse of disseminated Lyme granulocytic ehrlichiosis, and Lyme disease. borreliosis. Ann Med 1999;31:225-232. Clin Infect Dis 2002;34:1184-1191.
Chemotherapy 933 5
CHE933.indd 5 16.08.2005 15:01:42
21 Stricker RB, Harris NS, Yong DC, Winger EE: 36 Ekerfelt C, Ernerudh J, Forsberg P, Jonsson Clinical and seroepidemiologic characteristics AL, Vrethem M, Arlehag L, Forsum U: Lyme of Babesia WA-1 coinfection in patients with borreliosis in Sweden - diagnostic perfor- Lyme disease in California. J Invest Med 2003; mance of five commercial Borrelia serology 51(suppl 1):S145. kits using sera from well-defi ned patient
22 Eskow E, Rao RV, Mordechai E: Concurrent groups. APMIS 2004;112:74-78. infection of the central nervous system by Bor-37 Boltri JM, Hash RB, Vogel RL: Patterns of relia burgdorferi and Bartonella henselae: evi-Lyme disease diagnosis and treatment by famdence for a novel tick-borne disease complex. ily physicians in a southeastern state. J Com- Arch Neurol 2001;58:1357-1363. munity Health 2002;27:395-402.
23 Holden K, Boothby JT, Anand S, Massung RF: 38 Zore A, Ruzic-Sabljic E, Maraspin V, Cimper- Detection of Borrelia burgdorferi, Ehrlichia man J, Lotric-Furlan S, Pikelj A, Jurca T, Logchafeensis, and Anaplasma phagocytophilum ar M, Strle F: Sensitivity of culture and poly- in ticks (Acari: Ixodidae) from a coastal region merase chain reaction for the etiologic of California. J Med Entomol 2003;40:534- diagnosis of erythema migrans. Wien Klin
539. Wochenschr 2002;114:606-609. 24 Burgess EC, Amundson TE, Davis JP, Kaslow 39 Liveris D, Wang G, Girao G, Byrne DW, RA, Edelman R: Experimental inoculation of Nowakowski J, McKenna D, Nadelman R, Peromyscus spp. with Borrelia burgdorferi: ev-Wormser GP, Schwartz I: Quantitative detecidence of contact transmission. Am J Trop tion of Borrelia burgdorferi in 2-millimeter Med Hyg 1986;35:355-359. skin samples of erythema migrans lesions: cor
25 Wright SD, Nielsen SW: Experimental infec-relation of results with clinical and laboratory tion of the white-footed mouse with Borrelia findings. J Clin Microbiol 2002;40:1249- burgdorferi. Am J Vet Res 1990;51:1980- 1253. 1987. 40 Hicks CB: Confronting the clinical uncertainty
26 Harvey WT, Salvato P: `Lyme disease': ancient regarding syphilis. AIDS Clin Care 2003;15: engine of an unrecognized borreliosis pandem-64-65. ic? Med Hypotheses 2003;60:742-759. 41 Bruck DK, Talbot ML, Cluss RG, Boothby JT:
27 Stricker RB, Moore DH, Winger EE: Clinical Ultrastructural characterization of the stages and immunologic evidence for transmission of of spheroplast preparation of Borrelia burgdor- Lyme disease through intimate human con-feri. J Microbiol Methods 1995;23:219-228. tact. J Invest Med 2004;52:S151. 42 Preac-Mursic V, Wanner G, Reinhardt S, Wil
28 Pavia CS: Current and novel therapies for ske B, Busch U, Marget W: Formation and cul- Lyme disease. Expert Opin Investig Drugs tivation of Borrelia burgdorferi spheroplast L2003;12:1003-1016. form variants. Infection 1996;24:218-226.
49 Casjens S, Palmer N, van Vugt R, Huang WM, Stevenson B, Rosa P, Lathigra R, Sutton G, Peterson J, Dodson RJ, Haft D, Hickey E, Gwinn M, White O, Fraser CM: A bacterial genome in flux: the twelve linear and nine circular extrachromosomal DNAs in an infectious isolate of the Lyme disease spirochete Borrelia burgdorferi. Mol Microbiol 2000;35: 490-516.
50 Kraiczy P, Hellwage J, Skerka C, Becker H, Kirschfink M, Simon MM, Brade V, Zipfel PF, Wallich R: Complement resistance of Borrelia burgdorferi correlates with expression of BbCRASP-1, a novel linear plasmid-encoded surface protein that interacts with human factor H and FHL-1 and is unrelated to Erp proteins. J Biol Chem 2004;279:2421-2429.
51 Liang FT, Brown EL, Wang T, Iozzo RV, Fikrig E: Protective niche for Borrelia burgdorferi to evade humoral immunity. Am J Pathol
29 Doherty A: Lots of Links on Lyme Disease 2004.
6
2004;165:977-985.
52 Liang FT, Yan J, Mbow ML, Sviat SL, Gilmore RD, Mamula M, Fikrig E: Borrelia burgdorferi changes its surface antigenic expression in response to host immune responses. Infect Immun 2004;72:5759-5767.
53 Embers ME, Ramamoorthy R, Philipp MT: Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease. Microbes Infect 2004;6:312-318.
54 Thomas V, Anguita J, Barthold SW, Fikrig E: Coinfection with Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis alters murine immune responses, pathogen burden, and severity of Lyme arthritis. Infect Immun
43 Alban PS, Johnson PW, Nelson DR: Serum-2001;69:3359-3371. www.geocities.com/HotSprings/Oasis/ starvation-induced changes in protein synthe-55 Zeidner NS, Dolan MC, Massung R, Piesman 6455/lyme-links.html (February 1, 2005). sis and morphology of Borrelia burgdorferi. Mi-J, Fish D: Coinfection with Borrelia burgdor
30 Stricker RB, Phillips SE: Lyme disease without crobiology 2000;146:119-127. feri and the agent of human granulocytic erythema migrans: cause for concern? Am J 44 Brorson O, Brorson SH: A rapid method for ehrlichiosis suppresses IL-2 and IFN gamma Med 2003;115:72. generating cystic forms of Borrelia burgdorferi, production and promotes an IL-4 response in
31 Schoeler GB, Wikel SK: Modulation of host and their reversal to mobile spirochetes. AP-C3H/HeJ mice. Parasite Immunol 2000;22: immunity by haematophagous arthropods. MIS 1998;106:1131-1141. 581-588. Ann Trop Med Parasitol 2001;95:755-771. 45 Brorson O, Brorson SH: An in vitro study of 56 Moro MH, Zegarra-Moro OL, Bjornsson J,
32 Hannier S, Liversidge J, Sternberg JM, Bow-the susceptibility of mobile and cystic forms of Hofmeister EK, Bruinsma E, Germer JJ, Persman AS: Ixodes ricinus tick salivary gland ex-Borrelia burgdorferi to metronidazole. APMIS ing DH: Increased arthritis severity in mice tract inhibits IL-10 secretion and CD69 ex-1999;107:566-576. coinfected with Borrelia burgdorferi and Babepression by mitogen-stimulated murine 46 Kersten A, Poitschek C, Rauch S, Aberer E: sia microti. J Infect Dis 2002;186:428-431. splenocytes and induces hyporesponsiveness Effects of penicillin, ceftriaxone, and doxycy-57 Krause PJ, Telford SR 3rd, Spielman A, Si- in B lymphocytes. Parasite Immunol 2003;25: cline on the morphology of Borrelia burgdor-kand V, Ryan R, Christianson D, Burke G, 27-37. feri. Antimicrob Agents Chemother 1995;39: Brassard P, Pollack R, Peck J, Persing DH:
33 Rhen M, Eriksson S, Clements M, Bergstrom 1127-1133. Concurrent Lyme disease and babesiosis. Evi- S, Normark SJ: The basis of persistent bacte-47 Aberer E, Koszik F, Silberer M: Why is chron-dence for increased severity and duration of rial infections. Trends Microbiol 2003;11:80- ic Lyme borreliosis chronic? Clin Infect Dis illness. JAMA 1996;275:1657-1660.
86. 1997;25(suppl 1):S64-S70. 58 Oleson CV, Sivalingam JJ, O'Neill BJ, Staas 34 Liang FT, Jacobs MB, Bowers LC, Philipp MT: 48 Porcella SF, Schwan TG: Borrelia burgdorferi WE: Transverse myelitis secondary to coexis- An immune evasion mechanism for spirochet-and Treponema pallidum: a comparison of tent Lyme disease and babesiosis. J Spinal al persistence in Lyme borreliosis. J Exp Med functional genomics, environmental adapta-Cord Med 2003;26:168-171. 2002;195:415-422. tions, and pathogenic mechanisms. J Clin In-59 Krause PJ, Spielman A, Telford SR, Sikand
35 Guner ES: Complement evasion by the Lyme vest 2001;107:651-656. VK, McKay K, Christianson D, Pollack RJ, disease spirochete Borrelia burgdorferi grown Brassard P, Magera J, Ryan R, Persing DH: in host-derived tissue co-cultures: role of fi bro-Persistent parasitemia after acute babesiosis. nectin in complement-resistance. Experientia N Engl J Med 1998;339:160-165. 1996;52:364-372. 60 Allred DR: Babesiosis: persistence in the face
of adversity. Trends Parasitol 2003;19:51-55.
Chemotherapy 933 Stricker/Lautin/Burrascano
CHE933.indd 6 16.08.2005 15:01:42
61 Harrus S, Waner T, Aizenberg I, Foley JE, Po-71 Nocton JJ, Bloom BJ, Rutledge BJ, Persing land AM, Bark H: Amplification of ehrlichial DH, Logigian EL, Schmid CH, Steere AC: De- DNA from dogs 34 months after infection with tection of Borrelia burgdorferi DNA by poly- Ehrlichia canis. J Clin Microbiol 1998;36:73- merase chain reaction in cerebrospinal fl uid in
76. patients with Lyme neuroborreliosis. J Infect 62 Dumler JS, Bakken JS: Human granulocytic Dis 1996;174:623-627. ehrlichiosis in Wisconsin and Minnesota: a fre-72 Wormser GP, Nadelman RB, Dattwyler RJ, quent infection with the potential for persis-Dennis DT, Shapiro ED, Steere AC, Rush TJ, tence. J Infect Dis 1996;173:1027-1030. Rahn DW, Coyle PK, Persing DH, Fish D,
63 Chomel BB, Kasten RW, Sykes JE, Boulouis Luft BJ: Practice guidelines for the treatment HJ, Breitschwerdt EB: Clinical impact of per-of Lyme disease. The Infectious Diseases Socisistent Bartonella bacteremia in humans and ety of America. Clin Infect Dis 2000;31(suppl animals. Ann NY Acad Sci 2003;990:267- 1):1-14.
278. 73 Burrascano JJ: Lyme disease; in Conn's Cur 64 Nadelman RB, Wormser GP: Single-dose dox-rent Therapy. Philadelphia, Saunders, 1997, ycycline for the prevention of Lyme disease. N pp 140-143. Engl J Med 2001;345:1349-1350. 74 Liegner KB, Kochevar J: Guidelines for the
65 Wormser GP, Ramanathan R, Nowakowski J, clinical diagnosis of Lyme disease. Ann Intern McKenna D, Holmgren D, Visintainer P, Med 1998;129:422-423. Dornbush R, Singh B, Nadelman RB: Dura-75 The ILADS Working Group: Evidence-based tion of antibiotic therapy for early lyme dis-guidelines for the management of Lyme disease. A randomized, double-blind, placebo-ease. Expert Rev Anti Infect Ther 2004;2:S1- controlled trial. Ann Intern Med 2003;138: S13. 697-704. 76 Lawrence C, Lipton RB, Lowy FD, Coyle PK:
66 Stricker RB, Gaito A, Harris NS, Burrascano Seronegative chronic relapsing neuroborrelio- JJ: Treatment of early Lyme disease. Ann In-sis. Eur Neurol 1995;35:113-117. tern Med 2004;140:577. 77 Fraser DD, Kong LI, Miller FW: Molecular de
67 Klempner MS, Hu LT, Evans J, Schmid CH, tection of persistent Borrelia burgdorferi in a Johnson GM, Trevino RP, Norton D, Levy L, man with dermatomyositis. Clin Exp Rheuma- Wall D, McCall J, Kosinski M, Weinstein A: tol 1992;10:387-390. Two controlled trials of antibiotic treatment in 78 Hanson MS, Edelman R: Progress and contropatients with persistent symptoms and a his-versy surrounding vaccines against Lyme dis- tory of Lyme disease. N Engl J Med 2001;345: ease. Expert Rev Vaccines 2003;2:683-703. 85-92. 79 Valenzuela JG: Exploring the messages of the
68 Bransfield R, Brand S, Sherr V: Treatment of salivary glands of Ixodes ricinus. Am J Trop
82 Hunfeld KP, Wichelhaus TA, Rodel R, Acker G, Brade V, Kraiczy P: Comparison of in vitro activities of ketolides, macrolides, and an azalide against the spirochete Borrelia burgdorferi. Antimicrob Agents Chemother 2004;48: 344-347.
83 Brorson O, Brorson SH: An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to tinidazole. Int Microbiol 2004;7:139-142.
84 Stricker RB, Winger EE: Decreased CD57 lymphocyte subset in patients with chronic Lyme disease. Immunol Lett 2001;76:43-48.
85 Stricker RB, Burrascano J, Winger EE: Long- term decrease in the CD57 lymphocyte subset in a patient with chronic Lyme disease. Ann Agric Environ Med 2002;9:111-113.
86 Stricker RB, Winger EE: Normalization of the CD57 natural killer cell subset associated with prolonged antibiotic therapy in patients with
patients with persistent symptoms and a his tory of Lyme disease. N Engl J Med 2001;345: 1424-1425.
69 Phillips SE, Bransfield R, Sherr VT, Brand S, Smith HA, Dickson K, Stricker RB: Evalua tion of antibiotic treatment in patients with persistent symptoms of Lyme disease: An ILADS position paper. http://www.ilads.org/ (February 1, 2005).
70 Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC: Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid in Lyme arthritis. N Engl J Med 1994;330:229-234.
87 Small PM, Fujiwara PI: Management of tuberculosis in the United States. N Engl J Med 2001;345:189-200.
88 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.
89 Goto M: Chemotherapy of leprosy: theoretical basis of new guideline in Japan. Nihon Hansenbyo Gakkai Zasshi 2001;70:151-155.
90 Wallace RJ Jr, Tanner D, Brennan PJ, Brown Med Hyg 2002;66:223-224. BA: Clinical trial of clarithromycin for cutane
80 Korting HC, Walther D, Riethmuller U, Meu-ous (disseminated) infection due to Mycobacrer M: Comparative in vitro susceptibility of terium chelonae. Ann Intern Med 1993;119: Treponema pallidum to ceftizoxime, ceftriax-482-486. one and penicillin G. Chemotherapy 1986;32: 91 Rolain JM, Mallet MN, Raoult D: Correlation 352-355. between serum doxycycline concentrations
81 Korting HC, Haag R, Walter D, Riethmuller and serologic evolution in patients with Coxi- U, Meurer M: Efficacy of ceftizoxime in the ella burnetii endocarditis. J Infect Dis 2003; treatment of incubating syphilis in rabbits. 188:1322-1325. Chemotherapy 1993;39:331-335. 92 Johnson L, Stricker RB: Treatment of Lyme
disease: a medicolegal assessment. Expert Rev Anti Infect Ther 2004;2:533-557.
Chemotherapy 933 7
CHE933.indd 7 16.08.2005 15:01:43
Posts: 449 | From Pasadena, CA, usa | Registered: Aug 2005
| IP: Logged |
posted
This is good information and needs to be bumped to the top.
Posts: 499 | From Western NY | Registered: Dec 2000
| IP: Logged |
Dave6002
Frequent Contributor (1K+ posts)
Member # 9064
posted
Thanks, Squeegee and others, for the fulltext.
Wondering if the authors of the new guideline have read this article (they should have)and how could they deny these powerful facts presented in this article, unless the guideline is a political guideline not a scientific guideline.
I noticed that the fulltext was published in 2004, while the newer version was in Sept 2006. I guess the newer version may have a great deal of revisions and would like to read it.
Posts: 1078 | From Fairland | Registered: Apr 2006
| IP: Logged |
Truthfinder
Frequent Contributor (1K+ posts)
Member # 8512
posted
Thanks for posting this, but I can't read this copy. The other post was easier to read - maybe somebody broke up the paragraphs first?
Very interesting info about the "sanctioned" long-term abx therapies for OTHER diseases, but not for Lyme. No siree, can't have that, now can we.
I don't suppose there is a public link to this article?
Tracy
-------------------- Tracy .... Prayers for the Lyme Community - every day at 6 p.m. Pacific Time and 9 p.m. Eastern Time � just take a few moments to say a prayer wherever you are�. Posts: 2966 | From Colorado | Registered: Dec 2005
| IP: Logged |
posted
I posted the original full text and yes, I had broken it up when I copied it and saved it to my hard drive. (I have a very hard time reading big blocks of text, too).
I don't have a link to it -- can't remember where I found it. It's just in my archive of Lyme articles so I thought I'd post it.
Posts: 105 | From CA | Registered: Apr 2005
| IP: Logged |
bettyg
Unregistered
posted
do a search for this; i did in the wee morning hrs. for david i think was his name shown bringing this up today.
it shows both versions...type in the name of the title in medical, topic line only, leave everythign else blank; there were 4 things that come up when i did this earlier today!
IP: Logged |
The Lyme Disease Network is a non-profit organization funded by individual donations. If you would like to support the Network and the LymeNet system of Web services, please send your donations to:
The
Lyme Disease Network of New Jersey 907 Pebble Creek Court,
Pennington,
NJ08534USA http://www.lymenet.org/
UBBFriend: Email this page to someone!
Printer-friendly view of this topic