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Comment
2003 © Ashley Publications Ltd ISSN 1354-3784 1
Ashley Publications
www.ashley-pub.com
1. Introduction
2. Assertions and comments
3. Expert opinion and conclusion
The Lyme Wars: time to listen
Raphael B Stricker† & Andrew Lautin
†Department of Medicine, California Pacific Medical Center, San Francisco,
CA, USA
Lyme disease represents a public health threat of major proportions. The
murky science and acrimonious politics of Lyme disease have created barriers
to reliable diagnosis and effective treatment of this protean illness. Two
major clinical problems with the disease are the absence of a therapeutic
end point in treating Borrelia burgdorferi, the spirochetal agent of Lyme
disease, and the presence of tick-borne co-infections such as Babesiosis,
Anaplasmosis and Bartonellosis that may complicate the course of the
illness. From a pathophysiological standpoint, the affinity of B.
burgdorferi for multiple cell types and the presence of non-replicating
forms of the spirochete have contributed to persistent infection and failure
of simple antibiotic regimens. Newer approaches to the treatment of Lyme
disease should take into account its clinical complexity in co-infected
patients and the possible need for prolonged combination therapy in patients
with persistent symptoms of this potentially debilitating illness. The risk
and prevention of human transmission of Lyme disease merit further study.
Keywords: Anaplasma, Babesia, Bartonella, Borrelia, co-infections, Lyme
disease
Expert Opin. Investig. Drugs (2003) 12(10):
1. Introduction
Virtually from the moment of its discovery in 1975, Lyme disease has been a
controversial illness [1,2]. The controversy is grounded in the murky nature
of the disease, from its protean manifestations and inconsistent diagnostic
parameters to its uncertain treatment. In addition to these scientific
inconsistencies, the politics surrounding Lyme disease rivals the worst
medical defamation in history, from syphilis (always the ‘other country’s venereal disease’) to AIDS (the ‘scourge of alternative lifestyles’).
Perhaps the political apogee of Lyme disease came in 1993, when Joseph
Burrascano testified before the US Congress that Lyme disease was not "hard
to catch and easy to cure", as others had reassured the government. Rather,
the disease was an underreported and growing menace that would exact a huge
toll on the healthcare system if policy did not change [3,4]. For his
efforts, Burrascano was prosecuted by his state medical board and the ‘Lyme
Wars’ have become even more acrimonious.
What sustains this controversy? It is important to recognise that the
science of Lyme disease suffers from two major problems. First, there is no
test currently available that proves the eradication of Borrelia
burgdorferi, the spirochetal agent of Lyme disease, from the human body
[5,6]. Conversely, there is growing evidence for longterm persistence of the
Lyme disease spirochete in animal models [7-11] and humans [12-14] despite
alleged adequate treatment for the disease. The second problem is that Lyme
disease likes company, and over the past 20 years we have seen compelling
evidence for co-infections transmitted by ticks (which have been called
‘sewers of infectious disease’) along with the Lyme disease spirochete
[15-21]. Thus, the term ‘Lyme disease’ often signifies a poorly
characterised polymicrobial infection with no fixed end point. This nebulous
infectious disease presents a nightmare scenario for both the victim of Lyme
disease and any rational healthcare provider who must deal with the complex
complications of the tick-borne illness. A corollary to this nightmare is
the growing recognition of possible spread of the Lyme disease spirochete by
human contact [22,23].
With this background, the article by Charles Pavia [24] on current and novel
therapies for Lyme disease is yet another trivialising treatise that
presents inaccurate or incorrect information about this potential nightmare.
In our view, the banality of the article reflects an entrenched and growing
ignorance and neglect of the severity of Lyme disease, while its victims
continue to suffer. Below is a partial rundown of points presented in the
article with which we strongly take issue. We have listed these points in
their order of appearance and appended our corresponding commentary.
2. Assertions and comments
Assertion (1): B. burgdorferi can be readily cultivated in vitro using
special culture medium.
Comment (1): B. burgdorferi is difficult to culture by routine methods, and
virtually no clinical laboratory can perform this basic infectious disease
test [25,26]. This clinical drawback has severely limited the diagnosis of
Lyme disease. A similar problem is seen with syphilis, an illness caused by
the spirochete Treponema pallidum. Since this organism cannot be cultured in
vitro, the diagnosis of syphilis (like Lyme disease) is supported by
serological testing, prompting the observation that ‘any infection for which
diagnosis and assessment of treatment response depend on serologic testing
is one in which clinical certainty is elusive’ [27].
Assertion (2): About 20 – 25% of Lyme disease patients do not remember
developing a characteristic ‘bullseye’ erythema migrans (EM) rash.
Comment (2): According to recent health department statistics from Texas,
Connecticut and California, the EM rash fails to appear in 41 – 65% of Lyme
disease patients, and recognition of the rash may be even lower depending on
the location of the tick-bite and the awareness of the person who was bitten
[28,101]. The published incidence of the EM rash also reflects a type of
circular reasoning that pervades Lyme disease research: since the presence
of an EM rash is the best evidence for Lyme disease, it has become the most
common criterion for admission into Lyme disease studies. Since most
patients in these studies have an EM rash, the incidence of the rash becomes
inflated in the medical literature. The literature then perpetuates the myth
that the vast majority of Lyme disease patients have an EM rash [4,22].
Assertion (3): The Lyme enzyme-linked immunosorbent assay (ELISA) is the
preferred method to diagnose Lyme disease due to its sensitivity,
adaptability to automation and ease of quantitation.
Comment (3): The Lyme ELISA misses at least 50% of Lyme disease cases due to
the assay’s insensitivity and variability with antibiotic treatment [101].
It follows that the two-tiered testing system endorsed by the US Centers for
Disease Control and Prevention (CDC), which includes an ELISA screening test
followed by a confirmatory Western blot, will also miss 50% of Lyme disease
cases because a positive ELISA result is required to proceed to the
confirmatory Western blot test [28,101]. Parenthetically, the CDC criteria
were developed for surveillance of Lyme disease, not for diagnostic
purposes. This is an important distinction because it is inappropriate to
apply surveillance criteria to symptomatic patients whose clinical picture
already suggests the presence of Lyme disease. Thus, there is currently no
sanctioned, standardised, consistent serological test for Lyme disease in
the US [28,101].
Assertion (4): Only motile forms (of B. burgdorferi) are considered to be
viable and capable of replicating.
Comment (4): B. burgdorferi assumes different forms in different hosts
[29-35]. The most troublesome is the so-called cyst form that may lie
dormant in the human host, thus evading antibiotic therapy that targets
replicating bacteria [29-33]. The non-replicating cyst form is undoubtedly
the key to persistence of infection with the Lyme disease spirochete, and
any antibiotic approach to Lyme disease that fails to recognise this
pathogenic entity is doomed to failure [34,35].
Assertion (5): The Lyme disease vaccine was withdrawn due to lack of public
interest.
Comment (5): The GlaxoSmithKline Lyme vaccine (LYMErix™) was withdrawn in
the face of a class action lawsuit involving > 300 patients who claim that
they developed a ‘Lyme-like’ illness after receiving the vaccine.
Assertion (6): Early Lyme disease is readily treatable with a 2 – 3 week
course of antibiotics.
Comment (6): This statement is misleading for several reasons. First,
‘early Lyme disease’ often goes undetected due to lack of awareness of a
tick-bite and absence of an EM rash [28]. Second, recent studies have shown
that tick saliva carries immunosuppressive substances that allow tick-borne
agents to invade tissues while paralysing the local immune response [36,37].
Thus, the Lyme disease spirochete may rapidly disseminate and become
entrenched and resistant early in the disease (see below) [38-40]. Third,
co-infections may alter the course of ‘early Lyme disease’, and these
co-infections may make the Lyme disease patient more difficult to treat (see
below).
Assertion (7): To date, there is no evidence for the existence of any
antibiotic-resistant strains of B. burgdorferi’.
Comment (7): A serious understatement. B. burgdorferi is an extremely
complex organism. The Lyme disease spirochete contains at least 132
functioning genes, in contrast to T. pallidum, the spirochete that causes
syphilis, which contains only 22 such genes [41]. Although B. burgdorferi
may not be ‘resistant’ to antibiotics by conventional laboratory methods, we
know that the spirochete can enter cells such as fibroblasts, synovial
cells, endothelial cells and macrophages [42-47]. In these cells, B.
burgdorferi becomes functionally resistant to treatment, partly due to
‘camouflage’ proteins produced by the organism or adsorbed from the cell and
partly due to the altered morphology and replication of the spirochetal cyst
form (see above) [34,40,43]. This functional resistance leads to persistent infection despite supposedly adequate treatment for
Lyme disease. The immune evasion strategy of B. burgdorferi is reminiscent
of mycobacterial infections such as tuberculosis or leprosy [38-40].
Assertion (8): It is unclear whether a concurrent Anaplasma or Babesia
infection can influence the outcome of a standard course of treatment for
Lyme disease.
Comment (8): Animal models of co-infection with B. burgdorferi and either
Babesia microti or Anaplasma phagocytophila (the agent of human granulocytic
ehrlichiosis) have demonstrated an altered immune response and clinically
worse disease in these animals [48-50]. Similar exacerbation of clinical
symptoms and resistance to treatment has been observed in humans [16,51].
Assertion (9): A single dose of doxycycline given within 72 h after a
recognisable tick-bite was highly effective in preventing early Lyme
disease.
Comment (9): The study that showed the alleged benefit of prophylactic
single-dose doxycycline had inadequate follow up to prove the absence of
clinical infection following this simple treatment [52]. Furthermore, the
authors used development of an EM rash as an end point in the study. Since
41 – 65% of Lyme disease patients do not develop an EM rash, the study may
have missed more than half the patients who eventually came down with Lyme
disease after this theoretically inadequate prophylaxis. The use of
single-dose doxycycline also raises concern about antibiotic resistance
following this microbiologically unsound therapy.
Assertion (10): Healthcare providers who deal with Lyme disease can be
divided into two groups: ‘specialists’ who are often affiliated with ‘large
academic institutions’, versus ‘community-based’ providers in ‘private
(family) practice’. The former group tends to adhere to the guidelines of
the CDC and the Infectious Disease Society of America (IDSA) in diagnosing
and treating Lyme disease. In contrast, the latter group tends to rely on
‘anecdotal reports citing an alarming number of Lyme disease patients who
are supposedly co-infected with one or more of the following: Anaplasma,
Bartonella or Babesia. Such an unlikely scenario of multiple infections
arouses suspicion on the authenticity of these cases and those willing to
make such diagnoses’.
Comment (10): We feel that this is a very politically charged statement,
featuring two issues that define the Lyme Wars. The first issue concerns
the lofty ‘academic specialists’ who follow the CDC and IDSA guidelines in
diagnosing and treating Lyme disease. We have seen that the CDC guidelines
give a poor diagnostic yield for Lyme disease, since they were meant for
surveillance purposes and not for diagnosis [22,101]. The IDSA guidelines
were written by a panel of 12 Lyme disease ‘experts’, 11 of whom were
research scientists with minimal clinical experience in treating Lyme
disease. These guidelines have doomed thousands of suffering Lyme disease
patients to a lack of therapy based on the opinions of a handful of
researchers. With this knowledge, is it any wonder that ‘communitybased’
providers who deal with the clinical nightmare of Lyme disease have rejected
the CDC/IDSA guidelines and formulated their own diagnostic and therapeutic
parameters [53-55]? Pavia raises the second issue based on this clinical
dichotomy, stating that Lyme disease treatment outside the CDC/IDSA
guidelines represents a provider-driven policy that impugns the integrity of
the provider. The reality is that suffering patients seek out ‘Lyme-literate
’ providers because the ‘academic’ researchers have abandoned them. These
researchers and their followers offer nothing in the way of treatment for
the suffering of Lyme disease patients other than pseudopsychiatric
semantics [4,22] or meaningless labels such as chronic fatigue syndrome or
fibromyalgia, which are often manifestations of chronic, poorly treated Lyme
disease [56,57]. Pavia also refers to the alarming number of Lyme disease
patients who are supposedly co-infected with other tick-borne organisms.
Since this number is now ~ 20% or more of all Lyme disease cases [18,20,29],
the alarm should have sounded long ago.
Assertion (11): The Pavia paper praises the ‘highly significant’ results of
the study by Klempner et al. [58] that examined retreatment of Lyme disease
patients who had persistent symptoms of the disease. The study claimed that
it is unlikely that prolonged antibiotic treatment will offer any major
benefit to symptomatic patients who are no longer infectious.
Comment (11): The study by Klempner et al. [58] has been analysed in detail
elsewhere [55,102]. At the beginning of this article, we noted that one of
the main problems with Lyme disease is the lack of a test that proves the
eradication of spirochetal infection. Thus, we feel that the design of the
study by Klempner et al. was basically flawed, since the culture and
molecular techniques used in the study were insufficient to prove that
patients were ‘no longer infectious’ [102]. Furthermore, the choice of
‘prolonged’ antibiotic therapy for patients with neurological disease (1
month of intravenous ceftriaxone followed by 2 months of low-dose oral
doxycycline) was irrational and doomed to failure [55,102]. Consequently,
the study simply shows that inadequate retreatment of chronic Lyme disease
leads to inadequate results [102]. Unfortunately, because of the widespread
publicity given to this article and its prestigious publisher, the flawed
data has been widely used to deny care for symptomatic subjects.
Assertion (12): Pavia focuses on hyperbaric oxygen therapy (HBOT), shorter
course treatment with antibiotics and evernimicin therapy as future
treatment options for Lyme disease.
Comment (12): HBOT is currently being used as adjunctive treatment for
chronic Lyme disease [101]. Although in theory it is effective in creating a
more hostile environment for the Lyme disease spirochete, HBOT is a
cumbersome procedure that probably will never be available to the majority
of patients with chronic infection. The cost of multiple treatments is also
prohibitive. The Pavia paper fails to address the
hepatic toxicity of evernimicin, and it is doubtful that this toxic
antibiotic will ever be marketed for Lyme disease. Shorter course
antibiotic therapy was the subject of a recent study [59], and this
minimalist approach promises to yield more inadequately treated Lyme disease
sufferers. In contrast to these impractical or potentially toxic treatment
options, current and future Lyme disease therapy should focus on
combinations of antibiotics that are readily available and administered in a
rational manner, with monitoring of clinical and immunological parameters
[53,60-62]. In this regard, it is important to remember that the current
World Health Organization (WHO) recommendation for treating infection with
Mycobacterium tuberculosis is a combination of two antimicrobial agents
administered for 18 months, while the WHO-sanctioned treatment for leprosy
is a combination of three antimicrobial agents administered for 2 years
[63-65]. For a spirochete as complex and crafty as B. burgdorferi, these
guidelines are probably closer to what is needed for the eradication of
chronic spirochetal infection in Lyme disease. As stated previously,
recognition and evaluation of human transmission of Lyme disease will also
play a role in developing effective treatment strategies [22,23].
3. Expert opinion and conclusion
In conclusion, Lyme disease remains a public health threat of major
proportions. Continued trivialisation of this complex spirochetal illness
only serves to augment the threat by legitimising ignorance of Lyme disease
and neglect of Lyme disease patients. Until this trend is reversed, we will
continue to see thousands of patients suffering at the hands of the medical
establishment and desperately seeking care from the few providers who will
listen. As modern medicine rockets into the 21st Century, this ostracism of
suffering patients and persecution of dissenting healthcare providers can no
longer be tolerated. For their part, Lyme disease patients and their
providers must learn from the AIDS experience, where activism brought change
when it was perceived that nobody was listening. And as more people listen,
the ‘Lyme Wars’ may finally reach an end.
Acknowledgements
The authors thank Robert Bransfield, Joseph Burrascano, Kathleen Dickson,
David Dorward, Brian Fallon, Andrea Gaito, Julie Gerberding, Nick Harris,
William Harvey, Barbara Johnson, Anne Kjemtrup, Robert Lane, Kenneth
Liegner, Robert Lull, Daniel Moore, Scott Morrow, Steven Phillips, Walter
Prehn, Lynn Shepler, Virginia Sherr, Harold Smith, Gerald Sugarman and
Edward Winger for helpful discussion.
We also thank Pat Smith of the Lyme Disease Association, Phyllis Mervine,
Lee Lull, Peggy Leonard and Barb Barsocchini of the California Lyme Disease
Resource Center and Karen Forschner of the Lyme Disease Foundation for
continuing support. This article is dedicated to the memory of Paul Lavoie.
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The Lyme Wars: time to listen
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47. BROUQUI P, BADIAGA S, RAOULT D: Eukaryotic cells protect Borrelia
burgdorferi from the action of penicillin and ceftriaxone but not from the
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48. THOMAS V, ANGUITA J, BARTHOLD SW, FIKRIG E: Coinfection with Borrelia
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49. ZEIDNER NS, DOLAN MC, MASSUNG R, PIESMAN J, FISH D: Coinfection with
Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis
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C3H/HeJ mice. Parasite Immunol. (2000) 22:581-588.
50. MORO MH, ZEGARRA-MORO OL, BJORNSSON J et al.: Increased arthritis
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51. KRAUSE PJ, TELFORD SR 3rd, SPIELMAN A et al.: Concurrent Lyme disease
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• Influence of coinfection on Lyme disease severity and duration.
52. NADELMAN RB, WORMSER GP:Single-dose doxycycline for the prevention of
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53. BURRASCANO JJ: Lyme disease. In:Conn’s Current Therapy. WB Saunders
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•• An important review of Lyme disease diagnosis and treatment.
54. LIEGNER KB, KOCHEVAR J: Guidelines for the clinical diagnosis of Lyme
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55. BRANSFIELD R, BRAND S, SHERR V: Treatment of patients with persistent
symptoms and a history of Lyme disease. N. Engl. J. Med. (2001)
345:1424-1425.
• An abbreviated critique of [58], the flawed study of ‘long-term’
antibiotic therapy for Lyme disease.
56. LAWRENCE C, LIPTON RB, LOWY FD, COYLE PK: Seronegative chronic relapsing
neuroborreliosis. Eur. Neurol. (1995) 35:113-117.
57. FRASER DD, KONG LI, MILLER FW: Molecular detection of persistent
Borrelia burgdorferi in a man with dermatomyositis. Clin. Exp. Rheumatol.
(1992) 10:387-390.
58. KLEMPNER MS, HU LT, EVANS J et al.: Two controlled trials of antibiotic
treatment in patients with persistent symptoms and a history of Lyme
disease. N. Engl. J. Med. (2001) 345:85-92.
59. WORMSER GP, RAMANATHAN R, NOWAKOWSKI J et al.: Duration of antibiotic
therapy for early lyme disease. A randomized, double-blind,
placebocontrolled trial. Ann. Intern. Med. (2003) 138:697-704.
60. STRICKER RB, WINGER EE: Decreased CD57 lymphocyte subset in patients
with chronic Lyme disease. Immunol. Letters (2001) 76:43-48.
• Initial description of an immunological defect in chronic Lyme disease.
61. STRICKER RB, BURRASCANO J, WINGER EE: Longterm decrease in the CD57
lymphocyte subset in a patient with chronic Lyme disease. Ann. Agric.
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62. STRICKER RB, WINGER EE: Normalization of the CD57 natural killer cell
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Websites
101. www.geocities.com/HotSprings/Oasis/6455/lyme-links.html
Lots of links on Lyme disease - over 12,000 categorised links on Lyme
disease (2001).
•• The most extensive collection of Lyme disease references in existence.
102. http://www.ilads.org/stricker.htm PHILLIPS SE, BRANSFIELD R, SHERR VT
et al.: Evaluation of antibiotic treatment in patients with persistent
symptoms of Lyme disease: an ILADS position paper (2003).
•• A comprehensive critique of [58], the flawed study of ‘long-term’
antibiotic therapy for Lyme disease.
Affiliation
Raphael B Stricker MD1† & Andrew Lautin2 †Author for correspondence
1†Department of Medicine, California Pacific Medical Center, 450 Sutter
Street, Suite 1504, San Francisco, CA, USA
Tel: +1 415 399 1035; Fax: +1 415 399 1057; E-mail: rstricker@usmamed.com
2Department of Psychiatry, New York University School of Medicine, New York,
NY, USA
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