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EVALUATION OF ANTIBIOTIC TREATMENT IN PATIENTS WITH
PERSISTENT SYMPTOMS OF LYME DISEASE:
AN ILADS POSITION PAPER
by Phillips S, Bransfield
R, Sherr V, Brand S, Smith H, Dickson K, and Stricker R
April, 2003
The International Lyme and Associated Diseases Society (ILADS)*
P.O. Box 341461
Bethesda, MD 20827-1461
| Address
all correspondence to: |
Raphael
B. Stricker, M.D. |
| |
California Pacific
Medical Center |
| |
450 Sutter Street,
Suite 1504 |
| |
San Francisco, CA
94108 |
| |
Phone: (415) 399–1035 |
| |
Fax: (415) 399–1057 |
| |
E-mail: rstricker@usmamed.com |
Key words: Lyme disease,
borreliosis, long-term antibiotics, tickborne diseases.
* The International Lyme
and Associated Diseases Society (ILADS) is an international multidisciplinary
medical organization of researchers and clinicians. ILADS has created an international
forum to facilitate communication, scientific advancement and education of
healthcare providers on the subject of Lyme and associated tickborne diseases.
This paper was drafted by the authors and approved by the Board of Directors
of ILADS. Members who contributed substantially to writing this position statement
include:
| Steven
E. Phillips, M.D. |
Harold
A. Smith, M.D. |
| Greenwich Hospital |
Driver-Smith Med
Care |
| Greenwich, CT 06830 |
Bloomsburg, PA 17821 |
| |
|
| Robert Bransfield,
M.D. |
Kathleen Dickson,
B.S. |
| Riverview Medical
Center |
Pfizer, Inc. (Retired) |
| Red Bank, NJ 07701 |
Groton, CT 06340 |
| |
|
| Virginia T. Sherr,
M.D., F.A.P.A. |
Raphael Stricker,
M.D. |
| Private Practice
of Psychiatry |
California Pacific
Medical Center |
| Holland, PA 18966 |
San Francisco, CA
94108 |
| |
|
| Stephen Brand, Ph.D. |
|
| University of Rhode
Island |
|
| Kingston, RI 02881 |
|
TABLE
OF CONTENTS
ABSTRACT
Background and
Objective
Methods
Results
Conclusions
INTRODUCTION
METHODS
RESULTS
DISCUSSION
CONCLUSIONS
AUTHOR
CONTRIBUTIONS
REFERENCES
ABSTRACT
Background and Objective:
The history of Lyme disease has been characterized by intense controversy
over the diagnosis and treatment of this spirochetal infection. A recent high-profile
article by Klempner et al. [1] focused
attention on the optimal antibiotic treatment for chronic Lyme disease. Because
this research study has generated significant conflict and confusion in the
medical community, we undertook a critical analysis of its methodology and
conclusions.
Methods:
The International Lyme and Associated Diseases Society (ILADS) reviewed
the article according to established standards of evidence-based medicine.
Study design and scientific objectivity were analyzed in light of peer-reviewed
medical literature on chronic Lyme disease and associated tickborne illnesses.
Results:
Numerous methodologic weaknesses are noteworthy in the study. These include
inappropriate study design with respect to the antibiotic treatment regimen;
inappropriate selection and inadequate randomization of study patients; failure
to explain positive cerebrospinal fluid findings, and failure to report objective
neurocognitive assessments; failure to assess coinfection status of study
participants; exclusion of pertinent findings from the final report, with
inadequate follow-up of study participants; and failure to recognize that
spirochetal infection cannot be excluded without adequate culture techniques.
Conclusions:
The study by Klempner et al. contains a series of interrelated errors. It
fails to achieve its stated goal of being a long-term, properly randomized,
placebo-controlled treatment trial. The study appears to be scientifically
invalid and risks harming patients if its flawed conclusions are accepted
uncritically by physicians. In view of the uninterpretable results of this
study, further research into the use of long-term antibiotic therapy for chronic
Lyme disease is warranted.
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INTRODUCTION
Lyme disease is a multi-system
illness caused by infection with the spirochete Borrelia burgdorferi.
Although Lyme disease was officially recognized in the United States in 1975
in the Connecticut town from which it derives its name, the disease had been
discovered almost a century before in Europe, where the “bullseye”
rash known as erythema migrans (EM) and the late stage rash and deformity
of acrodermatitis chronicum atrophicans (ACA) were first recognized [2].
Rudolph Scrimenti first
documented the EM rash in the United States in 1970, five years before the
official labeling of Lyme disease [2].
Scrimenti noted a striking similarity between his patient’s expanding
ring-shaped skin lesion and the “erythema chronicum migrans” lesions
he knew, in part, from the writings of Sven Hellerstrom [3].
Scrimenti published Erythema chronicum migrans in the July 1970 issue
of the Archives of Dermatology, stating that this lesion was sometimes
associated with significant neurologic symptoms [2].
Further, he postulated that spirochetes and/or rickettsiae caused the illness,
which he thought was likely transmitted by ticks. His work established him
as the actual discoverer of the disease that later came to be called Lyme
disease. Yet both Scrimenti and Hellerstrom were openly ridiculed for their
beliefs [4].
In the ensuing years,
following Polly Murray’s report in 1975 of an epidemic of multi-system
illness including (but not limited to) arthritis in the now famous Connecticut
town of Lyme [4], chronic and persistent
sequellae of tick bites became common knowledge in both the scientific and
lay communities. Those notably convinced included researchers such as Allen
Steere, who in his early work wrote copiously on the subject of chronic neurologic
and arthritic manifestations of Lyme disease, even in cases following antibiotic
treatment [5]. In 1982, the spirochetal
etiology of the disease was proven by Willy Burgdorfer [6],
but this was only the beginning of what has since become a monumental task
in understanding the pathogenesis of Lyme disease and its chronic manifestations,
as outlined below.
A major problem with
the diagnosis of Lyme disease stems from the variable results of serologic
testing for its causative agent, B. burgdorferi. Indeed, well documented
but seronegative Lyme disease has been widely reported in the medical literature
[7–12], and the existence of seronegative
infection is substantiated by the observation that the great majority of repeatedly
infected deer remain seronegative for B. burgdorferi [13].
These observations raise doubt about the reliability of negative results using
current Lyme disease tests, particularly when testing is aimed at the diagnosis
of chronic as opposed to acute B. burgdorferi infections.
Just as seronegative
but active Lyme disease has been documented in the scientific literature,
so has active central nervous system (CNS) infection despite negative spinal
fluid tests for B. burgdorferi [14,15].
Negative results are often obtained on cerebrospinal fluid (CSF) of known
Lyme patients, including normal cell count and chemistry evaluations and absent
Lyme antibody titers [14,15].
Consequently the absence of antibodies against B. burgdorferi in CSF
cannot be relied on to rule out CNS infection with this organism. Given the
foregoing, the diagnosis of B. burgdorferi infection should be made
primarily on clinical grounds, with current serologies playing only supportive
roles.
In addition to problems
with diagnosis, it has been almost impossible to obtain a definition of cure
for this illness due to inherent problems in culturing the organism. Without
an easy method for culture, there has been no “gold standard” to
assess treatment efficacy. Despite this uncertainty, some physicians insist
that 30-day courses of antibiotic therapy are curative even for later stage
Lyme disease. This belief persists despite seminal studies documenting that
30-day courses of antibiotics do not eradicate disseminated B. burgdorferi
infection from mice, chimps and dogs [16–18].
Although animal data must be interpreted with caution, it is not surprising
that many humans with late stage Lyme disease also are not cured of their
symptoms with 30-day courses of antibiotics.
Indeed, there have been
a number of peer reviewed publications demonstrating persistent infection
with B. burgdorferi in humans despite multiple and extended courses
of antibiotic therapy [19]. Persistent
infection has been demonstrated repeatedly by both polymerase chain reaction
(PCR) and histopathology [20-23]. Chronic
infection has also been demonstrated by culture despite the well-known difficulties
in harvesting B. burgdorferi from Lyme patients, and culture positivity
has even been found in patients who are seronegative for the Lyme spirochete
[24–30]. In light of such data, it
would be illogical to assume that persistent symptoms in chronically ill Lyme
disease patients are not related to active infection with B. burgdorferi.
Ironically, and in direct opposition to the extensive body of published data,
some researchers have attributed chronic symptoms compatible with Lyme disease
to alternative vague diagnoses, such as “post-Lyme syndrome,” fibromyalgia,
or chronic fatigue syndrome [31,32].
The recent article by Klempner et al. [1]
amplified the dispute between widely differing medical factions and prompted
the current analysis.
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METHODS
The International Lyme
and Associated Diseases Society (ILADS), an international multi-specialty
medical organization, reviewed the article by Klempner et al. [1]
in an objective and didactic fashion. The review was accomplished using principles
of evidence-based medicine [33]. Specifically,
the study design, patient selection criteria, data reporting and outcomes
analysis were all subjected to scrutiny. The conceptual framework of the study
was also analyzed with reference to the published medical literature on chronic
Lyme disease and associated tickborne illnesses, which includes more than
12,000 articles in the peer reviewed medical literature [19].
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RESULTS
In reviewing the article
by Klempner et al [1], it became apparent
that there are multiple serious methodological flaws inherent in the fabric
of the work. First and foremost is the initial contention that the study was
intended to be a double blind, placebo-controlled trial of long-term antibiotic
treatment for chronic Lyme disease patients of both seronegative and seropositive
status. The authors used a treatment regimen consisting of one month of intravenous
ceftriaxone at 2 gm daily followed by two months of oral doxycycline at 200
mg daily [1]. These antibiotics differ
markedly in their mode of action and bioavailability, with no scientific evidence
backing the assumption that their effect is additive or that the combination
qualifies as “long-term” treatment. Consequently the trial amounted
to a short-term ceftriaxone protocol for re-treatment of patients who had,
without apparent success, experienced comparable treatment in the past, thereby
undermining the principal objective of the study. Furthermore, the doxycycline
dose used in the study (200 mg daily) was inadequate for CNS penetration [34].
Since the study population had neurocognitive symptoms, it is puzzling that
the authors would use a medication dosage that achieves only marginal CNS
concentration. To make matters worse, the acceptable medication compliance
rate was 75%, reducing the doxycycline dose to sub-therapeutic levels. This
was a regrettable oversight because enforcing a better compliance rate using
the correct dosage would have been simple, inexpensive, and safe.
A related problem with
the study derived from participants’ prior antibiotic treatment. If this
truly had been a long-term antibiotic treatment trial, one could have compared
short and long term antibiotic treatment efficacy given the participants’
prior “failure” with short-term antibiotics. However, since this
was in reality a short-term ceftriaxone re-treatment study, it fell prey to
obvious selection bias in that many of the patients had already “failed”
treatment with a short course of ceftriaxone, thus increasing the odds that
they would do so again. This approach introduced significant selection bias
into the study.
Selection bias was a
key problem throughout the trial. For example, evaluated patients were excluded
from participation if they tested positive by polymerase chain reaction (PCR)
for the presence of B. burgdorferi DNA, barring from the study the
very patients who may have been most likely to benefit from antibiotics. In
addition, despite the fact that PCR negativity was obligatory for inclusion
in the study population, PCR was then reported in the body of the work as
if it were a new “finding”. This may mislead readers to conclude
that chronic Lyme disease patients do not frequently have intermittently positive
PCR reactivity following treatment with antibiotics.
Criticism over the exclusion
of PCR positives was voiced in published correspondence by Bransfield et al.
[35], to which Weinstein and Klempner
replied, “We screened over 1800 patients for this study, and no patient
was excluded for this reason, since no patient was found to have a positive
PCR assay or culture for borrelia—a result that confirms the absence
of evidence of active infection in this clinical syndrome” [36].
However, the fact that the authors did not find even a single positive B.
burgdorferi PCR out of the 1800 previously identified Lyme disease patients
is in direct contrast to prevailing medical experience [20–30].
Although B. burgdorferi PCR has clinical disadvantages in sensitivity
(see Discussion), it has been shown to be a valuable tool for the documentation
of persistent infection in chronic Lyme disease patients [20–22,
28]. Because the authors failed to find,
even once, what other researchers have demonstrated repeatedly, doubt is raised
as to the accuracy of their PCR methods. In sum, the statement by Klempner
et al that they had confirmed the absence of active infection in this chronically
ill population was patently inaccurate, as ample evidence has verified the
persistence of B. burgdorferi infection in antibiotic-treated patients
with chronic Lyme disease [20–30].
Additionally, randomization
seems to have been insufficient in this research. Bransfield et al. state,
“Furthermore, at baseline, the placebo and antibiotic groups appeared
to have significantly different scores on the primary outcome measures. These
observations suggest that randomization may have been inadequate, thereby
invalidating the results of the study” [35].
Weinstein and Klempner respond, “The randomization protocol was adequate,
since baseline values for the primary outcome measures in all patients were
statistically equivalent in the placebo and antibiotic groups” [36].
However, the published data was in direct disagreement with their own statement
because the authors report a number of significant pre-test differences between
the placebo- and antibiotic-treated patients in the seronegative and seropositive
groups. For example, among seropositive patients the baseline scores on the
MOS Cognitive Scale were significantly worse in the antibiotic-treated cohort
than in the placebo cohort. Furthermore, within the seronegative group of
patients, the placebo cohort had significantly poorer baseline scores on the
SF-36 Mental Component, the MOS Pain Scale and the Fibromyalgia Impact Questionaire
than the antibiotic-treated cohort. These baseline differences could have
biased the outcome of the study.
Weinstein and Klempner
further stated, “Moreover, each patient served as his or her own control,
since the clinical response was measured by calculating a change in health
status for each patient” [35]. This
argument is unconvincing because the authors did not address their reported
pre-test differences. In addition, since the trial was conceived as a randomized,
placebo-controlled study, analysis of covariance in the randomized groups
would have been more appropriate than analysis of intrapatient variation to
address the issue of inadequate patient randomization [37].
This type of analysis was apparently not performed.
While the study focused
intensely on subjective neuropsychological testing, some noteworthy objective
findings were reported succinctly without any discussion. For example, Klempner
et al. found that over 25% of the enrollees had elevated CSF protein and that
8 had intrathecal production of B. burgdorferi antibodies. In patients
with a history of well-documented Lyme disease and such CSF findings, these
clinical parameters may be consistent with active neuroborreliosis. Instead,
the authors focused on measurements of questionable utility in assessing chronic
Lyme disease. Bransfield et al. criticized the authors in this regard by writing,
“The neuropsychological scales used in the study were insufficient to
assess the cognitive impairments in executive functioning and the psychiatric
dysfunctions that are seen in patients with persistent Lyme disease. The SF-36
is a subjective assessment scale, based on the patient’s self-perception.
There was a paucity of objective measures to assess the patient's status”
[35]. Weinstein and Klempner replied that
the enrollees were given an “extensive battery of neurocognitive tests
in addition to the SF-36. A forthcoming analysis of these data should help
to demonstrate any cognitive impairment, should it exist” [36].
Yet the question arises as to why this “extensive battery” of neurocognitive
tests was not discussed in this paper, where it might have aided in the serial
analysis of the patients' neurocognitive dysfunction during antibiotic treatment.
Such omission raises
the question as to what other data collected during this study was excluded
from the formal report. For example, Klempner publicly alluded to his testing
for CSF matrix metalloproteinases in these patients (Klempner MS, 11th Annual
Diseases of Summer Conference, South County Hospital, Wakefield, RI, 2001),
but this was not reported in the study. Since Klempner previously published
on the presence of these markers both in vitro and in vivo in
active neuroborreliosis [38, 39],
we anticipated that the paper might have included this important objective
data. Had it been revealed, it could have provided additional clues regarding
the presence or absence of active neuroborreliosis, and thus might have added
significantly to the study.
A final problem with
the study's data analysis is the exclusion of possible Jarisch-Herxheimer
reactions. As in syphilis, another spirochetal infection, Lyme disease patients
frequently experience this symptom intensification upon initiation of antibiotic
therapy [40–42], yet this was not
evaluated. Failure to discuss this symptom complex is a serious oversight,
since any assessment of interval change in patient status could not be conducted
properly without consideration of such a common phenomenon. Indeed, for patients
with active B. burgdorferi infection, worsening symptoms due to Jarisch-Herxheimer
reactions potentially could have been troublesome enough to prompt their withdrawal
from the study unless this complication had been discussed with them in advance.
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DISCUSSION
The methodologic deficits
described above reflect the fact that the complexities of B. burgdorferi
pathogenesis were not fully taken into consideration by Klempner et al. As
a result, the authors ignored the critical context for exploring diagnostic
factors and treatment responses in chronic Lyme disease. For example, B.
burgdorferi has the ability to survive in divergent conditions of mammals
and ticks by existing in a variety of forms that are ultrastructurally and
metabolically distinct. Even in the tick, altered morphologic forms of B.
burgdorferi are present [43], but
in the mammal, selective pressure from mammalian immune surveillance results
in these altered forms becoming more common. These “host adapted”
forms generally display altered morphology to varying degrees and are referred
to collectively as L-forms or spheroplasts. B. burgdorferi spheroplasts,
of which cystic forms and granules are sub-types, have been extensively documented
in vitro and in vivo [44–53],
both extracellularly and intracellularly [27,
47, 54–57].
Their ability to revert from host-adapted forms back to helical forms under
appropriate conditions has been demonstrated in vitro [47,
58, 59].
To the uninitiated, it
may be tempting to infer that B. burgdorferi cystic forms are degenerative
bacterial fragments. This is not the case, since researchers have demonstrated
protein synthesis requirements for spirochetal conversion into the spheroplast
form [44]. Indeed, it has been unequivocally proven that B. burgdorferi
cystic forms are virulent and infectious. Their infectivity, survival under
extreme environmental conditions, and ability to revert back to helical forms
in vivo have all been demonstrated by inoculation of B. burgdorferi
cysts into mice and subsequent recovery of helical spirochetes from the animals
[60]. As such, host-adapted forms of B.
burgdorferi are considered to be major factors in the relapsing and persistent
nature of Lyme disease [61–63].
Just as B. burgdorferi
spheroplasts have altered metabolic requirements for growth, so too, do they
have unique antibiotic sensitivities, altered surface protein expression,
dramatically reduced surface area presented for immune surveillance, and the
ability to cause multiple potential problems for PCR analysis. All of the
foregoing helps to explain observations of antibiotic resistance, seronegativity,
and even frequent PCR negativity in active disease [51,
54, 59,
63, 64].
The failure to address the complexities of the borrelial life cycle in the
work by Klempner et al. is a serious error. For example, the fact that cystic
forms demonstrate sensitivity to metronidazole while their helical kin are
resistant, illustrates the point that B. burgdorferi spheroplasts have
altered antibiotic resistance [65]. Attention
to these forms during the initial study design might have resulted in different
treatment decisions, with consideration that a cell wall-attacking cephalosporin
may not have been the ideal antibiotic choice for treatment of cell wall-deficient
organisms in patients with late-stage Lyme disease.
In addition, had the
authors addressed the intracellularity of B. burgdorferi, this might
have broadened their choices of antibiotic therapy. Although the utility of
ceftriaxone for Lyme disease has been documented, it has been similarly documented
that this agent frequently does not fully eradicate human B. burgdorferi
infections [19]. Cephalosporins do not
achieve intracellular penetration, a fact that may partially explain well-known
treatment failures associated with late stage Lyme disease. Indeed, B.
burgdorferi has been documented within a variety of cell types, including
but not limited to endothelium, fibroblasts, lymphocytes, macrophages, keratinocytes
and synovial cells [17, 51,
54, 66–70].
These findings are critically important since chronic infections are highly
dependent on intracellular asylum as a mode of persistence, and localization
within eukaryotic cells protects B. burgdorferi from antibiotics [71,
72]. It is particularly surprising that
the lead author agreed to use ceftriaxone in this study, since he previously
authored a paper on the fibroblast-mediated protection of B. burgdorferi
in vitro from concentrations of ceftriaxone achieved in vivo
for the treatment of Lyme disease [71].
Another conceptual
oversight in this study was the lack of consideration in the body of the
manuscript of co-infections commonly found in Lyme disease patients. In
addition to B. burgdorferi, Ixodes ticks transmit other pathogens
that may have infected the study patients, such as Babesia, Ehrlichia
and Bartonella species [73–80].
These tickborne coinfections apparently were not considered in the evaluation
of patients but could well have been clinically relevant and affected outcomes
in the study, since they occur in approximately 10% to 66% of Lyme disease
patients [73–78]. As with most
tickborne illness, the clinical spectrum of these coinfections spans sub-clinical
to life threatening presentations [75,
76], and they are underdiagnosed in
all age groups [73].
Despite the severity
of illness documented in this study's chronic Lyme disease patients, and the
fact that neither ceftriaxone nor doxycycline effectively treats certain coinfections,
this potential drawback was not mentioned in the body of the paper. Furthermore,
aside from non-spirochetal co-infections that can be tested for, there are
other tickborne spirochetal infections for which there is no commonly available
testing [81, 82].
These unknowns also should have been mentioned in the body of the study since
it is not clear to what extent they may cause or prolong illness or to what
extent they are amenable to antibiotic therapy.
In summary, the methodologic
problems of the study reflect an apparently inadequate appreciation of Lyme
disease pathogenesis and persistence in patients with chronic symptoms of
tickborne disease.
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CONCLUSIONS
In our analysis, the
study by Klempner et al. fell prey to a series of interrelated errors. The
study began by missing its initial design goal of being a long-term, properly
randomized, placebo-controlled antibiotic treatment trial for patients with
chronic Lyme disease, simply because the treatment provided was not long-term.
Many methodologic and conceptual aspects of the work were flawed, resulting
in patient selection bias, sub-optimal antibiotic treatment regimens, faulty
analysis and/or exclusion of data, and disregard for B. burgdorferi
microbiology and pathogenesis.
Based on its many errors,
much of the article by Klempner et al. is, in our opinion, scientifically
invalid and risks harming patients if it is accepted uncritically by physicians
who may not have the time or the expertise to analyze the work. Indeed, a
majority of medical practitioners may, after reading this paper, inappropriately
withhold treatment from patients with persistent Lyme disease [83].
This would be especially troubling since other peer reviewed medical research
demonstrates that extended treatment with months of the correct choice of
antibiotic therapies can be remarkably beneficial for patients with late-stage
Lyme disease [84–86]. Certainly,
long-term antibiotic treatment is medically accepted and approved for other
chronic infectious diseases such as tuberculosis and leprosy [87–89].
We hope that future studies of long-term treatment of Lyme disease will be
designed, implemented and analyzed in a more appropriate manner.
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AUTHOR CONTRIBUTIONS
Dr Phillips wrote the
initial manuscript, researched the initial references, initially coordinated
the project and participated in many editing reviews. Dr Bransfield wrote
the initial outline, wrote and researched sections of the article, participated
in many editing reviews and coordinated completion of the article. Dr Sherr
wrote and researched sections of the article, served as a liaison to the ILADS
board and participated in many editing reviews. Dr Brand wrote and researched
a section of the article related to research design and participated in some
reviews. Dr Smith wrote sections of the article, participated in many editing
reviews, rewrote one of the revisions and checked for the accuracy of the
references. Kathleen Dickson wrote sections and participated in editing reviews.
Dr Stricker wrote a section on the study protocol, edited the section on coinfections,
contributed assistance with the references, participated in final review of
the manuscript and coordinated completion and submission of the article.
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