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Lyme disease

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Lyme disease
Classifications and external resources
Nymphal and adult deer ticks can be carriers of Lyme disease. Nymphs are about the size of a poppy seed.
ICD-10 A69.2
ICD-9 088.81
DiseasesDB 1531
MedlinePlus 001319
eMedicine med/1346 

Lyme disease or Lyme borreliosis is the most common tick-borne disease in North America and Europe, and the second fastest-growing infectious disease in the United States after AIDS.<ref name=Funds>"Fighting the competition for funds to fight Lyme disease", The New York Times, 1990-03-25. Retrieved on 2006-11-19.</ref> It is named after the town of Old Lyme, Connecticut where a cluster of cases was identified in 1975, although clinical features of the disease had been described in Europe as early as 1909.<ref name=Sternbach>Sternbach G, Dibble C. "Willy Burgdorfer: Lyme disease.". J Emerg Med 14 (5): 631-4. PMID 8933327.</ref> Lyme disease has now been reported in 49 of 50 states in the U.S, and on every continent except Antarctica. The cause of Lyme disease is a bacterial infection with a spirochete from the species complex Borrelia burgdorferi sensu lato, which is most often acquired from the bite of an infected Ixodes tick. Borrelia burgdorferi was first identified in 1982 by Willy Burgdorfer, a tick-borne disease expert at Rocky Mountain Labs in Hamilton, Montana. While Borrelia burgdorferi sensu stricto is the predominant cause in the U.S., Lyme disease in Europe is more often caused by Borrelia afzelii or Borrelia garinii.

The disease varies widely in its presentation, which may include a rash and flu-like symptoms in its initial stage, followed by musculoskeletal, arthritic, neurologic, psychiatric and/or cardiac manifestations. Early detection and prompt antibiotic treatment most often result in an excellent prognosis. However early detection is difficult when the characteristic rash is not present, and even those who are diagnosed and treated early may remain symptomatic.<ref name="Nowakowski">Nowakowski J, Nadelman R, Sell R, McKenna D, Cavaliere L, Holmgren D, Gaidici A, Wormser G (2003). "Long-term follow-up of patients with culture-confirmed Lyme disease.". Am J Med 115 (2): 91-6. PMID 12893393.</ref>

Delayed or inadequate treatment may often lead to a chronic illness that is disabling and difficult to treat. Amid great controversy over diagnosis, testing and treatment, two different standards of care for Lyme disease have emerged.<ref name="Johnson-a">Johnson, Lorraine (2005-02). Lyme disease: two standards of care. International Lyme and Associated Diseases Society. Retrieved on 2006-11-17.</ref><ref name="Johnson-b">Johnson L, Stricker R (2004). "Treatment of Lyme disease: a medicolegal assessment.". Expert Rev Anti Infect Ther 2 (4): 533-57. PMID 15482219.</ref>

Contents

[edit] Symptoms

Lyme disease has many signs and symptoms, but skin signs, arthritis and/or various neurological symptoms are often present. Like syphilis, the symptoms frequently seem to resolve, yet the disease progresses. Conventional therapy is with antibiotics. People who suspect they have been exposed to Lyme disease should consult a doctor with knowledge of the disease immediately.

[edit] Acute (early) symptoms that may occur

Image:Lymebite.png

Erythema migrans rash (EM) - Contrary to popular belief, the characteristic "bull's-eye" rash with central clearing is not the most common form. Rashes that are homogeneously red are seen more frequently.<ref name="Smith">Smith RP, Schoen RT, Rahn DW, Sikand VK, Nowakowski J, Parenti DL, Holman MS, Persing DH, Steere AC (2002). "Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans" (PDF). Ann Intern Med 136 (6): 421-8. PMID 11900494.</ref><ref name="Edlow">Edlow JA (2002). "Erythema migrans". Med Clin North Am 86 (2): 239-60. PMID 11982300.</ref> Multiple painless EM rashes may occur, indicating disseminated infection. The true incidence of the rash is disputed, with estimates ranging from less than 50%<ref name="Donta-c">Donta ST (2002). "Late and chronic Lyme disease". Med Clin North Am 86 (2): 341-9, vii. PMID 11982305.</ref><ref name="ILADS">Cameron D, Gaito A, Narris N, Bach G, Bellovin S, Bock K, Bock S, Burrascano J, Dickey C, Horowitz R, Phillips S, Meer-Scherrer L, Raxlen B, Sherr V, Smith H, Smith P, Stricker R; ILADS Working Group (2004). "Evidence-based guidelines for the management of Lyme disease". Expert Rev Anti Infect Ther 2 ((1 Suppl)): S1-13. PMID 15581390.</ref> to over 80% of those infected. The symptoms of Lyme disease are fever, malaise, fatigue, headache, muscle and joint aches in large joints, sore throat, sinus infection

Other consequences, include facial paralysis - usually associated with Lyme meningitis or Rocky Mountain spotted fever, palpitations, kidney and intestinal pains.

The incubation period from infection to the onset of symptoms is usually 1–2 weeks, but can be much shorter (a couple of days), or even as long as one month.

[edit] Chronic (late) symptoms

The late symptoms of Lyme disease can appear months after infection.

Lyme disease may be misdiagnosed as multiple sclerosis, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome (CFS), or other (mainly autoimmune and neurological) diseases, which leaves the infection untreated and allows it to further penetrate the organism. Some of these conditions may be misdiagnosed as Lyme disease, although this is thought to be a rare occurrence. False positive Lyme diagnosis is most commonly due to false positive serology in a subset of patients who may suffer from syphillis, rheumatologic diseases, or infectious mononucleosis. More confounding is that patients may present with Lyme Disease and a related disease such as MS. This makes diagnosis exceptionally difficult. It should be noted that this kind of misdiagnosis is the exception rather than the rule as it is widely held that Lyme Disease is underdiagnosed and underreported ranging from factors of 10 to upwards of 40. It is important to remember that chronic fatigue syndrome (CFS) is by definition a diagnosis of exclusion, meaning it would be inaccurate to say that a patient does not have Lyme because he or she has CFS. The substantial overlap in symptomatology between Lyme and CFS makes this a crucial point.<ref name="Donta-c" />

[edit] Transmission

[edit] Transmission by ticks

Hard-bodied (Ixodes) ticks are the primary Lyme disease vectors. In Europe, Ixodes ricinus, known commonly as the sheep tick, castor bean tick, or European castor bean tick is the transmitter. In North America, Ixodes scapularis (black-legged tick or deer tick) has been identified as the key to the disease's spread on the east coast, while on the west coast the primary vector is Ixodes pacificus (Western black-legged tick). Another possible vector is Amblyomma americanum (Lone Star tick),<ref name="Clark">Clark K (2004). "Borrelia species in host-seeking ticks and small mammals in northern Florida." (PDF). J Clin Microbiol 42 (11): 5076-86. PMID 15528699.</ref> which is found throughout the southeastern U.S. as far west as Texas, and increasingly in northeastern states as well.

The longer the duration of tick attachment, the greater the risk of disease transmission, but, typically, for the spirochete to be transferred, the tick must be attached for a minimum of 12 hours, although, only the first part of this statement can be said to be strictly correct. (see Proper Removal of Ticks). Unfortunately only 20% of persons infected with Lyme by the deer tick are aware of any tick bite,<ref name="Wormser">Wormser G, Masters E, Nowakowski J, McKenna D, Holmgren D, Ma K, Ihde L, Cavaliere L, Nadelman R (2005). "Prospective clinical evaluation of patients from missouri and new york with erythema migrans-like skin lesions.". Clin Infect Dis 41 (7): 958-65. PMID 16142659.</ref> making early detection difficult in the absence of a rash. Tick bites usually go unnoticed due to the small size of the tick in its nymphal stage, as well as tick secretions that prevent the host from feeling any itch or pain from the bite. New research suggests that transmission can occur within a few hours of tick attachment, and that the rate of transmission by infected ticks may be much higher than previously assumed.

[edit] Congenital Lyme disease

Lyme disease can be transmitted from an infected mother to fetus through the placenta during pregnancy, possibly resulting in stillbirth.<ref name="MacDonald">MacDonald AB (1989). "Gestational Lyme borreliosis. Implications for the fetus" (PDF). Rheum Dis Clin North Am 15 (4): 657-77. PMID 2685924.</ref><ref name="Schlesinger">Schlesinger PA, Duray PH, Burke BA, Steere AC, Stillman MT (1985). "Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi". Ann Intern Med 103 (1): 67-8. PMID 4003991.</ref> The risk of transmission is minimized if the mother receives prompt antibiotic treatment, though physicians disagree as to the duration of treatment required.

[edit] Other modes of transmission

There is at least one case report of transmission by a biting fly.<ref name="Luger">Luger S (1990). "Lyme disease transmitted by a biting fly." (html). N Engl J Med 322 (24): 1752. PMID 2342543.</ref> Lyme spirochetes have been found in biting flies as well as mosquitos.<ref name="Magnarelli">Magnarelli L, Anderson J (1988). "Ticks and biting insects infected with the etiologic agent of Lyme disease, Borrelia burgdorferi." (PDF). J Clin Microbiol 26 (8): 1482-6. PMID 3170711.</ref> Some researchers believe biting insects do not feed long enough to transmit the infection, while others including Borrelia burgdorferi discoverer Willy Burgdorfer believe more research is needed.<ref name="Burgdorfer">Burgdorfer W (1998). "Increased evidence of mosquito/spirochete associations." (html). 11th International Scientific Conference on Lyme Disease, 1998.</ref> There is also some anecdotal, largely unconfirmed evidence of sexual transmission. Lyme spirochetes have been found in semen<ref name="Bach">Bach G (2001). "Recovery of Lyme spirochetes by PCR in semen samples of previously diagnosed Lyme disease patients." (html). 14th International Scientific Conference on Lyme Disease, 2001.</ref> and breast milk,<ref name="Schmidt">Schmidt B, Aberer E, Stockenhuber C, Klade H, Breier F, Luger A (1995). "Detection of Borrelia burgdorferi DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis.". Diagn Microbiol Infect Dis 21 (3): 121-8. PMID 7648832.</ref> though transmission by these routes has yet to be proven.

[edit] Microbiology

[edit] Strains

Lyme disease is caused by spirochetal bacteria from the genus Borrelia, which has well over three hundred known genomic strains. The Borrelia species known to cause Lyme disease are collectively known as Borrelia burgdorferi sensu lato, and have been found to have greater strain diversity than previously estimated.<ref name="Bunikis-a">Bunikis J, Garpmo U, Tsao J, Berglund J, Fish D, Barbour AG (2004). "Sequence typing reveals extensive strain diversity of the Lyme borreliosis agents Borrelia burgdorferi in North America and Borrelia afzelii in Europe" (PDF). Microbiology 150 (Pt 6): 1741-55. PMID 15184561.</ref> Until recently it was thought that only three genospecies caused Lyme disease: B. burgdorferi sensu stricto (predominant in North America, but also in Europe), B. afzelii, and B. garinii (both predominant in Eurasia). However, newly discovered genospecies have also been found to cause disease in humans: B. lusitaniae<ref name="Collares">Collares-Pereira M, Couceiro S, Franca I, Kurtenbach K, Schafer SM, Vitorino L, Goncalves L, Baptista S, Vieira ML, Cunha C (2004). "First isolation of Borrelia lusitaniae from a human patient" (PDF). J Clin Microbiol 42 (3): 1316-8. PMID 15004107.</ref> in Europe (especially Portugal), North Africa and Asia, B. bissettii<ref name="Postic">Postic D, Ras NM, Lane RS, Hendson M, Baranton G (1998). "Expanded diversity among Californian borrelia isolates and description of Borrelia bissettii sp. nov. (formerly Borrelia group DN127)" (PDF). J Clin Microbiol 36 (12): 3497-504. PMID 9817861.</ref><ref name="Maraspin">Maraspin V, Cimperman J, Lotric-Furlan S, Ruzic-Sabljic E, Jurca T, Picken RN, Strle F (2002). "Solitary borrelial lymphocytoma in adult patients". Wien Klin Wochenschr 114 (13-14): 515-23. PMID 12422593.</ref> in the U.S. and Europe, and B. spielmanii<ref name="Richter">Richter D, Postic D, Sertour N, Livey I, Matuschka FR, Baranton G (2006). "Delineation of Borrelia burgdorferi sensu lato species by multilocus sequence analysis and confirmation of the delineation of Borrelia spielmanii sp. nov". Int J Syst Evol Microbiol 56 (Pt 4): 873-81. PMID 16585709.</ref><ref name="Foldvari">Foldvari G, Farkas R, Lakos A (2005). "Borrelia spielmanii erythema migrans, Hungary". Emerg Infect Dis 11 (11): 1794-5. PMID 16422006.</ref> in Europe. Additional B. burgdorferi sensu lato genospecies suspected of causing illness, but not confirmed by culture, include B. valaisiana (Eurasia, especially England, Switzerland and the Netherlands); B. japonica, B. tanukii and B. turdae (Japan); B. sinica (China); and B. andersonii (U.S.). Some of these species are carried by ticks not currently recognized as carriers of Lyme disease. Note: At present, diagnostic tests are based only on B. burgdorferi sensu stricto (the only species used in the U.S.), B. afzelii and B. garinii.

Apart from this group of closely related genospecies, additional Borrelia species of interest include B. lonestari, a spirochete recently detected in the Amblyomma americanum tick (Lone Star tick) in the U.S.<ref name="Varela">Varela AS, Luttrell MP, Howerth EW, Moore VA, Davidson WR, Stallknecht DE, Little SE (2004). "First culture isolation of Borrelia lonestari, putative agent of southern tick-associated rash illness" (PDF). J Clin Microbiol 42 (3): 1163-9. PMID 15004069.</ref> B. lonestari is suspected of causing STARI (Southern Tick-Associated Rash Illness), also known as Masters disease in honor of its discoverer. The illness follows a Lone Star tick bite and clinically resembles Lyme disease, but sufferers usually test negative for Lyme.<ref name="Masters">Masters E, Granter S, Duray P, Cordes P (1998). "Physician-diagnosed erythema migrans and erythema migrans-like rashes following Lone Star tick bites". Arch Dermatol 134 (8): 955-60. PMID 9722725.</ref> There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed. The B. miyamotoi spirochete, related to the relapsing fever group of spirochetes, is also suspected of causing illness in Japan. Spirochetes similar to B. miyamotoi have recently been found in both I. ricinus ticks in Sweden and I. scapularis ticks in the U.S.<ref name="Scoles">Scoles GA, Papero M, Beati L, Fish D (2001). "A relapsing fever group spirochete transmitted by Ixodes scapularis ticks". Vector Borne Zoonotic Dis 1 (1): 21-34. PMID 12653133.</ref><ref name="Bunikis-b">Bunikis J, Tsao J, Garpmo U, Berglund J, Fish D, Barbour AG (2004). "Typing of Borrelia relapsing fever group strains". Emerg Infect Dis 10 (9): 1661-4. PMID 15498172.</ref>

[edit] Genomic characteristics

One of the most striking features of B. burgdorferi as compared with other eubacteria is its unusual genome, which is far more complex than that of its spirochetal cousin Treponema pallidum, the agent of syphilis.<ref name="Porcella">Porcella SF, Schwan TG (2001). "Borrelia burgdorferi and Treponema pallidum: a comparison of functional genomics, environmental adaptations, and pathogenic mechanisms". J Clin Invest 107 (6): 651-6. PMID 11254661.</ref> The genome of B. burgdorferi includes a linear chromosome approximately one megabase in size, with 21 plasmids (12 linear and 9 circular) - by far the largest number of plasmids found in any known bacterium.<ref name="Casjens">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 (2000). "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 35 (3): 490-516. PMID 10672174.</ref> Genetic exchange, including plasmid transfers, contributes to the pathogenicity of the organism.<ref name="Qiu">Qiu WG, Schutzer SE, Bruno JF, Attie O, Xu Y, Dunn JJ, Fraser CM, Casjens SR, Luft BJ (2004). "Genetic exchange and plasmid transfers in Borrelia burgdorferi sensu stricto revealed by three-way genome comparisons and multilocus sequence typing" (PDF). Proc Natl Acad Sci U S A 101 (39): 14150-5. PMID 15375210.</ref> Long-term culture of B. burgdorferi results in a loss of some plasmids and changes in expressed protein profiles. Associated with the loss of plasmids is a loss in the ability of the organism to infect laboratory animals, suggesting that the plasmids encode key genes involved in virulence.

[edit] Structure and growth

B. burgdorferi is a highly specialized, motile, two-membrane, spiral-shaped spirochete ranging from about 9 to 32 micrometers in length. It is often described as gram-negative and has an outer membrane with LPS, though it stains only weakly in the Gram stain. B. burgdorferi is a microaerophilic organism, requiring little oxygen to survive. It lives primarily as an extracellular pathogen, although it can also hide intracellularly (see Mechanisms of persistence section).

Like other spirochetes such as T. pallidum (the agent of syphilis), B. burgdorferi has an axial filament composed of flagella which run lengthways between its cell wall and outer membrane. This structure allows the spirochete to move efficiently in corkscrew fashion through viscous media, such as connective tissue. As a result, B. burgdorferi can disseminate throughout the body within days to weeks of infection, penetrating deeply into tissue where the immune system and antibiotics may not be able to eradicate the infection.

B. burgdorferi is very slow growing, with a doubling time of 12-24 hours (in contrast to pathogens such as Streptococcus and Staphylococcus, which have a doubling time of 20-30 minutes). Since most antibiotics kill bacteria only when they are dividing, this longer doubling time necessitates the use of relatively longer treatment courses for Lyme disease. Antibiotics are most effective during the growth phase, which for B. burgdorferi occurs in four-week cycles. Some clinicians have observed that chronic Lyme patients commonly experience a worsening of symptoms every four weeks; these periodic flare-ups are thought to correspond to the growth phase of B. burgdorferi.<ref name="Burrascano-guidelines">Burrascano JJ (2005). "Diagnostic hints and treatment guidelines for Lyme and other tick borne illnesses". 15th edition. Retrieved on 2006-05-01.</ref>

[edit] Mechanisms of persistence

While B. burgdorferi is susceptible to a number of antibiotics in vitro, there are contradictory reports as to the efficacy of antibiotics in vivo. B. burgdorferi may persist in humans and animals for months or years despite a robust immune response and standard antibiotic treatment, particularly when treatment is delayed and dissemination widespread. Numerous studies have demonstrated persistence of infection despite antibiotic therapy.<ref name="Nocton">Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC (1994). "Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis". N Engl J Med 330 (4): 229-34. PMID 8272083.</ref><ref name="Bayer">Bayer ME, Zhang L, Bayer MH (1996). "Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases". Infection 24 (5): 347-53. PMID 8923044.</ref><ref name="Preac-Mursic">Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross B, Baumann A, Prokop J (1989). "Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis". Infection 17 (6): 355-9. PMID 2613324.</ref><ref name="Pfister">Pfister HW, Preac-Mursic V, Wilske B, Schielke E, Sorgel F, Einhaupl KM (1991). "Randomized comparison of ceftriaxone and cefotaxime in Lyme neuroborreliosis". J Infect Dis 163 (2): 311-8. PMID 1988514.</ref><ref name="Oksi-c">Oksi J, Marjamaki M, Nikoskelainen J, Viljanen MK (1999). "Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis". Ann Med 31 (3): 225-32. PMID 10442678.</ref><ref name="Hudson">Hudson BJ, Stewart M, Lennox VA, Fukunaga M, Yabuki M, Macorison H, Kitchener-Smith J (1998). "Culture-positive Lyme borreliosis". Med J Aust 168 (10): 500-2. PMID 9631675.</ref><ref name="Lawrence">Lawrence C, Lipton RB, Lowy FD, Coyle PK (1995). "Seronegative chronic relapsing neuroborreliosis". Eur Neurol 35 (2): 113-7. PMID 7796837.</ref><ref name="Honegr">Honegr K, Hulinska D, Dostal V, Gebousky P, Hankova E, Horacek J, Vyslouzil L, Havlasova J (2001). "[Persistence of Borrelia burgdorferi sensu lato in patients with Lyme borreliosis]". Epidemiol Mikrobiol Imunol 50 (1): 10-6. PMID 11233667.</ref><ref name="Straubinger">Straubinger RK, Summers BA, Chang YF, Appel MJ (1997). "Persistence of Borrelia burgdorferi in experimentally infected dogs after antibiotic treatment" (PDF). J Clin Microbiol 35 (1): 111-6. PMID 8968890.</ref>

Various survival strategies of B. burgdorferi have been posited to explain this phenomenon,<ref name="Embers">Embers ME, Ramamoorthy R, Philipp MT (2004). "Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease". Microbes Infect 6 (3): 312-8. PMID 15065567.</ref> including the following:

  • Physical sequestration of B. burgdorferi in sites that are inaccessible to the immune system and antibiotics, such as the brain<ref name="Miklossy">Miklossy J, Khalili K, Gern L, Ericson RL, Darekar P, Bolle L, Hurlimann J, Paster BJ (2004). "Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease". J Alzheimers Dis 6 (6): 639-49; discussion 673-81. PMID 15665404.</ref> and central nervous system. New evidence suggests that B. burgdorferi may use the host's fibrinolytic system to penetrate the blood-brain barrier.<ref name="Grab">Grab DJ, Perides G, Dumler JS, Kim KJ, Park J, Kim YV, Nikolskaia O, Choi KS, Stins MF, Kim KS (2005). "Borrelia burgdorferi, host-derived proteases, and the blood-brain barrier". Infect Immun 73 (2): 1014-22. PMID 15664945.</ref>
  • Intracellular invasion. B. burgdorferi has been shown to invade a variety of cells, including endothelium,<ref name="Ma-b">Ma Y, Sturrock A, Weis JJ (1991). "Intracellular localization of Borrelia burgdorferi within human endothelial cells" (PDF). Infect Immun 59 (2): 671-8. PMID 1987083.</ref> fibroblasts,<ref name="Klempner-b">Klempner MS, Noring R, Rogers RA (1993). "Invasion of human skin fibroblasts by the Lyme disease spirochete, Borrelia burgdorferi". J Infect Dis 167 (5): 1074-81. PMID 8486939.</ref> lymphocytes,<ref name="Dorward">Dorward DW, Fischer ER, Brooks DM (1997). "Invasion and cytopathic killing of human lymphocytes by spirochetes causing Lyme disease". Clin Infect Dis 25 Suppl 1: S2-8. PMID 9233657.</ref> macrophages,<ref name="Montgomery">Montgomery RR, Nathanson MH, Malawista SE (1993). "The fate of Borrelia burgdorferi, the agent for Lyme disease, in mouse macrophages. Destruction, survival, recovery". J Immunol 150 (3): 909-15. PMID 8423346.</ref> keratinocytes,<ref name="Aberer">Aberer E, Kersten A, Klade H, Poitschek C, Jurecka W (1996). "Heterogeneity of Borrelia burgdorferi in the skin". Am J Dermatopathol 18 (6): 571-9. PMID 8989928.</ref> synovium,<ref name="Girschick">Girschick HJ, Huppertz HI, Russmann H, Krenn V, Karch H (1996). "Intracellular persistence of Borrelia burgdorferi in human synovial cells". Rheumatol Int 16 (3): 125-32. PMID 8893378.</ref><ref name="Nanagara">Nanagara R, Duray PH, Schumacher HR Jr (1996). "Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: possible factors contributing to persistence of organisms". Hum Pathol 27 (10): 1025-34. PMID 8892586.</ref> and most recently neuronal and glial cells. <ref name="Livengood">Livengood JA, Gilmore RD (2006). "Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi.". Microbes Infect [Epub ahead of print]. PMID 17045505.</ref> By 'hiding' inside these cells, B. burgdorferi is able to evade the immune system and is protected to varying degrees against antibiotics,<ref name="Georgilis">Georgilis K, Peacocke M, Klempner MS (1992). "Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro". J Infect Dis 166 (2): 440-4. PMID 1634816.</ref><ref name="Brouqui"> Brouqui P, Badiaga S, Raoult D (1996). "Eucaryotic cells protect Borrelia burgdorferi from the action of penicillin and ceftriaxone but not from the action of doxycycline and erythromycin" (PDF). Antimicrob Agents Chemother 40 (6): 1552-4. PMID 8726038.</ref> allowing the infection to persist in a chronic state. Paradoxically, many of these scientific studies were performed and published by critics of persistent Borrelia infection.
  • Altered morphological forms, i.e. spheroplasts (cysts, granules).
    • The existence of B. burgdorferi spheroplasts, which lack a cell wall, has been well documented in vitro,<ref name="Alban">Alban PS, Johnson PW, Nelson DR (2000). "Serum-starvation-induced changes in protein synthesis and morphology of Borrelia burgdorferi". Microbiology 146 ( Pt 1): 119-27. PMID 10658658 Full Text.</ref><ref name="Benach">Benach JL (1999). "Functional heterogeneity in the antibodies produced to Borrelia burgdorferi". Wien Klin Wochenschr 111 (22-23): 985-9. PMID 10666815.</ref><ref name="Mursic">Mursic VP, Wanner G, Reinhardt S, Wilske B, Busch U, Marget W (1996). "Formation and cultivation of Borrelia burgdorferi spheroplast-L-form variants". Infection 24 (3): 218-26. PMID 8811359.</ref><ref name="Cluss">Cluss RG, Goel AS, Rehm HL, Schoenecker JG, Boothby JT (1996). "Coordinate synthesis and turnover of heat shock proteins in Borrelia burgdorferi: degradation of DnaK during recovery from heat shock" (PDF). Infect Immun 64 (5): 1736-43. PMID 8613385.</ref><ref name="Kersten">Kersten A, Poitschek C, Rauch S, Aberer E (1995). "Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi" (PDF). Antimicrob Agents Chemother 39 (5): 1127-33. PMID 7625800.</ref><ref name="Angelov">Angelov L, Dimova P, Berbencova W (1996). "Clinical and laboratory evidence of the importance of the tick D. marginatus as a vector of B. burgdorferi in some areas of sporadic Lyme disease in Bulgaria". Eur J Epidemiol 12 (5): 499-502. PMID 8905312.</ref><ref name="Schaller">Schaller M, Neubert U (1994). "Ultrastructure of Borrelia burgdorferi after exposure to benzylpenicillin". Infection 22 (6): 401-6. PMID 7698837.</ref> in vivo,<ref name="Nanagara" /><ref name="Mursic" /><ref name="Phillips-c">Phillips SE, Mattman LH, Hulinska D, Moayad H (1998). "A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated". Infection 26 (6): 364-7. PMID 9861561.</ref><ref name="Hulinska">Hulinska D, Bartak P, Hercogova J, Hancil J, Basta J, Schramlova J (1994). "Electron microscopy of Langerhans cells and Borrelia burgdorferi in Lyme disease patients". Zentralbl Bakteriol 280 (3): 348-59. PMID 8167429.</ref> and in an ex vivo model.<ref name="Duray">Duray PH, Yin SR, Ito Y, Bezrukov L, Cox C, Cho MS, Fitzgerald W, Dorward D, Zimmerberg J, Margolis L (2005). "Invasion of human tissue ex vivo by Borrelia burgdorferi". J Infect Dis 191 (10): 1747-54. PMID 15838803.</ref>The fact that energy is required for the spiral bacterium to convert to the cystic form<ref name="Alban" /> suggests that these altered forms have a survival function, and are not merely end stage degeneration products. The spheroplasts are indeed virulent and infectious, able to survive under adverse environmental conditions, and have been shown to revert back to the spiral form in vitro, once conditions are more favorable.<ref name="Mursic" /><ref name="Brorson-a">Brorson O, Brorson SH (1997). "Transformation of cystic forms of Borrelia burgdorferi to normal, mobile spirochetes". Infection 25 (4): 240-6. PMID 9266264.</ref><ref name="Brorson-b">Brorson O, Brorson SH (1998). "In vitro conversion of Borrelia burgdorferi to cystic forms in spinal fluid, and transformation to mobile spirochetes by incubation in BSK-H medium". Infection 26 (3): 144-50. PMID 9646104.</ref><ref name="Gruntar">Gruntar I, Malovrh T, Murgia R, Cinco M (2001). "Conversion of Borrelia garinii cystic forms to motile spirochetes in vivo". APMIS 109 (5): 383-8. PMID 11478686.</ref><ref name="Murgia">Murgia R, Cinco M (2004). "Induction of cystic forms by different stress conditions in Borrelia burgdorferi". APMIS 112 (1): 57-62. PMID 14961976.</ref>
    • A number of other factors make B. burgdorferi spheroplasts a key factor in the relapsing, chronic nature of Lyme disease. Compared to the spiral form, spheroplasts have dramatically reduced surface area for immune surveillance. They also express different surface proteins - another reason for seronegative disease (i.e. false-negative antibody tests), as current tests only look for antibodies to surface proteins of the spiral form. In addition, B. burgdorferi spheroplasts are generally not susceptible to the antibiotics traditionally used for Lyme disease. They have instead shown sensitivity in vitro to antiparasitic drugs such as metronidazole,<ref name="Brorson-c">Brorson O, Brorson SH (1999). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to metronidazole". APMIS 107 (6): 566-76. PMID 10379684.</ref> tinidazole,<ref name="Brorson-d">Brorson O, Brorson SH (2004). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to tinidazole" (PDF). Int Microbiol 7 (2): 139-42. PMID 15248163.</ref> and hydroxychloroquine,<ref name="Brorson-e">Brorson O, Brorson SH (2002). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to hydroxychloroquine". Int Microbiol 5 (1): 25-31. PMID 12102233.</ref> to which the spiral form of B. burgdorferi is not sensitive.
  • Immune system suppression. Complement inhibition, induction of anti-inflammatory cytokines such as IL-10, and the formation of immune complexes have all been documented in B. burgdorferi infection.<ref name="Embers" /> Furthermore, the existence of immune complexes provides another explanation for seronegative disease (i.e. false-negative antibody tests of blood and cerebrospinal fluid), as studies have shown that substantial numbers of seronegative Lyme patients have antibodies bound up in these complexes.<ref name="Schutzer">Schutzer SE, Coyle PK, Reid P, Holland B (1999). "Borrelia burgdorferi-specific immune complexes in acute Lyme disease". JAMA 282 (20): 1942-6. PMID 10580460.</ref><ref name="Coyle-b">Coyle PK, Schutzer SE, Belman AL, Krupp LB, Golightly MG (1990). "Cerebrospinal fluid immune complexes in patients exposed to Borrelia burgdorferi: detection of Borrelia-specific and -nonspecific complexes". Ann Neurol 28 (6): 739-44. PMID 2285261.</ref><ref name="Schutzer-b">Schutzer SE, Coyle PK, Belman AL, Golightly MG, Drulle J (1990). "Sequestration of antibody to Borrelia burgdorferi in immune complexes in seronegative Lyme disease". Lancet 335 (8685): 312-5. PMID 1967770.</ref>

[edit] Diagnosis

The most reliable method of diagnosing Lyme disease is a clinical exam by an experienced practitioner, taking into account symptoms, history, and possible exposure to ticks in an endemic area. Clinicians who diagnose strictly based on the U.S. Centers for Disease Control (CDC) Case Definition for Lyme are in error, as the CDC explicitly states that this definition is intended for surveillance purposes only, and is "not intended to be used in clinical diagnosis."<ref name="CDC LD Definition">Lyme Disease (Borrelia burgdorferi): 1996 Case Definition. CDC Case Definitions for Infectious Conditions under Public Health Surveillance. Retrieved on 2006-03-15.</ref><ref name="CDC Testimony">CDC Testimony before the Connecticut Department of Health and Attorney General's Office. CDC's Lyme Prevention and Control Activities. Retrieved on 2006-03-15.</ref>

The EM rash, which does not occur in all cases, is considered sufficient to make a diagnosis of Lyme disease and prompt treatment without further testing. In fact because of the undisputed high rate of false negatives during the early stage of the disease (before a sufficient antibody response has been established), it is recommended that tests not be performed when a patient has an EM rash.<ref name="Edlow" /><ref name="Brown">Brown SL, Hansen SL, Langone JJ (1999). "Role of serology in the diagnosis of Lyme disease". JAMA 282 (1): 62-6. PMID 10404913.</ref><ref name="Hofmann">Hofmann H (1996). "Lyme borreliosis--problems of serological diagnosis". Infection 24 (6): 470-2. PMID 9007597.</ref>

The serological laboratory tests available are the Western blot and ELISA. In the two-tiered protocol recommended by the CDC according to their case definition, the ELISA is performed first, and if it is positive or equivocal, a Western blot is then performed to support the diagnosis. The reliability of testing in diagnosis remains controversial (see The Lyme controversy--Testing).

False-positive results for the Western blot IgM are described with varicella-zoster virus,<ref name="Feder">Feder HM Jr, Gerber MA, Luger SW, Ryan RW (1991). "False positive serologic tests for Lyme disease after varicella infection". N Engl J Med 325 (26): 1886-7. PMID 1961232.</ref><ref name="Woelfle">Woelfle J, Wilske B, Haverkamp F, Bialek R (1998). "False-positive serological tests for Lyme disease in facial palsy and varicella zoster meningo-encephalitis". Eur J Pediatr 157 (11): 953-4. PMID 9835449.</ref> Epstein-Barr virus,<ref name="Gossens">Goossens HA, Nohlmans MK, van den Bogaard AE (1999). "Epstein-Barr virus and cytomegalovirus infections cause false-positive results in IgM two-test protocol for early Lyme borreliosis". Infection 27 (3): 231. PMID 10378140.</ref><ref name="Berardi">Berardi VP, Weeks KE, Steere AC (1988). "Serodiagnosis of early Lyme disease: analysis of IgM and IgG antibody responses by using an antibody-capture enzyme immunoassay". J Infect Dis 158 (4): 754-60. PMID 3049839.</ref> cytomegalovirus.<ref name="Gossens" /> and herpes simplex type virus 2.<ref name="Strasfeld">Strasfeld L, Romanzi L, Seder RH, Berardi VP (2005). "False-positive serological test results for Lyme disease in a patient with acute herpes simplex virus type 2 infection". Clin Infect Dis 41 (12): 1826-7. PMID 16288417.</ref> However studies show the Western blot IgM has a specificity of 94-96% for patients with symptoms suggestive of Lyme disease.<ref name="Engstrom">Engstrom SM, Shoop E, Johnson RC (1995). "Immunoblot interpretation criteria for serodiagnosis of early Lyme disease" (PDF). J Clin Microbiol 33 (2): 419-27. PMID 7714202.</ref><ref name="Sivak">Sivak SL, Aguero-Rosenfeld ME, Nowakowski J, Nadelman RB, Wormser GP (1996). "Accuracy of IgM immunoblotting to confirm the clinical diagnosis of early Lyme disease". Arch Intern Med 156 (18): 2105-9. PMID 8862103.</ref>

False-negative test results have been widely reported in both early and late disease.<ref name="Lawrence" /><ref name="Coyle">Coyle PK, Schutzer SE, Deng Z, Krupp LB, Belman AL, Benach JL, Luft BJ (1995). "Detection of Borrelia burgdorferi-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease". Neurology 45 (11): 2010-5. PMID 7501150.</ref><ref name="Paul">Paul A (2001). "[Arthritis, headache, facial paralysis. Despite negative laboratory tests Borrelia can still be the cause]". MMW Mortschr Med 143 (6): 17. PMID 11247357.</ref><ref name="Pikelj">Pikelj F, Strle F, Mozina M (1989). "Seronegative Lyme disease and transitory atrioventricular block". Ann Intern Med 111 (1): 90. PMID 11247357.</ref><ref name="Oksi">Oksi J, Uksila J, Marjamaki M, Nikoskelainen J, Viljanen MK (1995). "Antibodies against whole sonicated Borrelia burgdorferi spirochetes, 41-kilodalton flagellin, and P39 protein in patients with PCR- or culture-proven late Lyme borreliosis" (PDF). J Clin Microbiol 33 (9): 2260-4. PMID 7494012.</ref>

Polymerase chain reaction (PCR) tests for Lyme disease may also be available to the patient. A PCR test attempts to detect the genetic material (DNA) of the Lyme disease spirochete, whereas the Western blot and ELISA tests look for antibodies to the organism. PCR tests are rarely susceptible to false-positive results but can often show false-negative results.

Given the testing difficulties described above, some patients are employing a vitamin D metabolites test as an alternative indicator. A finding of a low 25-hydroxyvitamin D level coupled with a high 1,25-dihydroxyvitamin D level can be associated with an infection by B. burgdorferi or other spirochetal bacteria. <ref name="Marshall">Marshall TG, Marshall FE (2004). "Sarcoidosis succumbs to antibiotics--implications for autoimmune disease". Autoimmun Rev. 3 (4): 295-300. PMID 15246025.</ref> Since such abnormal vitamin D levels can also be caused by other disease processes, further evaluation is warranted to rule those out before initiating treatment.

[edit] Prognosis

For early cases, prompt treatment is usually, but not always, curative.<ref name=Nowakowski /> However, the severity and treatment of Lyme disease may be complicated due to late diagnosis, failure of antibiotic treatment, simultaneous infection with other tick-borne diseases including ehrlichiosis, babesiosis, and bartonella, and immune suppression in the patient (sometimes resulting from inappropriate treatment with steroids).

A meta-analysis published in 2005 found that some patients with Lyme disease have fatigue, joint and/or muscle pain, and neurocognitive symptoms persisting for years despite antibiotic treatment.<ref name="Cairns">Cairns V, Godwin J (2005). "Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms.". Int J Epidemiol 34 (6): 1340-5. PMID 16040645.</ref> Patients with chronic Lyme disease have been shown to experience a level of physical disability equivalent to that seen in congestive heart failure.<ref name="Klempner">Klempner MS, Hu LT, Evans J, Schmid CH, Johnson GM, Trevino RP, Norton D, Levy L, Wall D, McCall J, Kosinski M, Weinstein A (2001). "Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease". N Engl J Med 345 (2): 85-92. PMID 11450676.</ref> The disease is rarely fatal in and of itself, although deaths have been reported.<ref name="Kirsch">Kirsch M, Ruben FL, Steere AC, Duray PH, Norden CW, Winkelstein A (1988). "Fatal adult respiratory distress syndrome in a patient with Lyme disease". JAMA 259 (18): 2737-9. PMID 3357244.</ref><ref name="Oksi-b">Oksi J, Kalimo H, Marttila RJ, Marjamaki M, Sonninen P, Nikoskelainen J, Viljanen MK (1996). "Inflammatory brain changes in Lyme borreliosis. A report on three patients and review of literature". Brain 119 (Pt 6): 2143-54. PMID 9010017.</ref><ref name="Waniek">Waniek C, Prohovnik I, Kaufman MA, Dwork AJ (1995). "Rapidly progressive frontal-type dementia associated with Lyme disease". J Neuropsychiatry Clin Neurosci 7 (3): 345-7. PMID 7580195.</ref><ref name="Cary">Cary NR, Fox B, Wright DJ, Cutler SJ, Shapiro LM, Grace AA (1990). "Fatal Lyme carditis and endodermal heterotopia of the atrioventricular node". Postgrad Med J 66 (772): 134-6. PMID 2349186.</ref><ref name="Reimers">Reimers CD, de Koning J, Neubert U, Preac-Mursic V, Koster JG, Muller-Felber W, Pongratz DE, Duray PH (1993). "Borrelia burgdorferi myositis: report of eight patients". J Neurol 240 (5): 278-83. PMID 8326331.</ref>

[edit] Treatment

Persons who remove attached ticks should be monitored closely for signs and symptoms of tick-borne diseases for up to 30 days. Single-dose doxycycline therapy may be considered for deer tick bites when the tick has been on the person for at least 36 hours.

Traditional treatment of acute Lyme disease usually consists of a minimum two-week to one-month course of antibiotics. In later stages, the bacteria disseminate throughout the body and may cross the blood-brain barrier, making the infection more difficult to treat. Chronic or late diagnosed Lyme is treated with oral or IV antibiotics, frequently ceftriaxone, for a minimum of four weeks.

With little research conducted specifically on chronic Lyme disease, treatment remains controversial. Currently there are two sets of peer-reviewed published guidelines; the International Lyme and Associated Diseases Society (ILADS) <ref>International Lyme and Associated Diseases Society (ILADS)</ref> advocates extended courses of antibiotics for chronic Lyme patients, while the Infectious Diseases Society of America <ref>Infectious Diseases Society of America</ref> does not recognize chronic infection and recommends no treatment for persistent symptoms following infection (see The Lyme controversy--Two standards of care). Double-blind, placebo-controlled trials of long-term antibiotics for chronic Lyme have produced mixed results (see The Lyme controversy--Long-term antibiotic therapy).

Many alternative (or supplemental) therapies have been suggested. For example, melittin, a peptide from bee venom, has been shown to exert "profound inhibitory effects" on lyme bacteria. <ref>Lubke LL, & Garon CF. The antimicrobial agent melittin exhibits powerful in vitro inhibitory effects on the Lyme disease spirochete. Clin Infect Dis. 1997 Jul;25 Suppl 1:S48-51. PMID 9233664.</ref> Despite its demonstrated potency, apparently no further research has been conducted on melittin as a possible lyme treatment. Clinical trials of large doses of IV sodium ascorbate (vitamin C) have been shown to kill cancer cells and possibly parasites in the body. Largely due to this, there are many chronic lyme disease sufferers turning to natural therapies. Another alternative therapy involves the use of electromagnetic frequency devices to kill the bacteria, an approach whose efficacy remains unproven.

[edit] The Lyme controversy

Although there is no doubt that Lyme disease exists, and most clinicians agree on the treatment of early Lyme disease,<ref name="Murray">Murray T, Feder H (2001). "Management of tick bites and early Lyme disease: a survey of Connecticut physicians.". Pediatrics 108 (6): 1367-70. PMID 11731662.</ref> there is considerable controversy as to the prevalence of the disease, the proper procedure for diagnosis and treatment of later stages, and the likelihood of a chronic, antibiotic-resistant Lyme infection. On one side are those who believe that Lyme disease is relatively rare, easily diagnosed with available blood tests, and easily treated with two to four weeks of antibiotics.<ref name="Wormser-b">Wormser G (2006). "Clinical practice. Early Lyme disease.". N Engl J Med 354 (26): 2794-801. PMID 16807416.</ref> On the other side are those who believe that Lyme disease is under-diagnosed, that available blood tests are unreliable, and that extended antibiotic treatment is often necessary.<ref name="Stricker">Stricker RB, Lautin A, Burrascano JJ (2006). "Lyme Disease: The Quest for Magic Bullets". Chemotherapy 52 (2): 53-59. PMID 16498239.</ref><ref name="Phillips-a">Phillips SE, Harris NS, Horowitz R, Johnson L, Stricker RB (2005). "Lyme disease: scratching the surface". Lancet 366 (9499): 1771. PMID 16298211.</ref><ref name="Phillips-b">Phillips S, Bransfield R, Sherr V, Brand S, Smith H, Dickson K, and Stricker R (2003). Evaluation of antibiotic treatment in patients with persistent symptoms of Lyme disease: an ILADS position paper (PDF). International Lyme and Associated Diseases Society. Retrieved on 2006-03-15.</ref><ref name="Harvey">Harvey WT, Salvato P (2003). "'Lyme disease': ancient engine of an unrecognized borreliosis pandemic?" (PDF). Med Hypotheses 60 (5): 742-59. PMID 12710914.</ref>

The majority of public health agencies such as the U.S. Centers for Disease Control maintain the former position. While this narrower position is sometimes described as the "mainstream" view of Lyme disease, published studies involving non-randomized surveys of physicians in endemic areas found physicians evenly split in their views, with the majority recognizing seronegative Lyme disease, and roughly half prescribing extended courses of antibiotics for chronic Lyme disease.<ref name="Ziska">Ziska MH, Donta ST, Demarest FC (1996). "Physician preferences in the diagnosis and treatment of Lyme disease in the United States". Infection 24 (2): 182-6. PMID 8740119.</ref><ref name="Eppes">Eppes SC, Klein JD, Caputo GM, Rose CD (1994). "Physician beliefs, attitudes, and approaches toward Lyme disease in an endemic area". Clin Pediatr (Phila) 33 (3): 130-4. PMID 8194286.</ref>

Since October 2006, the Lyme controversy has heated up dramatically beginning with the release of updated diagnosis and treatment guidelines from the Infectious Diseases Society of America (IDSA).<ref name=Showdown>"New Lyme Disease Guidelines Spark Showdown", U.S. Department of Health and Human Services, 2006-11-09. Retrieved on 2006-11-17.</ref> The new IDSA recommendations are even more restrictive than before, requiring either an EM rash or positive laboratory tests for diagnosis. Seronegative Lyme disease is no longer acknowledged, except in early Lyme. The authors of the guidelines maintain that chronic Lyme disease does not result from persistent infection, and therefore treatment beyond 2-4 weeks is not recommended by the IDSA, even in late stage cases.

The 2006 IDSA guidelines<ref name="IDSA">Wormser G, Dattwyler R, Shapiro E, Halperin J, Steere A, Klempner M, Krause P, Bakken J, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler J, Nadelman R (2006). "The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America.". Clin Infect Dis 43 (9): 1089-134. PMID 17029130.</ref> have come under fire from a variety of corners. The International Lyme and Associated Diseases Society (ILADS), a professional medical society, formally requested retraction of the IDSA guidelines<ref name=ILADS-Retraction>U.S. Newswire (2006-10-27). ILADS Demands Retraction of New IDSA Guidelines for Treatment of Lyme Disease. Press release. Retrieved on 2006-11-17.</ref>, arguing that the authors ignored all published data that conflicted with their opinions, and refused input from physicians and patients with differing views. The all-volunteer Lyme Disease Association, which is the largest Lyme advocacy group in the U.S., expressed concerns that the guidelines do not allow for physicians' clinical discretion, and that with more cases going undiagnosed and untreated by the stricter guidelines, more patients than ever will develop disabling, late-stage Lyme disease.<ref name=LDA-Retraction>Lyme Disease Association (10-10-2006). New IDSA Guidelines Forbid Doctors From Using Clinical Discretion in Diagnosing Lyme Disease. Press release. Retrieved on 2006-11-17.</ref>

In an unprecedented move, Connecticut Attorney General Richard Blumenthal initiated a formal investigation into the development of the IDSA guidelines in November 2006. The Attorney General's office is considering whether the IDSA violated antitrust laws through exclusionary conduct and monopolization in the development of the guidelines. "These guidelines were set by a panel that essentially locked out competing points of view," Blumenthal said. "Presumably, the IDSA is a non-profit making organization, but such organizations can still be used for anti-competitive purposes." <ref name="Hamilton">Hamilton, Elizabeth. "Lyme Disease Guidelines Focus of Antitrust Probe", Hartford Courant, 2006-11-17. Retrieved on 2006-11-17.</ref>

[edit] Two standards of care

Because the legal standard of care is defined by the consensus of treating physicians (rather than published guidelines), two standards of care for Lyme disease are now recognized in the U.S., a situation with significant legal implications for both patients and clinicians.<ref name="Johnson-a">Johnson, Lorraine (2005-02). Lyme disease: two standards of care. International Lyme and Associated Diseases Society. Retrieved on 2006-11-17.</ref><ref name="Johnson-b">Johnson L, Stricker R (2004). "Treatment of Lyme disease: a medicolegal assessment.". Expert Rev Anti Infect Ther 2 (4): 533-57. PMID 15482219.</ref>

ILADS (The International Lyme and Associated Diseases Society)<ref>ILADS (The International Lyme and Associated Diseases Society)</ref>
ILADS Mission Statement<ref>ILADS Mission Statement</ref> 		IDSA (The Infectious Diseases Society of America)<ref>IDSA (The Infectious Diseases Society of America)</ref>
IDSA Mission Statement<ref>IDSA Mission Statement</ref>
Peer-reviewed treatment guidelines ILADS Guidelines <ref name="ILADS">Cameron D, Gaito A, Narris N, Bach G, Bellovin S, Bock K, Bock S, Burrascano J, Dickey C, Horowitz R, Phillips S, Meer-Scherrer L, Raxlen B, Sherr V, Smith H, Smith P, Stricker R; ILADS Working Group (2004). "Evidence-based guidelines for the management of Lyme disease". Expert Rev Anti Infect Ther 2 ((1 Suppl)): S1-13. PMID 15581390.</ref> IDSA Guidelines <ref name="IDSA" />
Public statements "A small group of scientists...deny the existence of chronic Lyme disease," wrote ILADS president Raphael Stricker, M.D., referring in part to the IDSA. "Fearing 'over-diagnosis,' they publish guidelines endorsing an insensitive testing program that misses half the patients with the tick-borne illness. Fearing 'over-treatment,' they recommend antibiotic therapy barely adequate for acute infection and wholly inadequate for chronic Lyme disease. Soon they will publish the latest version of an already restrictive set of guidelines that will further pressure the Centers for Disease Control and Prevention and academic institutions to ignore chronic Lyme disease. The guidelines will encourage insurance companies to embrace up-front cost savings inherent in shorter treatment and deny payment for longer treatment, even if the Lyme patient is still sick but showing signs of improvement. Although the Lyme denialists claim support from mainstream medical groups, the reality is that the handful of them have managed to dictate policy to larger health care organizations through a closed process that rejects dissenting views."<ref name="Stricker-b">Stricker, Raphael B.. "Medical Revisionists Threaten Effective Lyme Treatment", Hartford Courant, 2006-07-31, p. A7.</ref> The IDSA has attacked ILADS as a "special interest group... which represents a few physicians who advocate unconventional treatments based on testimonials rather than scientifically sound clinical trials." (See Clinical Trials). “Nearly all people – more than 95 percent – who do get sick with Lyme disease and are treated with the recommended course of antibiotics get better and go on with their lives,” said Gary Wormser, M.D., lead author of IDSA’s 2006 guidelines on Lyme disease.
EM rash Present less than 50% of the time. Studies that show otherwise are flawed because they rely on circular logic, as subjects must meet CDC criteria which prioritize the rash over other disease manifestations. Among those who would be excluded from such studies are: 1) seronegative Lyme patients without a rash (even if there is definitive evidence of infection such as a positive PCR), 2) seropositive patients without a rash who present with fever, flu-like symptoms, joint and muscle pain, paresthesias and/or encephalopathy (symptoms not included in the restrictive CDC case definition), and 3) late-stage patients whose diagnosis was delayed because no rash was present. The exclusion of these groups leads to an artificially high estimate of the incidence of EM rash among those infected with Lyme. "The great majority of Lyme patients" present with an EM rash, according to studies of patients wi