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1996
LDF Conference Abstract -- Boston, MA
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9th
Annual International Conference on Lyme Borreliosis and Other
Tick-borne Disorders
Chronic Lyme Disease: Basic Science and Clinical Approaches
Abstracts
of Presentations
ANIMAL
MODELS
Stephen
W. Barthold, DVM, PhD
Professor, Yale University School of Medicine
Protective
and Disease-modulating Antibody-mediated Immunity to Borrelia
burgdorferi Antigens Expressed in vivo
Borrelia
burgdorferi
is a dynamic pathogen with a propensity for persistent infection
in immunologically responsive hosts, including humans. We have
utilized a well-defined mouse model of Lyme disease, in which
mice infected by syringe of tick develop heart and joint disease
that undergo spontaneous resolution and episodic recurrence over
the course of persistent infection. Spirochetes appear to persist
extracellularly within collagenous connective tissue, particularly
the skin. Using the mouse model, we have found that B. burgdorferi
undergoes dramatic changes in protein expression in different
environments. For example, OspA is abundantly expressed on spirochetes
in the midgut of unfed ticks, but is rapidly down-regulated when
ticks begin to take a blood meal. Spirochetes entering the host
do not express OspA, and are therefore not vulnerable to OspA
immunity. During infection, other proteins are expressed that
are probably required for tissue invasion. Several proteins have
been identified that are expressed exclusively in vivo and recognized
by the host immune response. Based on adoptive and passive transfer
studies, host humoral, but not cellular, responses directed against
in vivo-expressed proteins have varying degrees of protective
activity and are also involved in resolution (and recurrence)
of disease. Compartmentalization of host immunity to antibody
facilitates efforts to incriminate responsible antigens by screening
a genomic expression library with serum from infected mice. Incrimination
and characterization of the genes and proteins involved in persistent
infection and disease modulation are the frontier of Lyme disease
research, with the potential for development of second generation
preventive as well as therapeutic vaccines. This presentation
will provide an overview of this work.
Ronald
F. Schell, PhD
Professor, University of Wisconsin School of Medicine
Hamster
Model of Lyme Borreliosis
Munson, E.L., B.K. DuChateau, L.C.L. Lim, S. M. Callister and
R.F. Schell. Wisconsin State Laboratory of Hygiene and Department
of Medical Microbiology and Immunology, Gundersen Medical Foundation
Animal
models of Lyme borreliosis are extremely important for elucidating
the mechanisms of pathogenesis, chronicity and immunity. When
adult inbred LSH hamsters are injected in the hind paws with
106 Borrelia burgdorferi sensu lato, clinical manifestations
of Lyme arthritis (synovitis) are induced. Inflammation and swelling
of the hind paws are detected 7 days after infected, peak on
day 10 and gradually decline. A chronic synovitis characterized
by hypertrophic villi, focal erosion of articular cartilage and
subsynovial mononuclear infiltrate persists for approximately
1 year. When hamsters are vaccinated with whole cell preparation
of inactivated B. burgdorfer in alum, severe destructive
arthritis develops after challenge with representative isolates
of six seroprotective groups of B. burgdorferi sensu lato.
B. burgdorferi-specific T lymphocytes, especially CD4+
T lymphocytes, are responsible for the development of the severe
destructive Lyme arthritis. When vaccinated hamsters are depleted
of CD4+ T lymphocytes by administration of monoclonal antibody
GK1.5 and challenged, they failed to develop severe destructive
arthritis. Similarly, non vaccinated hamsters with or without
depletion of CD4+ T lymphocytes failed to develop severe destructive
arthritis. These studies illustrate the importance of cell-mediated
immunity in controlling or preventing the induction of events
leading to development of synovitis in non vaccinated hamsters
and severe destructive arthritis in vaccinated hamsters. Our
results also suggest that as more protective antigens are added
to develop a comprehensive Lyme vaccine, the ability of these
proteins to induce or elicit adverse effects may increase.
Mario
T. Philipp, PhD
Senior Research Scientist, Department Chairman
Tulane Regional Primate Research Center
Chronic
Lyme Disease in the Rhesus Monkey
Philipp MT (1), Bohm Jr RP (1), Dennis VA (1), England J (2),
Lowrie Jr RC (1), Roberets ED (1). (1) Department of Parasitology,
Tulane University Primate Research Center. (2) Department of
Neurology, Louisiana State University
We
investigated the appearance of arthritis and neuroborreliosis,
as well as humoral and cellular immune responses in rhesus macaques
inoculated with Borrelia burgdorferi sensu stricto (strain
JD 1) during 3,6, and 46 months post-inoculation (PI). sixteen
animals were inoculated by the bite of Ixodes scapularis nymphs,
3 by needle inoculation and 6 were controls. Signs of arthritis
were investigated clinically by physical examination, and post-mortem
both at the gross and microscopic levels. Signs of neuroborreliosis
were sought for in the same way and, in addition, by nerve conduction
studies and nerve biopsies. Longitudinal analysis (greater than
52 weeks PI) of serum antibody indicated a gradual increase in
the number of antigens recognized by IgG antibodies on Western
blots and a high anti-p39 IgG antibody ELISA titer that reached
a plateau of 1:8700 (geometric mean titer) by 10 wks PI. Blastogenesis
of peripheral blood mononuclear cells qualified in response to
whole killed spirochetes revealed that animals undergo periods
of responsiveness interspersed with prolonged intervals of unresponsiveness
(10-30 weeks), in face of a persistent antibody response. At
the gross level, no joint abnormalities were observed 3 months
PI, whereas all of the infected animals showed gross joint abnormalities
6 months PI. Microscopic lesions were apparent at both time points
in all animals, most frequently in the knee and elbow joints.
Forty six months PI , 1 of 6 animals examined post-mortem showed
marked cartilage destruction with synovial cell hyperplasia and
periarticular fibrosis in several joints. Peripheral neuritis
involving multiple nerves was the most prominent and consistent
neurologic manifestation at 3 months PI. In contrast, by 6 months
PI, inflammation was rarely seen, whereas axonal degeneration
was prominent. Neuropathologic changes were observed also in
the CNS, but to a lesser extent. Sural nerve biopsies indicated
a reduction in the number of myelinated nerve fibers in animals
which showed, by nerve conduction studies, a pattern and type
of peripheral neuropathy best characterized as primarily an axonal-degeneration
subtype of mononeuropathy multiplex. Nerve conduction eventually
returned to normal in all animals and, concomitantly, regenerative
changes such as neuroma or fibrosis were observed in biopsies
of some animals. Possible etiologies of the neuropathy observed
include localized direct infection within nerve, focal immune-mediated
attack on nerve, or focal ischemia of nerve.
PATHOGENESIS
OF CHRONIC LYME DISEASE
Alan
G. Barbour, MD
Department of Medicine and Microbiology
University of Texas Health Science Center
Borrelia's
Strategies for Survival: Implications for Chronic Disease
Two
mechanisms that members of the genus Borrelia use to avoid the
host's immune response are antigenic variation and residence
in tissues into which antibodies and lymphocytes have poor access.
These aspects and other aspects of the pathogenesis of persistent
infection will be reviewed. In particular, the issue of intracellular
localization of spirochetes will be examined.
Janis
Weis, PhD
Associate Professor, Department of Pathology, University of Utah
School of Medicine
Correlation
of Severity of Arthritis with Level of Persistence of Spirochetes
in Murine Lyme Disease
In
human Lyme disease symptoms with wide ranging levels of severity
have been observed. A mouse model of Lyme disease has been developed
by Barthold and colleagues that allows analysis of mice with
mild, moderate and severe pathologies after inoculation with
the spirochete Borrelia burgdorferi. To determine whether
the difference in symptoms reflects differences in the number
of spirochetes persisting in affected tissues, a sensitive PCR
technique was developed to detect B. burgdorferi DNA in
virtually any tissue of an infected mouse. This analysis, which
detects DNA from as few as 3 spirochetes revealed the presence
of B. burgdorferi DNA in many tissues from severely arthritis
C3H/HeJ mice as early as 1 week post infection. The heart, ear,
and ankle were particularly heavily infected although B. burgdorferi
DNA was also detected in spleen, liver, brain, kidney, bladder,
uterus, and lymph nodes. In contrast, much lower levels of spirochete
DNA were detected in tissues of infected BALB/c mice, which develop
less severe arthritis when infected with B. burgdorferi
than do C3H/HeJ mice. This difference was evident throughout
the 5 week analysis. The genetic resistance to severe arthritis
in the BALC/c mouse can be overcome with a high dose inoculum:
both severe arthritis and high levels of spirochetes in tissues
are observed. The genetic regulation of severe pathology was
analyzed by infecting the offspring of a cross between C3H/HeJ
and BALB/c mice. The f1 mice developed severe arthritis and displayed
high levels of Borrelia DNA in the heart and ankle when infected
with the highly virulent N40 strain, similar to the C3H/HeJ parent.
In contrast, infection of the F1 with the less virulent NB19
strain resulted in mild arthritis and persistence of relatively
fewer spirochetes in these tissues, similar to the BALB/c parent.
These findings support the model in which the severity of pathology
is directly related to level of persisting spirochetes in tissues.
Mark
Klempner, MD
Professor of Medicine and Vice Chairman for Scientific Affairs
New England Medical Center, Tufts University
Acquisition
and Induction of Enzymes which Degrade the Extracellular Matrix
by Borrelia burgdorferi and other Borrelia Species
Mark
S. Klempner, Linden Hu, Rick Rogers and George Perides. New England
Medical Center. Borrelia burgdorferi is inoculated into
the skin by a tick vector in the Ixodes ricinis/Ixodes persulcatus
species complex. After inoculation into the skin spirochetes
spread centripedally resulting in the characteristic erythema
migrans lesion. Subsequently, the organisms disseminate resulting
in a clinical syndrome which principally involves the central
nervous system, heart, diarthrodial joints and the skin. For
virtually all bacteria which disseminate from a skin or soft
tissue inoculation site bacterial proteases, which digest extracellular
matrix proteins, facilitate spreading in the skin and subsequent
invasion into the lymphatic or vascular circulations. We have
found that B. burgdorferi lacks these proteases but is
able to spread from its inoculation site in the skin. Instead,
B. burgdorferi has evolved a mechanism for accomplishing this
step in pathogenesis by utilizing human proteases which are generated
at the inoculation site and become bound to the bacterial surface.
More specifically, at the vascular injury site created by the
tick vector, B. burgdorferi binds human urokinase type
plasminogen activator (uPA) and human plasminogen (Pgn) which
generates bioactive human plasmin on the surface of the spirochete.
Human plasmin bound to B. burgdorferi is a highly stable,
non-immunogenic, potent serine protease with broad substrate
specificity including extracellular matrix and basement membrane
components. Other borrelia species also bind uPA and Pgn and
generate plasmin on the surface of the spirochete. We have also
discovered that B. burgdorferi induces the release of
enzymes that degrade the extracellular matrix from cells in the
skin and the central nervous system. Utilization of host proteases
instead of proteases of microbial origin could explain why the
immune response to B. burgdorferi proteases of microbial
origin could explain why the immune response to B. burgdorferi
infection is blunted. These observations represent a new mechanism
for bacterial virulence which may identify new targets for prevention,
diagnosis, and treatment of Lyme disease.
David
W. Dorward, PhD
NIH/Rocky Mountain Laboratories
Effects
of Borrelia burgdorferi on Human B- and T-cells
David W. Dorward and Elizabeth R. Fischer. NIH/Rocky Mountain
Laboratories
Since
discovering late in 1994 that virulent B. burgdorferi
can target, invade, and kill primary and cultured human T- and
B-lymphocytes, we have investigated the mechanics of such interactions
to help understand the role they may play in the onset, development,
and persistence of Lyme disease. In vitro co-incubations of low
(less than 8) or high (greater than 30) passage spirochetes with
SKW 6.4 B-cells or H9 T-cells were used as a model to quantitate
and study the consequences of interactions on cell structure
and viability. Co-incubations were synchronized by mixing and
incubating cells and spirochetes at 4 ¡C for 1 hr, prior
to raising (time 0) the mixtures to a metabolically active temperature
of 37 ¡C. The ratio of spirochetes to host cells was typically
100:1. Low passage B. burgdorferi Sh-2-82 and B. garinii
IP90 were capable of invading and killing SKW 6.4 cells. Significant
killing was not detected in mixtures of a recent mouse re-isolate
of B. afzelii ACA1 and SKW 6.4 cells, or in mixtures involving
H9 cells or high passage spirochetes. Attachment and invasion
were detectable in all mixtures examined. When [35S]-labeled
spirochetes were incubated with lymphocytes that were immobilized
onto immuno-magnetic beads, nearly 10% of low passage B. burgdorferi
Sh-2-82 co-precipitated with SKW 6.4 cells after 30 min. Just
over 1% of high passage spirochetes were recovered during the
same period. Pre-incubation of spirochetes with pooled acute
human anti-Lyme disease sera reduced adherence and invasion to
control levels. Electron microscopy of synchronized co-incubation
mixtures showed that invasion of SKW 6.4 cells by B. burgdorferi
Sh-2-82 began within 10 min of raising mixture temperature. Intercellular
spirochetes occurred within vacuoles to which lysosomal fusion
was not observed. By 30 min, numerous spirochetes were observed
either extending or detached from host cells, yet surrounded
by a layer(s) of membrane(s) and cytoplasm, apparently derived
from the host cells. Immune fluorescence provided evidence of
CD19 on the surface of spirochetes after co-incubation with SKW
6.4 cells. Progressive rounding and destruction of host cells
was observed from 1-3 hours of incubation. Observation of spirochetes
free within the cytoplasm of host cells corresponded to noticeable
loss of host cell integrity.
Prior
to these studies invasion and killing of human lymphocytes was
unrecognized among bacterial pathogens. These results indicate
that attachment and invasion of human lymphocytes by Lyme disease
spirochetes is active and rapid. Susceptibility to killing involves
as yet unidentified factors. These finding also raise the possibility
that the spirochetes could acquire lymphocytic membranes and
surface markers upon or even prior to transmission by infected
ticks, which would be expected to have profound effects on recognition
by the immune system.
Elizabeth
Aberer, MD
Department of Dermatology, University of Graz School of Medicine
Why
is Chronic Lyme borreliosis Chronic?
Aberer E.(1), Koszik F.(2), and Silberer M( 2). Departments of
Dermatology, (1) University of Graz and (2) Vienna (Division
of Immunology, Allergy & Infectious Diseases), Austria
In
spite of marked cellular and humoral immune responses in acrodematitis
chronica atrophicans (ACA) B. burgdorferi (Bb) can be
isolated from long-standing skin lesions. Recently it was shown
that the most important cell for antigen presentation, the epidermal
Langerhans cell (LC) is heavily damaged in erythema migrans (EM).
To evaluate whether the immune response and the number or function
of LC is altered we studied the immunophenotype of cutaneous
leucocytes in ACA. Lesional skin biopsies from 19 patients with
ACA and 9 patients with EM were investigated by immunoperoxidase
single labeling or double-labeling procedures. In EM the total
number of CD1a+ cells reduced in the epidermis of ACA skin semi-automatic
image analysis revealed a density of 811(+336 SD) CD1a+
but only 13(+143 SD) HLA-DR+ dendritic cells while in
normal skin most of the epidermal CD1a+ cells are HLA-DR+. The
majority of cells in the dermis of ACA were composed of CD68+
macrophages and CD45+ memory T-cells with a predominance of helper/inducer
cells. About 75% of the cells were further activated expressing
HLA-DR and CD54 and its receptor CD18. In this study, the most
prominent immunohistochemical changes were seen on the epidermal
dendritic cell population. Our data suggest that MHC class II
molecules are strongly down regulated on LC not only in the early
but also in the late stage skin manifestation of LB. This phenomenon
antigen presenting cells might be a protective mechanism against
the presentation of cellular auto antigens and might be the cause
for the impaired capacity of LC to eliminate Bb antigens.
Charles
Pavia, PhD
Associate Professor, New York Medical College
Anti-borrelial
Activity of Serum from Patients with Late Lyme Disease
C.S. Pavia, S. Bittker and D. Cooper. NYCOM Immunodiagnostic
Laboratory and New York Medical College
Sera
from patients with late, chronic Lyme disease (arthritis) were
evaluated for their ability to kill Borrelia burgdorferi. This
was done using a well established animal model for human borrelial
infection (for in vivo analysis) and by using an in vitro borreliacidal
assay. Separate groups of mice (C3H strain) received intraperitoneal
injections of 0.5 ml of high titer serum from human patients
with (i) early (erythema migrans) or (ii) late Lyme disease (arthritis).
Some of these patients were culture-positive; all were seropositive
and antibiotic-free. Twenty four hours after passive serum transfer,
all of the mice, including matched controls given the appropriate
normal sera lacking borrelia antibodies, were challenged intradermally
with 100,000 organisms of two New York isolates (B31, P103) or
of a California strain (CA-287). These Borrelia were derived
from low passage cultures in BSK media. Seven to 10 days after
challenge, the mice were sacrificed and cultures for the urinary
bladder and peripheral blood were established in BSK media. Late
Lyme sera fully protected the mice against Borrelia challenge
infection with all three isolates (based on negative cultures
of urinary bladder and blood) but, in marked contrast, early
stage Lyme sera were generally ineffective in preventing infection.
In a similar fashion, late Lyme sera inhibited the growth of
B. burgdorferi in micro-cultures established in BSK media. Immunoblot
analysis reveled that the protective properties of late Lyme
sera were associated with a multi-protein antibody response.
This included strong reactivity with the outer surface proteins
A (31kDa) and B (34 kDa), which was lacking in sera from those
with early stage disease. These findings show that patients with
untreated Lyme disease of long duration can develop a potent
anti-borrelial humoral immune response which can be protective
against infection and possibly reinfection.
LABORATORY
DIAGNOSIS OF LYME DISEASE
Richard
C. Tilton, PhD
Senior VP and Chief Scientific Officer
BBI-North American Clinical Laboratories
Western
Immunoblot for Lyme Disease: Determination of Sensitivity, Specificity
and Interpretive Criteria using Commercially available Performance
Panels
Richard C. Tilton, PhD, Mary Sand, PhD, Mark Manak, PhD BBI-North
American Clinical Laboratories. Biotech Research Laboratories
The
recent CDC/ASTPHLD conference on the standardization of Lyme
disease serology indicated that there was a need for performance
panels so that manufacturers as well as end users might have
an objective standard for validation of diagnostic test kits.
At least 2 such panels are currently available. One comprising
45 member sera from the Centers for Disease Control and Prevention,
and a second one from the Boston Biomedica comprising 15 member
sera and laboratory data on each serum including ELISA, immuno-blotting,
and IFA by a variety of reference and commercially available
methods.
The
BBI-NACL Western blot was compared to other commercial blot strips
using the 45 member clinically characterized CDC Performance
Panel. Both NACL and CDC proposed criteria were used to determine
sensitivity and specificity for IgG and IgM antibodies. A 2nd
study used the same panel to compare BBI-NACL blots to both CDC
generated Western blot results and clinical criteria. The CDC
Western blot was less specific than the NACL Blot.
The
BBI performance panel was tested using 7 commercially available
FDA approved ELISA tests, IFA, a research level lgG and IgM,
IFA and 2 western blot products. This panel shows the variety
of responses expected with each test modality as well as provides
a serum panel for the validation of new, or newly adopted methods
for B. burgdorferi antibody testing.
Mark
Manak, PhD
Senior Vice President, Biotech Research Laboratories
Use
of PCR Assays to Monitor the Clearance of B. burgdorferi
DNA from Blood following Antibiotic Therapy
M. Manak, I. Gonzalez-Villase–or, S. Crush-Stanton, and
R.C. Tilton. Biotech Research Laboratories; BBI-North American
Laboratory; Boston Biomedica, Inc.
A
PCR approach was used to monitor the effectiveness of antibiotic
therapy on the persistence of B. burgdorferi sequences
in the blood of Lyme disease patients. For this study, patients
with serologically confirmed Lyme disease were followed at regular
intervals following initial presentation. Blood samples were
processed within 24 hours of collection into plasma and buffy
coat fractions. DNA extracts were amplified by PCR using specific
primers representing conserved sequences in the OspA gene. Specific
amplification was detected by Southern blot hybridization using
internal sequences as probes. As few as 3-10 copies of the B.
burgdorferi DNA in the sample could be detected. Positive
PCR results were obtained mainly with the buffy coat fraction,
although occasional plasma fractions were also positive. The
results were analyzed for a total of 24 patients for whom complete
PCR and antibiotic therapy history were available. Nine of 15
patients not undergoing therapy at the time of initial collection
were positive for B. burgdorferi by PCR. Within 1 week
of administration of antibiotic treatment 7 of 8 initially PCR
positive patients became PCR negative. The remaining patient
became PCR negative after 5 weeks of therapy. Four late stage
patients under therapy continued to show sporadic PCR positive
results. When an alternative antibiotic was administered in tow
of these patients, both became PCR negative within one week following
the change in therapy. One patient who had been PCR negative
while under therapy, became PCR positive within 2 weeks of cessation
of therapy. These studies demonstrate the usefulness of PCR results
in monitoring the effectiveness of antibiotic therapy in Lyme
disease patients.
Bruno
L. Schmidt, MD
Ludwig Boltzmann Institute for Dermato-ven. Serodiagn.
PCR
in the Diagnosis of Patients with Early and Late Lyme borreliosis:
Comparison of Methods
Schmidt, B.L., Wagner, C. and Luger, A. Ludwig Boltzmann Institute
for dermato-venerological serodiagnosis, Hospital of the City
of Vienna Lainz, Austria
Objectives
of Research: To determine the sensitivity of PCR in urine samples
from infected patients in dependence of DNA-preparation, primer
selection, and amplification methods.
Methods:
Procedures of DNA preparation for PCR included centrifugation
and boiling of specimens, centrifugation and boiling in the presence
of a cation exchange resin and absorption of DNA on glass beads
in the chaotropic salt solutions. Primers specific for the OspA-,
the polymerase- and the flagellin-gene of Bb, were tested
with standard, heminested, nested and one-tube nested PCR assays.
Results:
Centrifugation followed by boiling the pellet in the presence
of Chelex-100 was found to be superior to other methods tested.
Sensitivity of PCR can vary up to 103 dependent on selected primers
and results are not always predictable from experiments with
culture dilutions. Sensitivity and specificity of nested PCR
is superior that standard PCR, however, with primers tested it
was impossible to get comparable results with a one-tube nested
PCR.
Conclusion:
In urine samples from patients with Lyme borreliosis, known to
harbour only low numbers of spirochetes (less than 50/ml), the
nested PCR is superior in comparison to other methods. In addition,
results indicate that primers are decisive for sensitivity.
PREVENTION
OF LYME DISEASE
Franois
Meurice, MD
Associate Director, SmithKline Beecham Pharmaceuticals
Progress
in the Clinical Development of a Lyme Disease Vaccine in the
USA
F. Meurice (1), D. Fu (2), and D. Krause (1). (1) SmithKline
Beecham Pharmaceuticals, USA; (2) SmithKline Beecham Biologicals,
Belgium
Lyme
disease (LD) was reported at an increasing rate in the United
States in 1994 and the geographical distribution of reported
cases seems to be progressively spreading. Classical protection
recommendations have proven either largely insufficient of impractical.
Therefore, development of a safe and protective human vaccine
is increasingly viewed as an attractive option. SmithKline Beecham
Biologicals has used recombinant DNA technology to express outer
surface protein A of Borrelia burgdorferi in lipidated
form (lipoprotein OspA), for use as an antigen in such a vaccine.
This preparation was shown to protect C3H/HeJ mice when challenged
by naturally infected ticks collected from the Northeastern U.S.,
an intensely endemic area. An aluminum hydroxide formulation
of the Osp A candidate vaccine has been used in two clinical
trials in the U.S. in 1994, following Phase I studies in Belgium.
A
double blinded, placebo controlled, dose-range study was conducted
in 350 healthy adult residents of three New England islands on
which LD is highly endemic. An Osp A antibody response was detected
in greater than 97% of subjects receiving vaccine. A second trial
addressed the issue of vaccination of subjects previously infected
with LD. The safety and reactogenicity profile of the candidate
vaccine in this population was similar to the previous observations:
all doses were well tolerated, although mild local reactions
were common (mostly soreness at the injection site: 40-85%).
Transient systemic reactions were reported by less than or equal
to 40% of subjects and included headache, fatigue and arthralgia.
Adverse events did not increase following subsequent injections.
The
success of Phase I and II of the clinical development program
of this vaccine has encouraged its further development. A large
scale Phase III placebo controlled trial of the vaccine's efficacy
in the prevention of LD is ongoing and will be described. If
successful, the appropriate use of this product may serve to
reduce the incidence of LD.
John
M. Zahradnik, MD
Director, Clinical Research, Connaught Laboratories, Inc.
Overview
of Lyme Disease Vaccine Trials
J. Zahradnik, F. Koster, J. Gwaltney, G. Bryant, M. Blatter,
J. Froeschle, M. Klempner, H. Simon, G Wormser, To Doherty, and
D. Allegra; Connaught Laboratories, Inc., Swiftwater, PA; University
of New Mexico; University of VA Health Science Center; Gundersen
Medical Foundation; Pittsburgh Pediatric Research Inc.; New England
Medical Center; Physicians Research Center; Westchester County
Medical Center; Old Lyme Family Practice; and Infectious Disease
Associates
Lyme
disease is a tick transmitted, multisystem inflammatory disorder
caused by the spirochetal agent, Borrelia burgdorferi.
Among various antigens identified from this organism, one has
proven to be of interest as a potential immunogen. This antigen
is the outer surface lipoprotein A (Osp A), demonstrated to induce
protection in immunized animals. Osp A was expressed in E. coli
organisms and after appropriate pre-clinical studies, this recombinant
protein was evaluated in initial safety and immunogenicity trials
involving more than 1000 adult volunteers. Various doses have
been studied in subjects who have never been infected with B.
burgdorferi, as well as, adults who have previously been
infected. In these trials the vaccine has proven to be both well
tolerated and immunogenic when administered as two or three doses
in this population. This presentation will describe these trials
and discuss issues of immunogenicity and safety.
EMERGING
TICK-BORNE DISEASES
Louis
A. Magnarelli, PhD Vice Director, The CT Agricultural Experiment
Station
Ehrlichia
equi
in Ixodes scapularis: Relevance to Lyme Borreliosis
Laboratory
studies were conducted during 1990 through 1995 to search for
ehrlichiae in ticks. As described in published results, serologic
analyses of blood cells (hemocytes) from female Ixodes scapularis
revealed the presence of rickettsia-like organisms in cytoplasm.
These bacteria reacted positively with dog anti-Ehrlichia
canis antiserum by indirect fluorescent antibody (IFA) staining
methods and coexisted with Borrelia burgdorferi in 6.7%
of the 537 I. scapularis nymphs and adults tested. During
1995, PCR analysis revealed the DNA of the human granulocytic
ehrichiosis (HGE) agent, presumably Ehrlichia equi or
a closely related organism, in tissues from 59 (50%) of 118 adults
and 1 of 2 nymphal I. scapularis tested from Connecticut.
Further laboratory testing by IFA staining methods demonstrated
positive reactivity of hemocytic, rickettsia-like organisms with
human sera from persons diagnosed with HGE or human monocytic
ehrlichiosis (i.e., Ehrlichia chaffeensis infection).
In separate analyses of 40 human sera from persons who had Lyme
borreliosis, antibodies to E. equi, E. chaffeensis, or
Babesia microti, the causative agent of human babesiosis,
were detected in 8 to 20% specimens. Laboratory studies indicate
the presence of different human pathogens in Ixodes scapularis
populations and that persons living in tick-infected areas are
sometimes exposed to multiple tick-borne agents. Ehrlichial or
Babesia organisms may occur concurrently with B. burgdorferi
in humans and may complicate Lyme borreliosis infections. Therefore,
clinical diagnoses of tick-related illnesses should include laboratory
testing for ehrlichiosis, babesiosis, and Lyme borreliosis.
David
H. Persing, MD, PhD Mayo Clinic
The
Cold Zone: A Convergence of Tick-transmitted Diseases in areas
Endemic for Lyme Disease
The
main focus of our laboratory over the past several years has
been to study the mechanisms of pathogenesis and persistence
of Lyme disease, and to investigate the basis of the remarkable
biological variation in disease expression. We have focused on
two major areas, using an eclectic blend of conventional methods
and new technology: 1/ an examination of the role of genetic
heterogeneity of Borrelia burgdorferi, the Lyme disease
spirochete, in disease expression and 2/ the role of coinfecting
pathogens in alteration of host susceptibility. An extensive
genetic analysis of over 200 isolates of B. burgdorferi
from the U.S. and worldwide has provided us with an unprecedented
appreciation of the genetic diversity of this organism on the
North American continent. Using this information as a foundation
for analysis of human clinical material, we can examine the role
of B. burgdorferi genetic heterogeneity in the differential
expression of human disease by recovering and sequencing spirochetal
nucleic acids directly from human tissues. To do this reliably,
we have developed ultrasensitive PCR-based methods for recovery
and analysis of spirochetal nucleic acids directly from clinical
specimens.
In
addition to studying human specimens, we are studying a murine
model of infection with a naturally-occurring population of spirochetal
variants whose members have been differentiated antigenically
and genetically. Another explanation for biologic variation in
the clinical presentation of Lyme disease might be unrecognized
coinfection with other tick-transmitted pathogens. Since it is
now becoming clear that cotransmission with B. burgdorferi
of other pathogens, including Babesia microti and granulocytic
Ehrlichia spp., may occur via the same tick vector, an
examination is needed of the role of these known immunosuppressive
agents in the modulation of Lyme disease. One of the most important
findings of our prospective study of Block Island, RI residents
has been the recognition of an apparent increase in the severity
of Lyme disease in patients coinfected with B. microti.
Our plan is to characterize these patients more closely at an
immunologic level and by molecular monitoring of infections caused
by B. burgdorferi and B. microti. To better study
the interactions between these agents in a microbiologically
defined disease model, we have developed mouse models of infection
and coinfection with these pathogens.
J.
Stephen Dumler, MD
Associate Professor of Pathology
Director of Medical Microbiology, The Johns Hopkins Medical Institutions
Is
Human Granulocytic Ehrlichiosis (HGE) another Lyme disease? A
Comparison of Clinical, Laboratory, and Epidemiologic Features
Human
granulocytic ehrlichiosis (HGE) is a newly described illness
caused by a zoonotic pathogen in the genus Ehrlichia that
is transmitted via the bite of Ixodes ricinus complex
ticks. The causative agent is an obligate intracellular bacterium
that lives within phagosomes of mammalian peripheral blood neutrophils.
The ecology and epidemiology of HGE and its causative agent directly
parallel those of Lyme borreliosis (LB) and Borrelia burgdorferi
owing to the shared tick vector. As for LB, the agent of HGE
is found within vector ticks where both HGE and LB occur and
infects small mammals such as Peromyscus leucopus. Moreover,
HGE and LB are geographically co-distributed and a proportion
of LB and HGE patients have evidence of concurrent infection
by B. burgdorferi, Babesia microti, or the HGE agent.
Currently,
HGE is characterized as an cute febrile illness with or without
headache, myalgias, gastrointestinal or respiratory symptoms
and signs, CNS involvement, leukopenia, thrmbocytopenia, and
elevations in hepatic transaminase levels. The usual presentation
is acute and relatively severe, with life-threatening complications
in 7% and death secondary to opportunistic infections in up to
5% of patients. Persistent infection associated with disease
caused by Ehrlichia species is well documented in animals
and is increasingly recognized in humans. Conversely, LB is subacute
to chronic and is defined by the presence of erythema migrans
rash with or without arthritis, arthralgias, cardiac conduction
abnormalities, or meningitis, and is rarely associated with leukopenia
or thrombocytopenia. Although infection may be chronic, fatalities
directly attributable to LB are rare or non-eixtent. The known
features of HGE and LB define very different clinco-pathologic
entities. However, the clinical outcome of persistent infection
by the HGE agent or Babesia microti in association with
LB is not known. Given the potential for host defense defects
and immune suppression observed with Ehrlichia and Babesia
infections, the role of these diseases in confounding laboratory
diagnosis and as contributors to morbidity in chronic, therapy-refractory,
and seronegative LB needs to be evaluated.
CLINICAL
DIAGNOSIS OF CHRONIC LYME DISEASE
Lesley
Ann Fein, MD, MPH
St. Barnabas Hospital and Mountainside Hospital
Multivariate
Analysis of 160 Patients with Lyme Disease
Data
of 160 patients treated for Lyme disease were examined in a retrospective
multifactorial analysis. Of these patients 27% reported a history
of tick bite; 34% reported an erythema migrans rash; on initial
evaluation, 2% had abnormal EKG, 6% abnormal MRI findings consistent
with Lyme disease, 67% had arthralgia and 47% reported swollen
joints.
A
breakdown based on 15 musculoskeletal and 15 neurological parameters
was analyzed; laboratory testing was evaluated at the initial
visit and at intervals during and after treatment. Of all patients,
69% were seronegative at the initial diagnosis. An additional
14% seroconverted by 3 months after initiation of therapy, 8%
after 6 months of therapy, and 2% after nine 9 months or more
of therapy. The total % of seropositive patients after 9 months
was 89%. Thus 21% of all patients would not be diagnosed on the
basis of tests at the initial visit if testing is the sole criterion
for treatment. Auto immune parameters revealed abnormalities
in 10% initially and 5 % after nine months of treatment.
Urine
antigens were positive in 9% of seropositive patients and 18%
of seronegative patients. When all tests are considered before,
during or after therapy, the end result in an extremely small
group who remain negative on testing by the end of therapy.
Specific
bands on Western blot analysis were analyzed separately and in
combination; relapse rates, complications and response to treatment
was analyzed in a multivariate analysis to be presented in tabular
form.
Of
all patients 35% received intravenous antibiotics during their
course of therapy. 6.8% received 2 courses of IV. The largest
group of IV patients were in the second treatment group. Of these,
65% had a response to Claforan whereas 46% responded to Rocephin
Nancy
A. Shadick, MD, MPH
Associate Rheumatologist, Brigham and Women's Hospital
The
Long-term follow-up of LD: A Population-based Retrospective Cohort
Study N.A. Shadick, C.B. Phillips, O. Sangha, A.H. Fossel, K.
Fossel, E.A. Wright, R.A. Lew, M.H. Liang. Robert B. Brigham
Multipurpose Arthritis and Musculoskeletal Diseases Center, Brigham
and Women's Hospital
Objectives:
To document the frequency of and to identify risk factors for
long term sequelae from acute Lyme disease.
Design:
Population-based retrospective cohort study.
Participants:
Subjects with prior Lyme disease were compared with randomly
selected population controls.
Setting:
An island in the northeast endemic for Lyme disease.
Main
Outcome Measures: A standardized physical examination, functional
status assessment (SF36), neurocognitive test battery and serological
analysis.
Results:
In univariate analyses, the Lyme group (n=176) (mean duration
from infection to evaluation, 5.2 years) had a higher prevalence
of arthralgias (p<0.0001), fatigue (P<0.004), memory (p<0.004)
and word finding difficulties (p<0.003) than controls (n=160).
They had more knee swelling on physical exam (p<0.03) poorer
functional status (p<0.004) and on neurocognitive testing,
the Lyme group had lower attention scores than controls (p<0.05).
Seventy-three (73) individuals complained of persistent symptoms
following Lyme disease and were more likely to have had neurologic
symptoms or manifestations during their acute illness (p<0.01)
and a longer duration of infection (p<0.02) than those who
had completely recovered. Forty-seven (47) individuals reported
relapses after initial treatment, and were more likely to have
had erythromycin, penicillin or tetracycline than amoxicillin
or doxycycline as initial oral therapy (p<0.007).
Conclusions:
Risk factors for persisting symptoms after Lyme disease include
neurologic dissemination and a longer duration of infection.
M.H.
Ziska, MD
Lyme Disease Foundation
Disseminated
Lyme Disease and Pregnancy
M.H. Ziska, Lyme Disease Founcation, Hartford, CT; T. Giovanello,
BBi-North American Clinical Laboratory; M.J. Johnson, Eastern
Conn. State University; J. Baly, Trinity College
The
relationship between Lyme disease and pregnancy is not clear.
Limited data exists about acute Lyme disease contracted during
pregnancy and the effects of disseminated Lyme disease contracted
during pregnancy and the effects of disseminated Lyme disease
on pregnancy. There is no consensus on the clinical management
of Lyme disease during pregnancy. The objective of this prospective,
open-ended study was to determine the management of disseminated
Lyme borreliosis (LB) during pregnancy.
Methods:
Clinical and laboratory information regarding LB and pregnancy
was collected from mothers and newborns. Maternal and fetal serum,
urine, and placenta samples were analyzed at the BBI-NACL using
ELISA, Western blot, PCR, culture, and antigen detection tests.
Results:
A cohort of nine patients living in LB endemic areas was analyzed.
Five patients (55%) have had history of EM, 6 patients (66%)
had laboratory confirmation later in the course of the disease.
LB was contracted 2 to 96 months (median 53.8 months) before
conception. Median length of treatment before conception was
5.5 months. Seven women were symptomatic at the time of conception,
6 of whom received antibiotics through the entire pregnancy.
Except for one case, all test results were negative. On the follow
up (4 to 16 months), all but one infant had no complications.
Antibiotic therapy was continued in 4 women after delivery, whose
symptoms worsened. Seven women, 5 of which were symptomatic,
breast-fed.
Conclusion:
No case of transplacental transmission was documented using serological
and PCR assays. Histopathological studies need to be applied.
Women who are symptomatic at the time of conception are more
likely to be treated for the entire pregnancy. Breast-feeding
by LB symptomatic mothers has no harmful effect on the infant.
More studies are needed to develop further diagnostic and treatment
recommendations.
Kenneth
B. Liegner, MD
New York Medical College
Lyme
Disease and the Clinical Spectrum of Antibiotic-responsive Chronic
Meningoencephalomyelitides
K.B. Liegner (1), P.M. Duray (2), M. Agricola (1). (1) Private
Practice, (2) National Cancer Institute.
- Initially
seronegative, culture +, chronic meningoencephalomyelitides (CMEM),
relapsing course; convincing evidence of chronic persistent infection
despite intensive therapy.
- Initially
seronegative w. h/o rash c/w ECM, evolving in CMEM with hydrocephalus
and deterioration to a primitive level of neurological function.
OspA Ag + and immune complex + in CSF during life and at post-mortem
examination. Florid CMEM histologicaly.
- Initially
seronegative w. h/o tick bite and rash, multi-system symptoms
evolving to CMEM. CSF pleocytosis, elevated protein and elevated
CSF IgG synthesis rates responding to 8 month course of IVAB
Rx. Lyme-specific immune complexes and key bands on WB develop
on serial CSF examinations during and after Rx. 13 year interval
between onset of infection and laboratory evidence of LD.
- CMEM
satisfying criteria for M.S. clinically and on CSF parameters.
Epidemiological exposure risk for LD but initially seronegative,
PCR -, and OspA Ag and Lyme-specific immune-complex negative.
Clear neurologic improvement with empiric IVAB Rx w. cefotexime
for 5 months. CSF upon repeat examination shows virtually complete
resolution of CSF "M.S." markers, development of Lyme-specific
immune complexes in serum, and key bands on WB, and improvement
in MRI of neuraxis. Neurologic deterioration post cessation of
Rx. Repeat CSF exam again markedly abnormal. Re-institution of
IVAB Rx leads to clear neurologic improvement.
Patricia
K. Coyle, MD
Professor of Neurology, SUNY at Stony Brook School of Medicine
Neurologic
Complications of Late and Chronic Lyme Disease
Lyme
disease is due to a tick-borne spirochete, Borrelia burgdorferi.
Both the central and peripheral nervous systems are major target
organs in this infection. Late Lyme disease can be operationally
defined as the symptomatic abnormalities associated with untreated
B. burgdorferi infection or greater than three months
duration. Chronic Lyme disease can be operationally defined as
the symptomatic abnormalities which are temporally related to
B. burgdorferi infection, and which continue as persistent
problems for months to years following antibiotic treatment.
Neurologic
complications are major features of both late and chronic Lyme
disease. Three characteristic syndromes have been reported in
late Lyme disease. These are mild encephalopathy, characterized
by problems in attention, memory, word retrieval, and processing;
a chronic polyradiculoneuropathy; and encephalomyelitis with
parenchymal involvement. In addition a variety of more unusual
syndromes have been reported in a limited number of patients.
Chronic Lyme disease is characterized by major cognitive, pain,
and fatigue complaints, as well as a variety of minor neurologic
complaints. This presentation will describe the neurologic complications
of late and chronic Lyme disease; will outline their associated
laboratory abnormalities; and will review current thinking on
the underlying pathogenetic mechanisms involved in these neurologic
manifestations. The encephalopathy of late and chronic Lyme disease
will be discussed in detail.
Brian
A. Fallon, MD
Assistant Professor of Clinical Psychiatry
Columbia University, NYS Psychiatric Institute
Lyme
Disease vs. Depression vs. Somatization: Cognitive Tests and
Functional Imaging
B.A. Fallon, J. Keilp,, I. Prohovnik, J. Mann. Columbia U/NYSPI
Not
infrequently physicians are faced with the task of differentiating
persistent Lyme Disease (LD) from Somatization and Depression.
This becomes most difficult when serologies are equivocal or
negative. Given the possibility of placebo response to antibiotics,
it behooves clinicians to make use of objective tools that may
aid in differential diagnosis.
The
use of neuropsychological tests to differentiate Lyme-related
vs. depression-related cognitive problems will be discussed,
focusing on tests of memory (selective Reminding test/ Wechsler
Memory test), attention (Digit Span), visual motor performance
and tracking (Digit Symbol Modalities), and verbal fluency (Controlled
Oral Word Association Test).
Functional
imaging (SPECT) differs from structural imaging (MRI, CT) in
that SPECT gives high resolution images of the localized cerebral
flow and neurochemical activity of the brain whereas routine
MRI provides a static image of the anatomy of the brain. The
application of SPECT imaging to neuropsychiatry and to Lyme disease
in particular will be addressed, emphasizing patterns typical
of depression vs. Lyme encephalopathy.
This
talk will conclude by describing a controlled study of function
brain imaging using Xenon 133 Regional Cerebral Flow (RCBF) among
Lyme patients with complaints of persistent memory problems despite
antibiotic treatment. The RCBF of 11 Lyme patients was contrasted
with the RCBF of 22 age- and sex-matched normal controls. Analysis
of individual normalized detector values reveled significant
differences at three sites in the left hemisphere. Patients had
lower relative flows at the inferior, posterior parietal detector
and higher relative flows at the superior peri-rolandic detector
and on the most posterior detector in the occipital lobe. The
pattern at these detector sites is characteristic of Alzheimer's
disease. The implications of these findings will be discussed.
Further research is needed.
Benjamin
J. Luft, MD
Professor, Acting Chair, Department of Medicine
State University of New York at Stony Brook School of Medicine
Chronic
Lyme Disease: An Evolving Syndrome
Lyme
disease, initially described as an arthritic disease, has unfolded
over the past 15 years as a multistage, multisymptom disease
of great complexity and variability. Several key factors are
involved in the development of Lyme disease; the spirochetal
agent, the tick and the host. The spirochete shows strain heterogeneity
with at least three major genospecies: Borrelia burgdorferi,
B. garinii and B. afzelii. Different genospecies appear
to be associated with distinct clinical manifestations. Multiple
strains of B. burgdorferi can infect the same tick and
human infection can include single or multiple spirochete strains.
In the case of the ticks, environmental factors such as temperature,
humidity and source of blood meal may alter the major outer surface
proteins (Osp) of the spirochete within the tick vector. This
can affect the spirochete infectivity. Ticks can be co-infected
with multiple organisms, including Babesia and Ehrlichia species.
The immune response plays a definite role in the infectivity
and pathogenesis of B. burgdorferi. Osp A, a major outer
surface protein with relative molecular mass of 31, 000, stimulates
B cells and cytokine production. Humans with chronic arthritis
are more likely to show an immune response to Osp A.
Chronic
Lyme disease has become an increasing concern for health care
providers. Retrospective studies confirm that a proportion of
patients treated for Lyme disease experience prolonged post treatment
problems. Persistent complaints are generally non-specific and
include arthralgias, myalgias, cognitive difficulties, fatigue,
malaise, dizziness, stiff neck and photophobia. Chronic Lyme
disease patients may be seropositive or seronegative with or
without a documented history of Lyme disease.
Since
Lyme disease is a clinical diagnosis, research must continue
to improve diagnostic assays using recombinant proteins which
are more sensitive and specific than the whole organism sonicate
used for both ELISA and Western blots. Possible biological markers
of chronic Lyme disease, such as positive Borrelial antigen,
Borrelial DNA and pleocytosis in the CSF or synovial fluid, need
to be assessed and validated. Elimination of biological markers
in combination with sensitive indices of neuropsychological symptoms
will be useful for the evaluation of treatment modalities.
Claude
F. Garon, PhD
Chief, Microscopy Branch, Rocky Mountain Laboratories
National Institutes of Health
The
Antimicrobial Agent Melittin, Exhibits Powerful in vitro
Inhibitory Effects on the Lyme Disease Spirochete
Lori L. Lubke and Claude F Garon. Rocky Mountain Laboratories,
NIAID
Borrelia
burgdorferi
has demonstrated an extraordinary capacity to resist the effects
of powerful eukaryotic and prokaryotic replication inhibitors.
Biologically significant concentrations of inhibitors such as:
aphidicolin, Ara C, cis Platinum, CPX, Hydroxyurea, Mimosine,
Nalidixic Acid, Trioxsalen and Boromethylglycine showed little
or no effect on growth when added to BSK II cultures. The effects
of the various inhibitors were monitored by dark field, transmission
and field emission scanning electron microscopy as well as DNA
precursor incorporation and OD. In contrast, however, the antimicrobial
agent, melittin, a 26 amino acid, cationic, amphipathic, peptide
contained in honeybee venom, showed almost immediate and profound
inhibitory effects. At concentrations of 100 microM melittin,
spirochete motility ceased within minutes and the culture was
effectively killed. Similarly treated cultures without melittin
were unaffected and grew normally. Ultrastructral examination
of spirochetes reveled interesting alterations apparently limited
to bacterial surface components. Transmission electron microscopy
revealed distinct pores along the spirochetal surface with an
absence of intact endoflagella. Field emission scanning electron
microscopy showed bled-like protrusions over the surface of the
spirochete with a large collection of bleb-like material in the
background. While surface damage appeared widespread rather than
limited to a specific area of the cell, no osmotic lysis was
visible. Melittin is an antimicrobial peptide thought to work
by inserting into the bacteria (and eukaryotic) membrane causing
aggregation and membrane micellization. The extraordinary sensitivity
of Borrelia burgdorferi to this small peptide may provide
both a useful research reagent and important clues to the development
of effective drugs against Lyme disease.
Louis
Corsaro, MD
Northern Westchester Hospital., Columbia University
Intramuscular
Bicillin for Persistent Pediatric Lyme Disease
L. Corsaro, M. Montemayer, B. Fallon. Northwestern Westchester
Hospital, Columbia University
Objective:
A preliminary study designed to evaluate the therapeutic efficacy
of Benzathine penicillin given intramuscularly on a weekly basis
to patients with chronic active Lyme borreliosis in a private
pediatric out-patient setting.
Methods:
The diagnosis of Lyme disease was based on at least one serological
test along with typical articular or neurological symptoms of
Lyme disease. Either LA Bicillin or CR Bicillin was administered
intramuscularly on a weekly basis to patients who had relapse
of clinical symptoms following oral or intravenous antibiotic
therapies.
Results:
Twenty-five children who have met the study criteria for seropositive
disease were evaluated. All patients had failed to sustain improvement
after courses of oral or intravenous antibiotic therapies. Five
of these patients had received IV Rocephin and all five had failed
to sustain improvement despite having received between 4 and
27 weeks of IV therapy. Symptom-free periods prior to receiving
intramuscular Bicillin were evaluated with the symptom-free periods
post-intramuscular Bicillin. Of the twenty-three children available
to assess the relapse status after treatment, nineteen remain
symptom-free, three had mild symptoms that did not require therapy
and one had relapsed and was being retreated.
Conclusion:
A chart review and follow-up studies suggest that intramuscular
Bicillin may be particularly effective treatment for children
with antibiotic refractory persistent Lyme disease whether previously
treated orally or with intravenous antibiotics.
Joseph
Burrascano, Jr., MD
Southampton Hospital
Use
of Vancomycin in Chronic Persistent Lyme Disease
Because
symptoms of Lyme disease that persist despite aggressive antibiotic
therapy have been related to persistent infection, an expanded
search for newer antibiotic regimens was undertaken.
Vancomycin
has been shown to be effective in killing Borrelia burgdorferi
in vitro, and a case report demonstrated the efficacy of
this agent in a patient with ongoing symptoms unresponsive to
other treatments. An expansion of that trial is now reported.
Twenty
one patients with severe chronic Lyme disease unresponsive to
more conventionally used oral and parenteral antibiotics were
prescribed standard doses of vancomycin using a pulsed dosing
schedule. Two patients had to drop out due to allergic reactions.
Of the nineteen remaining patients, eighteen had a favorable
response; in eleven the response was significantly greater than
with any other agent previously used. In two such patients there
was no apparent cure. None of these nineteen patients had any
treatment related reactions, signs of nephro- or ototoxicity,
or significant superinfections.
I
conclude that vancomycin may be a safe and effective alternative
for treating patients with severe, resistant Lyme disease when
other agents have failed.
Sam
T. Donta, MD
Professor of Medicine, Boston University Medical Center
Tetracycline
Therapy of Chronic Lyme Disease
There
are a number of questions regarding both the diagnosis and treatment
of chronic Lyme disease. Serologic tests are often helpful, but
may be negative in patients with clinical symptoms indistinguishable
from those with positive results. The optimal duration and type
of antibiotic therapy have yet to be defined. This report reviews
our experience with patients treated with tetracycline.
Patients
with clinical symptoms compatible with chronic Lyme disease (i.e.
fatigue plus musculoskeletal and/or neurologic symptoms) were
evaluated clinically and serologically. In the absence of a reasonable
alternative diagnosis, both seropostive and seronegative patients
were given a trial of oral tetracycline, 500mg tid, for 3 months.
If symptoms improved, therapy was continued for up to 8 months.
The
results were:
- 75%
of patients with specific reactions by Western Blot were negative
by ELISA, tetracycline therapy led to cure or significant clinical
improvement in 75% of patients; improvement did not usually begin
until after 4-6 weeks had elapsed (range: 2-10 weeks),
- there
were no obvious differences in therapeutic responses between
seropositive and seronegative patients,
- 30%
of improved patients had relapsing symptoms 1-6 weeks after stopping
therapy; these symptoms improved either spontaneously over several
weeks to months or with another 1-3 month course of tetracycline,
- treatment
failures seldom responded to alternative treatment regimens,
including IV cephalosporins.
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