EVALUATION OF ANTIBIOTIC TREATMENT IN PATIENTS WITH PERSISTENT SYMPTOMS OF LYME DISEASE: AN ILADS POSITION PAPER

http://www.ilads.org/files/position2.pdf

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
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.
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* 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
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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 multisystem
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.
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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.
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 retreatment
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].
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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
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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.
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
9
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
10
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.
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, suboptimal
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.
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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