And the Empire Strikes back...
- From: "the 3rd Man" <sir_der05@xxxxxxxxx>
- Date: 20 Mar 2007 21:59:37 -0700
Clinical Infectious Diseases 2007;44:1137-1139
© 2007 by the Infectious Diseases Society of America. All rights
reserved.
1058-4838/2007/4408-0026$15.00
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CORRESPONDENCE
Reply to Pollock, Donta, Wilson, and Arne
Gary P. Wormser,1 Raymond J. Dattwyler,2 Eugene D. Shapiro,5,6 John J.
Halperin,3,4 Allen C. Steere,9 Mark S. Klempner,10 Peter J. Krause,8
Johan S. Bakken,11 Franc Strle,13 Gerold Stanek,14 Linda K.
Bockenstedt,7 Durland Fish,6 J. Stephen Dumler,12 and Robert B.
Nadelman1
Divisions of 1Infectious Diseases and 2Allergy, Immunology, and
Rheumatology, Department of Medicine, New York Medical College,
Valhalla, and 3New York University School of Medicine, New York, New
York; 4Atlantic Neuroscience Institute, Summit, New Jersey; the
Departments of 5Pediatrics and 6Epidemiology and Public Health and
7Section of Rheumatology, Department of Internal Medicine, Yale
University School of Medicine, New Haven, and 8Department of
Pediatrics, University of Connecticut School of Medicine and
Connecticut Children's Medical Center, Hartford, Connecticut;
9Division of Rheumatology, Allergy and Immunology, Massachusetts
General Hospital, Harvard Medical School, and 10Boston University
School of Medicine and Boston Medical Center, Boston, Massachusetts;
11Section of Infectious Diseases, St. Luke's Hospital, Duluth,
Minnesota; 12Division of Medical Microbiology, Department of
Pathology, The Johns Hopkins Medical Institutions, Baltimore,
Maryland; 13Department of Infectious Diseases, University Medical
Center Ljubljana, Ljubljana, Slovenia; and 14Medical University of
Vienna, Vienna, Austria
It is important to realize that guidelines cannot always account
for individual variation among patients. They are not intended to
supplant physician judgment with respect to particular patients or
special clinical situations. The Infectious Diseases Society of
America considers adherence to these guidelines to be voluntary, with
the ultimate determination regarding their application to be made by
the physician in the light of each patient's individual
circumstances.
Reprints or correspondence: Dr. Gary P. Wormser, Rm. 245, Munger
Pavilion, New York Medical College, Valhalla, NY 10595
(Gary_Wormser@xxxxxxxx).
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TO THE EDITOR-Dr. Pollock [1] is correct that the report by
Phillips et al. [2] is the key citation in support of the concept that
viable Borrelia burgdorferi may persist in the bloodstream, despite
prior courses of antibiotic treatment. However, 3 follow-up studies
have been unable to reproduce the findings (without even a single
positive blood culture result) [3-6]. In fact, the novel culture
medium employed by Phillips et al. [2] was unable to support the
growth of B. burgdorferi when the spirochete was directly introduced
into it.
There is no convincing evidence of persistence of B. burgdorferi
in the skin of North American patients who are treated for Lyme
disease [7, 8]. The European study that Pollock [1] cites, in which
Borrelia species were recovered from normal-appearing skin at the site
of a resolved erythema migrans skin lesion in 19 (1.7%) of 1148
asymptomatic patients for whom samples were cultured [9], would have
been more compelling had the positive culture results been confirmed
by an independent detection method performed on the skin samples, such
as PCR. Notably, in the 5 cases in which Borrelia species isolates
could be compared both before and after antibiotic treatment, the
Borrelia strains were not identical in 4 of the pairs of isolates and
were not even from the same species for the fifth [9]. The efficacy of
benzathine penicillin G (35%) is too low to justify recommending the
drug now that other, much more effective antibiotic regimens are
available [10].
In response to the assertion of Dr. Donta [11], it has not been
established that the long-term persistence (6 months) of subjective
symptoms after treatment occurs more frequently in patients with Lyme
disease than in patients with other types of infection or in patients
without any infection. Although the frequency of symptoms in patients
after treatment of Lyme disease exceeded that of symptoms in control
subjects in several retrospective studies, the validity of this
observation is uncertain, because these studies included patients
whose diagnosis and treatment of Lyme disease would often not satisfy
current standards [12, 13]. Moreover, the range of subjective
complaints by patients with Lyme disease is also observed among
patients with numerous other diagnoses and is definitely not "unique"
to this infection [14]. A well-designed prospective study that
includes a cohort of control subjects who do not have Lyme disease
would help to address this issue.
Dr. Donta's clinical experience with "several thousand
patients" [11, p. 1134] with post-Lyme disease syndrome is somewhat
surprising, in light of the difficulty experienced in finding eligible
subjects for the 3 published controlled-treatment trials of post-Lyme
disease syndrome conducted by other investigators. To enroll just 184
subjects in total, intensive efforts were required that included
increasing the time period for recruitment [3, 15] and adding
additional study sites [3].
Clinically directive conclusions cannot be drawn from
uncontrolled treatment trials in subjects who have only subjective
symptoms. Furthermore, the lack of specificity of the criteria used by
Dr. Donta [11] for diagnosing Lyme disease on the basis of results of
serologic tests [16, 17] raises the question of whether most of his
study subjects ever actually had Lyme disease [18]. Approximately 40%
of the general population would be considered to be seropositive on
the basis of the criteria Dr. Donta used [11; R. Porwancher, A. Levin,
and Immunetics, unpublished data].
The assertion that long-term infection with B. burgdorferi
suppresses humoral immune responses is not supported by available
data, which demonstrate that the profile of antibodies generated to B.
burgdorferi expands over time [19, 20]. Evidence also indicates that
B. burgdorferi is principally found in an extracellular location,
rather than an intracellular one, as Dr. Donta hypothesizes [11, 21].
We do agree that more research is needed to understand post-Lyme
disease syndrome; for that reason, we have proposed a standardized
case definition in the guidelines that could be used in future studies
[4].
Mr. Wilson's concerns [22] relate to his premise that the
majority of patients with Lyme disease do not have the well-recognized
objective features of this infection, such as erythema migrans or
joint swelling, and instead only manifest 1 subjective complaint from
an extensive list. Furthermore, patients with such nonspecific
symptoms are assumed to have persistent B. burgdorferi infection,
irrespective of prior antibiotic therapy for Lyme disease or negative
laboratory test results. Following this line of reasoning, diagnosis
would need to be made on the basis of the ability to differentiate
these complaints from similar ones that occur commonly in the general
population or in patients who have a variety of other conditions,
including chronic fatigue syndrome and fibromyalgia, among many others
[23-26]. Overdiagnosis of Lyme disease would be inevitable.
Mr. Wilson's theory [22] is not supported by convincing
scientific studies. In contrast to the assertions made, studies show
that the majority of patients with B. burgdorferi infection present
with erythema migrans [27], that there is no convincing evidence for
the persistence of B. burgdorferi after antibiotic treatment in
patients whose only complaints are subjective at the completion of
antibiotic therapy (see above discussion) [3-6], and that
seroreactivity is both expected and routinely observed in acute-phase
and/or convalescent-phase serum specimens obtained from patients who
have objective extracutaneous manifestations of Lyme disease [4, 28,
29].
Unfortunately, overdiagnosis of Lyme disease resulting in
unnecessary, costly, and potentially dangerous antibiotic treatment is
well known in the United States and has also been documented in Canada
[30-35]. In 1 study from British Columbia, which is a low-risk area,
only 2 (3%) of 65 patients were judged to have Lyme disease when
evaluated at a Borrelia referral clinic at the University Hospital in
Vancouver; moreover, definite alternative diagnoses could be
established for 77% of the patients [33].
Because of differences both among the species of Borrelia that
cause infection and among the clinical manifestations of Lyme disease
in Europe, compared with the United States, we developed the
guidelines [4] for use in the United States. Consequently, we did not
cite many worthwhile European studies. We agree with Dr. Arne [36]
that fewer controlled trials of treatment of children with erythema
migrans have been conducted in the United States than in Europe [37].
Acknowledgments
Potential conflicts of interest. G.P.W. has received
consulting fees from Baxter and research support from Immunetics and
is a founder of Diaspex, a company that does not offer products or
services. R.J.D. is a speaker for Pfizer and a part owner of
Biopeptides Corporation, a biotechnology company developing vaccines
and laboratory diagnostics, including for Borrelia burgdorferi. J.J.H.
is an expert witness on behalf of Lymerix (GlaxoSmithKline). A.C.S.
has received consulting fees from Baxter. P.J.K. has a patent pending,
with a university, on a babesiosis diagnostic procedure that is not
yet on the market. All other authors: no conflicts.
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