Table of Contents:
Response To "The Overdiagnosis Of Lyme Disease"
Journal of the American Medical Association, 1993;269:1812-1816
By: Carl Brenner, Marc C. Gabriel, John S. O'Donnell
* Lyme Disease Electronic Mail Network *
* LymeNet Newsletter *
Volume 1 - Number 10 - 5/04/93
RESPONSE TO "THE OVERDIAGNOSIS OF LYME DISEASE"
II. News from the Wires
V. How to Subscribe, Contribute and Get Back Issues
I. ***** INTRODUCTION *****
The following issue offers a response to the JAMA article authored by Dr.
Allen Steere of Tufts University School of Medicine entitled "The
Overdiagnosis of Lyme Disease." Attached below is the abstract of the
paper, followed by the response authored by the tri-editors of this
We highly recommend our readers obtain a copy of Dr. Steere's article for
their own independent review. We are confident that our methodological
and philosophical arguments will prove to be borne out by future research,
and that many of our readers who have read the original article will concur
with our conclusions.
As usual, this newsletter may be reproduced freely as long as it is not
modified or abridged in any way. If your publication does not have a
reprint agreement with the Newsletter and you would like permission,
contact me via e-mail or FAX.
II. ***** NEWS FROM THE WIRES *****
TITLE: The Overdiagnosis of Lyme Disease
SOURCE: Journal of the American Medical Association
AUTHORS: Allen C. Steere, MD; Elise Taylor; Gail L. McHugh, MS; Eric L.
OBJECTIVE: To analyze the diagnoses, serological test results, and treatment
results of the patients evaluated in a Lyme disease clinic, both prior to
referral and from current evaluation.
DESIGN: Retrospective case survey of prescreened patients.
SETTING: Research and diagnostic Lyme disease clinic in a university
PATIENTS: All 788 patients referred to the clinic during a 4.5-year period
who were thought by the referring physician or the patient to have a
diagnosis of Lyme disease.
MAIN OUTCOME MEASUREMENTS: Symptoms and signs of disease, immunodiagnostic
tests of Lyme disease, and tests of neurological function.
RESULTS: Of the 788 patients, 180 (23%) had active Lyme disease, usually
arthritis, encephalopathy, or polyneuropathy. One hundred fifty-six patients
(20%) had previous Lyme disease and another current illness, most commonly
chronic fatigue syndrome or fibromyalgia; and in 49 patients, these symptoms
began soon after objective manifestations of Lyme disease. The remaining 452
patients (57%) did not have Lyme disease. The majority of these patients
also had the chronic fatigue syndrome or fibromyalgia; the others usually
had rheumatic or neurological diseases. Of the patients who did not have
Lyme disease, 45% had had positive serological test results for Lyme disease
in other laboratories, but all were seronegative in our laboratory. Prior
to referral, 409 of the 788 patients had been treated with antibiotic
therapy. In 322 (79%) of these patients, the reason for lack of response was
CONCLUSIONS: Only a minority of the patients referred to the clinic met
diagnostic criteria for Lyme disease. The most common reason for lack of
response to antibiotic therapy was misdiagnosis.
III. ***** RESPONSE TO "THE OVERDIAGNOSIS OF LYME DISEASE" *****
Carl Brenner, Marc C. Gabriel, John S. O'Donnell
Although Lyme disease has been recognized as a distinct clinical
entity for nearly 20 years , there are still gaping holes in our
knowledge about the most fundamental questions of incidence, diagnosis and
treatment. This is due primarily to the many difficulties posed by the
nature of the illness (non-specific symptoms, protean manifestations, long
latency period and/or apparent asymptomatic infection in some individuals,
etc.) and our limited arsenal in the areas of both testing and treatment.
The resulting knowledge gap leaves room for reasonable people to disagree
on almost every facet of Lyme disease research.
A recent study by Steere et al.  published in the April 14, 1993
issue of the Journal of the American Medical Association (JAMA) suggests
that Lyme disease is widely overdiagnosed. Because the study's conclusions
are so striking and its primary author is considered one of the world's
leading experts in Lyme disease research, the publication of this article
has generated considerable medical and media attention and will likely have
significant impact on how Lyme disease is perceived in both the medical and
We believe that the study contains multiple serious flaws which
leave its conclusions unsupported. We are concerned that this paper's
publication may lead to ill-advised complacency about Lyme disease in this
country, may compromise patients' access to treatment at all stages of the
disease -- thus exposing more of them to the risk of potentially
devastating long term sequelae -- and may even influence the amount and
direction of future allocations of funds for Lyme disease research. We thus
feel it imperative to address the methodological and philosophical flaws in
Our specific concerns about the Steere et al. paper are as follows:
The authors report that 98% of the patients (176 out of 180) found
to have active Lyme disease, but none of the patients (0 out of 452) who
had never had Lyme disease but who were evaluated for suspected Lyme at
their clinic, were seropositive by enzyme-linked immunosorbent assay
(ELISA) and/or Western Blot. If this is correct, it means the authors have
developed an extremely sensitive and specific group of tests that vastly
outperform any of the existing antibody tests or testing protocols that
have been reviewed in the Lyme literature. Indeed, the authors state that
of the 452 patients in the study who were determined to have never had Lyme
disease, 203 (45%) had obtained "false" positive results from another
It is difficult to accept uncritically the authors' claim that
their antibody testing protocols are superior to others currently in use.
Independent reviews of a wide variety of today's antibody detection tests
-- immunofluorescent assays, enzyme-linked immunosorbent assays and
assorted immunoblots -- have indicated generally dismal performance, marked
by significant interlaboratory and intralaboratory variability [3-5]. The
authors offer no independent evaluations or persuasive arguments to
distinguish their tests from others in current use. Instead, it appears
that Steere and his co-authors are relying inappropriately on imperfect
testing techniques -- from a single laboratory -- to make the diagnosis of
Lyme disease. The presumption seems to be that their tests are better than
others because the correlation between seropositivity and actual Lyme
disease is highest; on the other hand, the definition of "actual Lyme
disease" in the study is derived almost exclusively from their test
results. The reasoning is entirely circular.
Moreover, the nearly exclusive reliance on serologies for diagnosis
leads to the systematic underestimation of the prevalence of seronegative
Lyme disease. This point cannot be overemphasized. Although false negative
serologies are widely recognized as common in early Lyme disease, it is
often claimed that they are extremely rare phenomena later in the course of
the illness [6-8]. The many cases of seronegative, culture-positive "late"
Lyme disease that have been identified and reported [9-12], however, make
this claim even more untenable than it is unverifiable. In one study on
transplacental transmission of Borrelia burgdorferi , over half of the
mothers who had adverse pregnancy outcomes and whose fetuses or neonates
demonstrated the presence of B. burgdorferi were themselves seronegative.
Thus, when the study population is determined by factors other than
serology -- when the inevitable bias toward seropositivity is removed --
the true incidence of seronegative Lyme disease emerges.
One example from this study merits special attention:
"A 24-year old white woman was admitted in February 1985 in labor
at term of her pregnancy. Ultrasound examination showed that the fetus was
dead when she arrived at the hospital. Following the delivery of her
stillborn infant and completion of the fetal autopsy, a retrospective
interview established that she had acquired Lyme borreliosis in the first
trimester of her pregnancy outside of Salt Lake City, Utah. Postpartum
serological studies yielded conflicting results because the Centers for
Disease Control found strongly reactive results by IFA and ELISA, as did
the New York State Department of Health; however, the Yale University
laboratory of Dr. Allen Steere could detect no evidence of specific
antibodies for B. burgdorferi. Fetal viscera showed B. burgdorferi in the
liver, adrenal, brain, heart and placenta. . . "
The implications of this finding for the patients studied in "The
Overdiagnosis of Lyme Disease" are obvious and profound, given that over a
quarter of the study population was determined by the authors to have
received "false positive" test results from other laboratories. False
negatives in Dr. Steere's laboratory may very well account for a
significant portion of the discrepancy among results.
Steere et al. further compromise their estimates of the numbers of
patients with Lyme disease by creating inappropriate conditions for
diagnosis which in some cases are impossible to meet. The authors state
that "a history of exposure in an area where B. burgdorferi has been
recovered from ticks" was required for a diagnosis of Lyme disease in their
study. This approach systematically excludes all patients from areas that
have not been investigated for B. burgdorferi infestation. In light of the
fact that thousands of clear-cut cases of Lyme disease, complete with
physician-verified erythema migrans, and/or clinical findings and positive
serologies, have been reported from "non-endemic" and unstudied areas, such
a restriction is inappropriate. The patient in the study quoted above
apparently contracted Lyme disease in Utah and was also seronegative on Dr.
Steere's ELISA. Either of these two factors alone would have been
sufficient in Steere et al.'s JAMA study to exclude the diagnosis of Lyme
disease, though of course the patient clearly did suffer from B.
It is remarkable that the authors made no attempt to use any direct
testing methods, such as culture, histological tissue examination, or
antigen or nucleic acid detection systems, to verify the accuracy of their
diagnoses. Although the latter techniques are relatively new, several tests
of considerable utility have been reported [13-15]. If one is carrying out
a study that purports to be the final word on the correct diagnosis of a
disease, every effort should be made to use the latest and most accurate
diagnostic techniques before publishing the study. The diagnostic criteria
and methods used by Steere et al. are both outdated and marred by an
unacceptable level of subjectivity on the part of the researchers.
Response to Treatment:
Steere et al. divide their patient population into three categories:
patients with active Lyme disease, patients with a history of
Lyme disease and another current illness, and patients with another
illness. Interestingly, of the patients thought to have active Lyme
disease, at least 52 had already been antibiotically treated before
evaluation by the authors. Thus, Steere et al. implicitly acknowledge that
treatment failures are a common phenomenon in Lyme disease.
Yet under the study protocols, lack of responsiveness to antibiotic
therapy is a primary criterion for the determination that active Lyme
disease is not present: "We did not find age, sex, or duration of symptoms
to be of help in diagnosing fibromyalgia, but the presence of tender points
upon examination and lack of response to antibiotic therapy were important
clues in diagnosing fibromyalgia." These criteria are clearly not
consistent with the authors' own findings regarding the prevalence of
treatment failures among patients whom they determined to harbor active
disease; further, it is well known that every one of the primary symptoms
associated with fibromyalgia or chronic fatigue syndrome (persistent
headache, fatigue, myalgias, arthralgias, sleep disturbance, etc.) are
common in active Lyme disease and cannot be used for differential
diagnosis. Finally, in cases where the patient did improve with antibiotic
therapy but relapsed afterwards, the authors conclude anecdotally that the
positive response was probably due to the placebo effect.
We strongly take issue with the fact that the alternate interpretation
for these treatment responses -- that borrelial infection
persisted after antibiotic treatment -- is completely ignored. There are
now culture-confirmed treatment failures in the medical literature for all
stages of Lyme disease [9,12,16-19], sometimes even after long term,
high-dosage antibiotic therapy [17-19]. Other studies employing the
polymerase chain reaction have indicated the persistence of B.
burgdorferi-specific DNA in the cerebrospinal fluid of many patients who
remain symptomatic after antibiotic therapy . In light of these
findings, the authors' exclusive interpretation that treatment failure was
due to misdiagnosis seems rather reckless. Although persistent symptoms
after treatment by no means implies the continued presence of B.
burgdorferi, unresponsiveness to short term antibiotic therapy cannot be
interpreted to exclude it.
In addition, the use of psychiatric symptoms to exclude the
diagnosis of Lyme disease (". . . psychiatric disorders such as
anxiety, depression or somatization clearly played a role in the illness
of some of these patients . . . ") is entirely inappropriate.
Controlled studies have indicated that a high percentage (66%) of
seropositive Lyme disease patients report an episode of major
depression during the course of their illness, most (90%) for the
first time . A wide variety of minor and major psychiatric disorders
have been reported in Lyme disease [21-23], similar to the findings in
neurosyphilis . The authors may be unaware of these findings or may be
ignoring them; in either case, the study's patient evaluation techniques
are compromised. Also disturbing is the authors' classification of
the neurological sequelae that developed in 15 of the 156 patients who were
determined to have previous Lyme disease and another current illness.
Although discussion of these patients' symptoms was vague, the syndromes
listed in the accompanying table -- vertigo, peripheral neuropathies,
radiculopathy and seizure disorder -- have all been described in patients
with active Lyme disease [7,8,25]. Steere and his colleagues ruled out
active disease in these patients because "neurological test results for
Lyme disease were negative." Such a conclusion is insupportable, as there
are many reports of culture-positive and PCR-positive patients with active
disease and normal neurological findings [15,26,27]. Further, many clinical
findings in Lyme disease, such as Bell palsy or Lyme meningitis, often
resolve even without treatment , but this certainly cannot be equated
with microbiological "cure." The presence of subjective symptoms in
combination with the absence of clinical findings after treatment is
frustrating for both physician and patient, but it is clearly inappropriate
to simply declare the patient borrelia-free in these circumstances.
Finally, even if the authors are correct and active disease was not present
in any of these 15 patients, the incidence of serious neurological sequelae
in the "post-Lyme" patient population implies that the "post-Lyme syndrome"
can be quite severe. The shunting of these patients into the "non-Lyme"
category gives the impression that Lyme disease could not have been
responsible for any of their symptoms, an extremely questionable conclusion
that suggests that Lyme disease and its sequelae are more benign than they
really are. On a broader level, the authors are asking us to believe that
one-fifth of the entire study population had a history of Lyme disease,
were all cured, and then went on to develop a variety of other illnesses,
virtually all of which have identical symptoms to active Lyme disease. This
Implications and Conclusions:
The methodology used by Steere et al. for categorizing diagnoses
with adverse antibiotic treatment outcomes can thus be summarized as
- Treatment failures occurred in other physicians' treatment of Lyme disease.
- However, treatment failures apparently never occurred when the authors
treated Lyme disease.
- In cases where Lyme disease was diagnosed in a patient who did not
improve permanently with short term antibiotic therapy, the determination
was made retrospectively that Lyme disease was not present.
Rather than engaging in a serious attempt to explore the rate of
treatment failure in their study by utilizing direct detection methods, the
authors chose to rely entirely on anecdotal observations and then reported
these as objective fact: These patients do not have Lyme disease. This
retrospective determination was made despite ongoing unchanged
symptomatology, despite extensive literature documenting culture-confirmed
persistent infection following antibiotic treatment, and without
investigation via direct methods for the presence of B. burgdorferi. That
this is offered as "science" in a leading medical journal is appalling.
Interestingly, the authors never followed up on the patients who
were determined to have active Lyme disease and who were therefore treated
with "appropriate" antibiotic regimens. Did all of these patients recover
completely? If so, it would imply that Lyme disease is always easily cured,
an assumption that is belied by both the medical literature and the
authors' own willingness to re-treat. If there were later relapses, then
the authors' contention that treatment failures are due primarily to
misdiagnosis is obviously false, unless they had been mistaken in their
diagnosis of Lyme disease in these patients, in which case the diagnostic
conclusions of the study are rendered useless. No matter how these
questions are answered, the internal contradictions of the study are
It is no longer acceptable to continue to deny that treatment
failures often occur in Lyme disease. The literature now provides
substantial documentation on this point, and is beginning to elucidate the
mechanisms responsible. Early dissemination of B. burgdorferi to the
central nervous system [27,28] and intracellular localization and
persistence [29,30] have been identified as contributors to treatment
failure in Lyme disease. Instead of anecdotal and subjective "studies" like
"The Overdiagnosis of Lyme Disease," we urgently need to know the true
incidence of Lyme disease, the percentage of patients in whom the Lyme
spirochete survives after therapy, and the efficacy of further antibiotic
treatment in these patients. Some authors are already attempting to come to
terms with these issues [31,32]. Unfortunately, Steere et al. clearly are
not. Instead, the authors have employed a flawed methodology that "defines
away" Lyme disease and does a disservice both to patients and to unwary
physicians who as a result of this article may adopt an inappropriately
skeptical approach to the diagnosis .
***** REFERENCES *****
1] Steere AC, Malawista SE, Snydman DR, et al. Lyme arthritis: an epidemic
of oligoarticular arthritis in children and adults in three Connecticut
communities. Arthritis Rheum 1977;20:7-17.
2] Steere AC, Taylor E, McHugh GL, et al. The overdiagnosis of Lyme
disease. JAMA 1993;269:1812-6.
3] Hedberg CW, Osterheim MT, MacDonald KL, et al. An interlaboratory study
of antibody to Borrelia burgdorferi. J Infect Dis 1987;155:1325-7.
4] Proceedings of the First National Conference on Lyme Disease Testing.
CDC/ASTPHLD, November, 1990.
5] Bakken LL, Case KL, Callister SM, et al. Performance of 45 laboratories
participating in a proficiency testing program for Lyme disease serology.
6] Dattwyler RJ, Volkman DJ, Luft BJ et al. Seronegative Lyme disease:
dissociation of specific T- and B-lymphocyte responses to Borrelia
burgdorferi. N Engl J Med 1988;319:1441-6.
7] Steere AC. Lyme disease. N Eng J Med 1989;321:586-96.
8] Rahn DW, Malawista SE. Lyme disease: recommendations for diagnosis and
treatment. Ann Intern Med 1991;114:472-81.
9] Preac-Mursic V, Weber K, Pfister HW, et al. Survival of Borrelia
burgdorferi in antibiotically treated patients with Lyme borreliosis.
10] MacDonald AB. Gestational Lyme borreliosis: implications for the
fetus. Rheumatic Disease Clinics of North America 1989;15:657-77.
11] Lavoie PE, et al. Culture positive seronegative transplacental Lyme
borreliosis infant mortality. Arthritis Rheum 1987; 3(Suppl):S50.
12] Häupl Th, Krause A, Rittig M, et al. Persistence of Borrelia
burgdorferi in chronic Lyme disease: altered immune regulation or evasion
into immunologically privileged sites? (Abstr. 149, Fifth Int'l Conf. on
Lyme Borreliosis, Arlington VA 1992.)
13] Dorward DW, Schwan TG, Garon CF. Immune capture and detection of
Borrelia burgdorferi antigens in urine, blood or tissues from infected
ticks, mice, dogs and humans. J Clin Microbiol 1991;29:1162-70.
14] Rosa PA, Schwann TG. A specific and sensitive assay for the Lyme
disease spirochete Borrelia burgdorferi using the polymerase chain
reaction. J Infect Dis 1989;160:1018-29.
15] Keller TL, Halperin JJ, Whitman M. PCR detection of Borrelia
burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis patients.
16] Schmidli J, Hunzicker T, Moesli P, et al. Cultivation of Borrelia
burgdorferi from joint fluid three months after treatment of facial palsy
due to Lyme borreliosis. J Infect Dis 1988;158:905-6.
17] Hassler D, Riedel K, Zorn J, et al. Pulsed high-dose cefotaxime
therapy in refractory Lyme borreliosis (letter). Lancet 1991;338:193.
18] Liegner KB, Rosenkilde CE, Campbell GL, et al. Culture-confirmed
treatment failure of cefotaxime and minocycline in a case of Lyme
meningoencephalomyelitis in the United States. (Abstr. 63, Fifth Int'l
Conf. on Lyme Borreliosis, Arlington VA 1992.)
19] Masters E, Lynxwiler P, Rawlings J. Spirochetemia two weeks post
cessation of six months of continuous p.o. amoxicillin therapy. (Abstr.
65, Fifth Int'l Conf. on Lyme Borreliosis, Arlington VA 1992.)
20] Fallon BA, Nields JA. Psychiatric manifestations of Lyme borreliosis:
Part I, A controlled study of major depression. (Abstr. 47, Fifth Int'l
Conf. on Lyme Borreliosis, Arlington VA 1992.)
21] Barnett W, Sigmund D, Roelke U, et al. Endogenous
paranoid-hallucinatory syndrome caused by Borrelia encephalomyelitis.
22] Roelke U, Barnett W, Wilder-Smith E, et al. Untreated
neuroborreliosis: Bannwarth's syndrome evolving into acute
schizophrenia-like psychosis. J Neurol 1992;239:129-31.
23] Fallon BA, Nields JA, Burrascano JJ, et al. The neuropsychiatric
manifestations of Lyme borreliosis. Psychiatric Quarterly 1992;63:95-117.
24] Rundell JR, Wise MG. Neurosyphilis: a psychiatric perspective.
25] Reik L, Smith L, Khan A, et al. Demyelinating encephalopathy in Lyme
disease. Neurology 1985;35:267-9.
26] Pfister H-W, Preac-Mursic V, Wilske B, et al. Latent Lyme
neuroborreliosis: presence of Borrelia burgdorferi in the cerebrospinal
fluid without concurrent inflammatory signs. Neurology 1989;39:1118-20.
27] Luft BJ, Steinman CR, Neimark HC, et al. Invasion of the central
nervous system by Borrelia burgdorferi in acute disseminated infection.
28] Garcia-Monco JC, Villar BF, Alen JC, et al. Borrelia burgdorferi in
the central nervous system: experimental and clinical evidence for early
invasion. J Infect Dis 1990;161:1187-93.
29] Ma Y, Sturrock A, Weis JJ. Intracellular localization of Borrelia
burgdorferi within human endothelial cells. Infect Immun 1991;59:671-8.
30] Georgilis K, Peacocke M, Klempner MS. Fibroblasts protect the Lyme
disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro. J
Infect Dis 1992;166:440-4.
31] Brenner C. Lyme disease: asking the right questions. Science
32] Liegner KB. Lyme disease: the sensible pursuit of answers. J Clin
Microbiol, in press.
33] Tuohy L. Victim of Lyme disease settles malpractice suit. Hartford
Courant. May 18. 1993, p. C8.
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