LymeNet Newsletter vol#1 #10 
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 LymeNet Newsletter vol#1 #10

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                      Volume 1 - Number 10 - 5/04/93

                               SPECIAL ISSUE

I.    Introduction
II.   News from the Wires
III.  Response
IV.   References
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.



TITLE: The Overdiagnosis of Lyme Disease
SOURCE: Journal of the American Medical Association
REFERENCE: 1993;269:1812-1816
AUTHORS: Allen C. Steere, MD; Elise Taylor; Gail L. McHugh, MS; Eric L.
         Logigian, MD

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
incorrect diagnosis.

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.


           Carl Brenner, Marc C. Gabriel, John S. O'Donnell

     A recent study published in the April 14, 1993 issue of the Journal of
the American Medical Association (JAMA) suggests that Lyme disease is widely
overdiagnosed.  The primary author of the study, Dr. Allen Steere of the
Tufts University School of Medicine, is the man who first described Lyme
disease as a distinct clinical entity in the United States, and is considered
one of the world's leading experts in Lyme disease research.  The publication
of his article, entitled "The Overdiagnosis of Lyme Disease," generated much
media attention and will clearly have a significant impact on how Lyme
disease is perceived both in the medical and lay communities.

     We believe that the study contains multiple serious flaws.  It relies on
outdated and indirect laboratory technologies that have never performed
adequately during independent testing, it makes assumptions about treatment
response that have been repeatedly demonstrated to be false, and it is
riddled with internal inconsistencies, circular reasoning, and speculation
masquerading as fact.  We are concerned that this paper's publication will
instill a false sense of security about Lyme disease in this country, will
compromise patients' access to treatment at all stages of the disease --
thus subjecting more people to potentially devastating long term sequelae --
and could possibly even influence the amount and direction of future
allocations of money for Lyme disease research.  We thus feel it is our
responsibility to highlight the methodological and philosophical flaws
inherent in this work.

     It should be noted that although Lyme disease has been recognized as a
distinct clinical entity for almost 20 years now, there are still gaping
holes in our knowledge about even 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 the limited medical 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.  We urge all physicians and researchers to set aside their
personal biases, to gather and examine their data as dispassionately as
possible and to avoid declarations of certainty where the data do not warrant

     Our specific concerns about the Steere et al. paper are as follows:


     The authors report that 98% of the patients (176 out of 180) who had
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 so, it means that they have developed an astonishingly
sensitive and specific group of tests that vastly outperform any of the
existing antibody tests or testing protocols that have been previously
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 laboratory.

     There is no compelling rationale whatsoever for accepting the claim that
this test is superior to the other antibody tests currently in use today.
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 [1-3].  It
strains credulity to believe that this test is any different, especially
when it has not, to our knowledge, been submitted for independent review.  It
is much more likely that Steere and his co-authors are exhibiting
inappropriate over-reliance on laboratory results -- from a single lab, no
less -- to make the diagnosis of Lyme disease.  The presumption seems to be
that this test is 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 this article is clearly derived almost
exclusively from the results generated by this test.  The reasoning is
entirely circular.

     Such an approach also 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 frequently stated that they are extremely
rare in late Lyme disease [4-6].  This is a classic canard -- misleading and
in fact inherently unprovable (since the diagnosis of late Lyme, at least
according to the Centers for Disease Control criteria, requires a positive
serology).  If seronegative, culture-positive Lyme disease had never been
described in the medical literature, such a conclusion would be appropriate;
this is not, however, the case, as many such cases have been identified and
reported [7-10].  In one study on transplacental transmission of Borrelia
burgdorferi [8], over half of the mothers who had adverse pregnancy outcomes
and whose fetuses or neonates demonstrated the presence of B. burgdorferi
were themselves seronegative.  This may very well represent a more accurate
picture of the true incidence of seronegative Lyme disease, since it is one
of the few studies that avoids the inevitable but understandable bias toward
seropositivity inherent in the current diagnostic climate.

     One example from this study is worth specific mention:
     "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. . . "

     It is frightening to contemplate the implications if this is the same
test that was used in the JAMA study, since, as mentioned earlier, Steere et
al. concluded that 203 of the patients in the study -- over a quarter of the
entire study population -- had received "false positive" serologies from
other laboratories.

     In addition, Steere et al. should not create a condition for diagnosis
that is impossible to be met in many cases.  The authors state in the JAMA
paper 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.  By definition, such an approach systematically excludes all patients
from areas that have not been investigated by epidemiologists for B.
burgdorferi infestation.  This is an inappropriate restriction in light of
the fact that thousands of clear-cut cases of Lyme disease, complete with
physician-verified erythema migrans, or clinical findings and positive
serologies, have been reported from "non-endemic" areas.  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 Dr. Steere's JAMA study to exclude the
diagnosis of Lyme disease, though of course the patient clearly did suffer
from B. burgdorferi infection and in fact passed it on to her fetus,
resulting in stillbirth.  This finding should be kept in mind when
evaluating the utility of the diagnostic criteria used in the JAMA study.

     It is remarkable that the authors made no attempt to use any direct
testing methods, such as antigen detection or DNA probes via the polymerase
chain reaction (PCR), to verify the accuracy of their diagnoses.  Although
these techniques are relatively new, several tests of considerable utility
have been reported [11-13].  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 used in this study are both
outdated and clearly marred by an extremely high level of subjectivity on
the part of the researchers.


     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, at least 52 of the patients thought to have active Lyme
disease had already been antibiotically treated before evaluation by Steere
and his colleagues.  Thus, the authors acknowledge that treatment failures
are a common phenomenon in Lyme disease (at least with other physicians'
patients).  Indeed, there are now culture-confirmed treatment failures in
the literature for all stages of the disease [7,10,14-16], sometimes even
after long term, high-dosage antibiotic treatment [10,15,16].  Other studies
employing the polymerase chain reaction (PCR) have indicated the persistence
of B. burgdorferi-specific DNA in the cerebrospinal fluid (CSF) of many
patients who remain symptomatic after antibiotic therapy [13].

     Yet later in the JAMA paper, unresponsiveness to antibiotic therapy is
used as a main criterion to conclude 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."  This passage demonstrates a startling internal
inconsistency that renders the conclusion that active disease was not
present highly questionable, especially since every one of the primary
symptoms associated with fibromyalgia or chronic fatigue syndrome
(myalgias, arthralgias, sleep disturbance, headache, etc.) are common in
active Lyme disease.  Although persistence of symptoms after treatment is
by no means an indication that the patient harbors persistent infection, the
many reported treatment failures do not allow the researcher to conclude
that a lack of response to antibiotics indicates the absence of infection.

     Of even greater concern is the fact that in some cases where the patient
did improve with antibiotic therapy but relapsed afterwards, the conclusion
was that the positive response was due to the placebo effect.  This
subjective interpretation is completely unsubstantiated and self serving.
It is equally valid to conclude that the antibiotic regimen suppressed the
infection without eradicating it.  Until studies on the efficacy of long
term antibiotic therapy are carried out in a controlled setting, anecdotal
observations such as these should be interpreted with extreme caution.

     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 wholly anecdotal and inappropriate.  Controlled
studies have indicated that a high percentage (67%) of seropositive Lyme
disease patients report an episode of major depression during the course
of their illness, most (90%) for the first time [17].  A wide variety of
minor and major psychiatric disorders have been reported in Lyme disease
[18-20], similar to the findings in neurosyphilis [21].  The authors are
either unaware of these findings or willfully ignoring them; in either
case, physician bias is clearly interfering with objective evaluation.

     Also alarming is the authors' cavalier attitude toward, for example,
the neurological sequelae that developed in 15 of the 156 patients who were
thought to have previously had Lyme disease but who were now felt to be
suffering from another disorder.  Although discussion of these patients'
symptoms was extremely vague, the syndromes listed -- vertigo, peripheral
neuropathies, radiculopathy and seizure disorder -- have all been described
in patients with active Lyme disease [4,6,22].  Steere and his colleagues
ruled out active disease in these patients because "neurological test
results for Lyme disease were negative."  Such a conclusion is entirely
unwarranted, since there are reports of culture-positive and PCR-positive
patients in the literature with active disease and normal neurological
findings [13,23].

     In any case, many of the clinical findings in Lyme disease, such as
Lyme meningitis, resolve even without treatment [6], but this certainly does
not mean that the patient has attained microbiological "cure."  The presence
of subjective symptoms combined with the absence of clinical findings after
treatment is frustrating for both physician and patient, but it is completely
inappropriate to blindly declare that a cure has been reached in all of these
cases.  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 this population of patients (10%) is far higher than what would
be expected in the population at large.  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 inappropriate conclusion
that suggests that Lyme disease and its sequelae are more benign than they
really are.

Implications and Conclusions

     The authors' apparent views on adverse treatment outcomes can thus be
interpreted as follows:

     "Treatment failures are common when other physicians treat Lyme disease,
     but never occur when we treat Lyme disease.  If we suspected Lyme
     disease in a patient, and he did not respond to antibiotic therapy, then
     the patient had fibromyalgia.  The symptoms remained identical, and we
     didn't bother to investigate whether the original agent was still
     present, but we JUST KNOW that we cured him and that he now has some
     other illness."

     That this passes as "science" in a leading medical journal is appalling.
Rather than engaging in a good faith 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.

     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 the patients recover
completely?  If so, it implies that Lyme disease is always easily cured, an
assumption that we know, from the culture- and PCR-confirmed treatment
failures in the Lyme literature (and from the authors' own willingness to
re-treat), to be false.  If there were relapses, then the authors' contention
that treatment failures are due primarily to misdiagnosis is clearly false,
unless they had themselves 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, at least one
facet of the study gets thrust into the glaring light of internal

     It is unacceptable to continue to deny that treatment failures occur
when they have been repeatedly documented in the academic literature, and
when the mechanisms by which they occur -- early dissemination of B.
burgdorferi to the central nervous system [24,25] and intracellular
localization and persistence [26,27] -- are becoming clearer.  It is time to
set aside the old bromides and instead make a concerted effort to determine
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.  Although it is perhaps conceivable that Dr.
Steere and his colleagues may be right about some of their conclusions, this
study provides no proof of it and should not be received as if it does.

     Of course Lyme disease is sometimes diagnosed when it is not present.
It is also not diagnosed when it is present.  There are many reasons for the
confusion: the sorry state of the current antibody tests, the relative
unavailability of direct detection methods, the wide variety of disease
manifestations, and physician and patient ignorance.  The federal response
to the public health issues posed by Lyme disease has been woefully
inadequate, a situation that is perpetuated, unfortunately, by studies such
as Dr. Steere's.

     We call upon Dr. Steere and his colleagues to immediately submit their
antibody tests for independent evaluation, to validate their diagnostic
conclusions by enrolling each of the patients from this study into another
that uses PCR detection, and to carry out controlled, double-blind studies
on the efficacy of longer term antibiotic treatment in cases where treatment
failures occur.  Until these measures are taken, all conclusions from this
study should be regarded as highly speculative rather than as objective

IV. ***** REFERENCES *****

1] Hedberg CW, Osterheim MT, MacDonald KL, et al. An interlaboratory study of
antibody to Borrelia burgdorferi. J Infect Dis 1987;155:1325-1327.

2] Proceedings of the First National Conference on Lyme Disease Testing.
CDC/ASTPHLD, November, 1990.

3] Bakken LL, Case KL, Callister SM, et al. Performance of 45 laboratories
participating in a proficiency testing program for Lyme disease serology.
JAMA 1992;268:891-895.

4] 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;319:1441-1446.

5] Steere AC. Lyme disease. N Eng J Med 1989;321:586-596.

6] Rahn DW, Malawista SE. Lyme disease: recommendations for diagnosis and
treatment. Ann Intern Med 1991;114:472-481.

7] Preac-Mursic V, Weber K, Pfister HW, et al. Survival of Borrelia
burgdorferi in antibiotically treated patients with Lyme borreliosis.
Infection 1989;17:355-359.

8] MacDonald AB. Gestational Lyme borreliosis: implications for the fetus.
Rheumatic Disease Clinics of North America 1989;15:657-677.

9] Lavoie PE, et al. Culture positive seronegative transplacental Lyme
borreliosis infant mortality. Arthritis Rheum 1987; 3(Suppl):S50.

10] 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.)

11] Dorward DW, Schwan TG, Garon CF. Immune capture and detection of Borrelia
burgdorferi antigens in urine, {*filter*} or tissues from infected ticks, mice,
dogs and humans. J Clin Microbiol 1991;29:1162-1170.

12] 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;160:1018-1129.

13] Keller TL, Halperin JJ, Whitman M. PCR detection of Borrelia
burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis patients.
Neurology 1992;42:32-42.

14] Schmidli J, Hunzicker T, Moesli P, et al. Cultivation of Borrelia
burgdorferi from joint fluid three months after treatment of {*filter*} palsy
due to Lyme borreliosis. J  Infect Dis 1988;158:905-906.

15] Hassler D, Riedel K, Zorn J, et al. Pulsed high-dose cefotaxime therapy
in refractory Lyme borreliosis (letter). Lancet 1991;338:193.

16] 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.)

17] 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.)

18] Barnett W, Sigmund D, Roelke U, et al. Endogenous paranoid-hallucinatory
syndrome caused by Borrelia encephalomyelitis. Nervenarzt 1991;62:445-7.

19] Roelke U, Barnett W, Wilder-Smith E, et al. Untreated neuroborreliosis:
Bannwarth's syndrome evolving into acute schizophrenia-like psychosis.
J Neurol 1992;239:129-131.

20] Fallon BA, Nields JA, Burrascano JJ, et al. The neuropsychiatric
manifestations of Lyme borreliosis. Psychiatric Quarterly 1992;63:95-117.

21] Rundell JR, Wise MG. Neurosyphilis: a psychiatric perspective.
Psychosomatics 1985;26:287-295.

22] Reik L, Smith L, Khan A, et al. Demyelinating encephalopathy in Lyme
disease. Neurology 1985;35:267-269.

23] 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;39:1118-1120.

24] 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;161:1187-1193.

25] Luft BJ, Steinman CR, Neimark HC, et al. Invasion of the central nervous
system by Borrelia burgdorferi in acute disseminated infection.
JAMA 1992;267:1364-1367.

26] Ma Y, Sturrock A, Weis JJ. Intracellular localization of Borrelia
burgdorferi within human endothelial cells. Infect Immun 1991;59:671-678.

27] Georgilis K, Peacocke M, Klempner MS. Fibroblasts protect the Lyme
disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro.
J Infect Dis 1992;166:440-444.


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Sat, 21 Oct 1995 10:33:41 GMT
 [ 1 post ] 

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