1999 LDF Conference Abstract -- New York City, NY

Return to Conference Archive

12th Annual International Conference on Lyme Borreliosis and Other Tick-borne Disorders
Chronic Lyme Disease: Basic Science and Clinical Approaches

Abstracts of Presentations

KEYNOTE SPEAKER FRIDAY APRIL 9, 1999

Willy Burgdorfer, Ph.D., M.D. (Hon)
National Institutes of Health
National Institute of Allergy and Infectious Diseases
Rocky Mountain Laboratories
903 South Fourth Street
Hamilton, MT 59840-2999

The Complexity of Arthropod-borne Spirochetes (Borrelia spp) with Reference to the Lyme Disease Agent Borrelia burgdorferi
Willy Burgdorfer, Ph.D., M.D. (Hon)

Reference is made to the discoveries of the louse-borne relapsing fever spirochete, Spirochete obermeieri by the German physician, Dr. Otto Obermeier in 1868, and about 35 years later, of the tick-borne relapsing fever spirochete, Borrelia duttonii by the British investigators Dutton and Todd in Kenya, Ross and Milne in Uganda, and by the German microbiologist Dr. Robert Koch in East Africa.

The development of these spirochetes in their arthropod vectors, the louse Pediculus humanus humanus, and the argasid (soft-shelled) tick, Ornithodoros moubata has been the subject of intensive research with controversial findings: some investigators suggested spirochetes shortly after ingestion undergo a negative phase during with they develop into cysts (blebs, vesicles) which become the sources of new (young) spirochetes. Key references supporting this "granulation theory" are presented. To most other borreliologists, the cysts (blebs, vesicles) are the products of spirochetal degeneration. To them, spirochetes multiply by binary fission only.

The discovery in the fall of 1981 of a new tick-borne spirochete (Borrelia burgdorferi) sensu stricto, as the long sought cause of Lyme disease in the United States and in Europe signaled the beginning of a new era in the research of arthropod-borne spirochetes. Successful isolation and culturing of spirochetes from vectors, hosts, and patients, the use of immunochemical stains, and the application of transmission and scanning electron microscopy provided the means to reevaluate certain biologic aspects of spirochetes including their development in vitro an in vivo. Recent findings on this subject are presented.

Lyme Disease Research in Context of the National Institutes of Health
Dennis Dixon, Ph.D.

The purpose of this presentation is to place Lyme disease (LD) research in the context of the National Institutes of Health (NIH). The NIH is comprised of Institutes and Centers (www.nih.gov). Institutes are further organized into Intramural and Extramural components. The former consists of staff scientists who conduct basic and scientific studies and the latter consists of scientific programs administered by grants and contracts. The National Institute of Allergy and Infectious Diseases (NIAID) is the lead Institute for coordinating research on LD, and is assisted by the LD Coordinating Committee to ensure communication of research needs and opportunities across Institutes. NIAIDs Intramural components, at the Bethesda campus and at Rocky Mountain Laboratories in Montana, and the Extramural component have robust programs in Lyme disease. The Intramural Program is advised by the Board of Scientific Councilors. The National Advisory Allergy and Infectious Diseases Council is the principal advisory body to the NIAID Extramural program. Other advisory groups include Data and Safety Monitoring Boards for large scale clinical treatment trials, and a Lyme Advisory Panel for the largest treatment trial. General themes of emphasis in the Extramural scientific programs focus on diagnosis, treatment, and prevention. These three areas of focus are evident in the LD program and will be summarized in the presentation.

Patricia K. Coyle, M.D.
Professor of Neurology
Department of Neurology
State University of New York at Stony Brook
HSC T12, 020
Stony Brook, NY 11794

Neurologic Lyme Disease Update
Patricia K. Coyle, M.D.

Objective: To review current information on neurolgic Lyme disease.

Methodology: Literature review and Stony Brook experience.

Results: Lyme disease is the major human spirochetal infection in the United States and Europe. It is due to a tick-borne pathogen, Borrelia burgdorferi. Neurolgic involvement occurs in up to 40% of symptomatic infections. A number of recent developments are helping to shed light on how neurolgic disease occurs. B. burgdorferi shows strain heterogeneity, and there appear to be neurotropic strains. The spirochete can change surface proteins, and there may be differential antigen expression within the intrathecal vs. systemic compartment. Dual tick pathogen infections appear to have implications for more severe infections. Although there are well characterized neurolgic syndromes associated with early disseminated and late stage infection, unusual syndromes such as acute central nervous system demyelinating disease have also been noted. Diagnosis of neurolgic Lyme disease may be aided by second generation antibody tests, to document a unique or preferential intrathecal immune response. Optimal treatment of neurolgic Lyme disease remains to be defined; at the current time intravenous ceftriaxone remains the treatment of choice. Neurolgic disease can occur following oral antibiotic therapy, suggesting that penetration into the CNS is important. The recent experience of 30 early Lyme disease patients seen at Stony Brook during the summer of 1998 will be reviewed, with regard to clinical syndromes, neurolgic symptoms, and laboratory data.

Conclusion: Neurolgic Lyme disease continues to be a major clinical concern. It can lead to morbidity, and better diagnostic and therapeutic options need to be developed.

Ronald Van Heertum, M.D.
Professor and Vice Chairman of the Department of Radiology
New York Presbyterian Hospital
Columbia University College of Physicians and Surgeons
177 Fort Washington Ave
Milstein Hospital Building 2-131
Department of Radiology
New York, NY 10032

Functional Brain Imaging in the Diagnosis of Chronic CNS Lyme Disease
Ronald Van Heertum, M.D.

Lyme disease, caused by infection with the spirochete Borrelia burgdorferi, is often diagnosed by a combination of clinical findings including a history of deer tick exposure, systemic symptoms, appearance of a characteristic rash and positive Lyme titers. Chronic central nervous system (CNS) involvement, which, frequently manifests as nonspecific neurobehavioral symptoms, presents a major diagnostic challenge to the treating physician. Conventional structural imaging methods such as CT and MRI are frequently not helpful. As a result, patients maybe misdiagnosed or even labeled as malingering. Recently, however, functional brain imaging, using radionuclide techniques, have been reported to show promise as a contributory adjunct technique in the diagnosis of chronic CNS Lyme disease. The objectives of this presentation are: 1) review the currently available brain imaging techniques; 2) discuss the relative strengths and weaknesses of the available techniques; 3) describe the findings on brain SPECT in chronic CNS Lyme disease, and 4) review recent data supporting the role of Brain SPECT in differentiating CNS Lyme disease from other disorders such as Alzheimer's disease, mild head trauma and major depression.

Lymerix™ Alternate Schedule Studies
Dennis L. Parenti, M.D.

Lymerix™, SmithKline Beecham Biologicals' recombinant outer surface protein A (OspA) vaccine, was approved by the FDA for prevention of Lyme disease for those aged 15 to 70 years on a 0, 1, 12 month schedule. Flexibility of dosing schedules is highly desirable to ensure rapid and convenient immunization due to the seasonal aspect in some parts of the country. The mechanism of protection of the OspA based vaccine suggests that high and sustained antibody levels would be required to prevent infection. In the field efficacy trial, it was noted that vaccine failures had post vaccinations titers below those of the controls. Statistical methods were used to identify a serological correlate of protection. An IgG anti-OspA antibody titre of 1200 EL.U/ml prior to the start of the tick season appears to provide high probability of protection. In the field efficacy trial, >90 % of the subjects had antibody titers > 1200 EL.U.

Alternative dosing schedules have been investigated in 2 clinical studies. A total of 750 subjects were vaccinated in one study which compared the reactogenicity and immunogenicity of Lymerix™, either on a 0, 1, 6 month schedule or on a 0, 1, 12 month schedule. The results demonstrated that equivalent antibody titers were elicited with the two immunization schedules.
Another clinical study evaluated the safety and immunogenicity of three doses of Lymerix™ on a 0, 1, 2 month schedule. This study demonstrated that the 0, 1, 2 immunization schedule provides similar antibody responses to the licensed schedule.
In both clinical trials discussed above, at least 93% of the vaccines had IgG titres >1200 EL.U/ml one month after the 3rd dose.

In conclusion, Lymerix™ elicits comparable protective immune responses following three doses on a 0, 1, 2 or 0, 1, 6 or 12 month schedule which would allow maximal 0, 1, 2 to 12 month flexibility.

Safety and Efficacy of a Commercial Recombinant OspA Vaccine for Dogs
Andrew K. Eschner, DVM

The first commercially available, non-adjuvanted, monovalent recombinant OspA vaccine for the prevention of Lyme disease in dogs was launched to the veterinary medical community in 1996. Research has shown that one of the major outer surface proteins of Borrelia burgdorferi, designated OspA, is a potent immunogen and provides protection against spirochete infection in a variety of animals. The primary goal of the research presented herein was to establish that a purified recombinant OspA protein would be both safe and efficacious in dogs.

The safety and efficacy of the recombinant OspA canine Lyme disease vaccine was determined in both laboratory (efficacy and safety) and field trials (safety) utilizing both commercially acquired specific-pathogen-free laboratory dogs and dogs in the population at large (multi-center field safety trial). Efficacy trials were conducted using 9-10 week old purpose-bred Beagle dogs which were randomly assigned to treatment and control groups. All aspects of animal housing, care and research methods complied with Animal Welfare Guidelines as set forth in the 9CFR (Code of Federal Regulations) and met Institutional Animal Care and Use Committee (IACUC) requirements. A natural tick challenge model utilizing live-caught, nymphal Ixodes scapularis ticks known to be infected with Borrelia burgdorferi was employed. In total, three efficacy trials were conducted prior to licensure by the United States Department of Agriculture: a 3 week short-term, a 5 month medium-term and a 1 year long-term trial.

Vaccine efficacy was determined principally by spirochete re-isolation techniques on skin punch biopsies harvested at various times post-challenge. Clinical signs and antibody titers were also assessed. Vaccine safety was determined by assessment of local and systemic reactions at various times after immunization and also by a USDA mandated field safety trial involving over 1,400 dogs of various ages which were followed for a four month time period. The non-adjuvanted, recombinant OspA canine Lyme disease vaccine was proven to be highly effective in preventing both spirochete dissemination and clinical signs of canine Lyme borreliosis in short and long term efficacy (DOI) trials. No adverse effects were noted in the laboratory setting and the vaccine was markedly reaction-free in a field safety trial.

OspA Induces Lyme Arthritis In Hamsters
Cindy L. Croke, Erik L. Munson, Steven D. Lovrich, John A. Christopherson, Monica Remington, Steven M. Callister and Ronald F. Schell. Wisconsin State Laboratory of Hygiene and Departments of Medical Microbiology and Immunology and Bacteriology, University of Wisconsin, Madison, and Microbiology Research Laboratory, Gundersen Medical Foundation,
La Crosse, Wisconsin.

Recently, we presented evidence that adverse effects, particularly severe destructive Lyme arthritis (SDLA), can develop in vaccinated hamsters after challenge with Borrelia burgdorferi sensu lato isolates. Hamsters were vaccinated with whole-cell preparations of inactivated B. burgdorferi sensu stricto isolates in alum. SDLA was readily evoked in vaccinated hamsters after challenge with homologous or other B. burgdorferi isolates. Arthritis was evoked before high levels of protective borreliacidal antibody developed or after the levels of protective antibody declined. We now show that vaccination with recombinant Osp A, the vaccine against Lyme disease, can also induce SDLA. Hamsters were vaccinated with 30, 60, or 120 mg of recombinant Osp A or an Osp A vaccine for dogs. Eleven days after vaccination with the recombinant Osp A, vaccinated hamsters were challenged in the hind paws with 106 B. burgdorferi isolates 297 or C-1-11. Swelling was detected 7 days after infection, peaked on day 11 and gradually decreased. In addition, histologic evidence of erosive and destructive arthritis was demonstrated in the hind paws of Osp A vaccinated hamsters challenged with B. burgdorferi. These findings demonstrate that vaccination with Osp A can induce adverse effects. Vaccination of humans with Osp A should not be recommended until the vaccine has been shown to be incapable of inducing SDLA.

Steven M. Callister, Ph.D.
Gundersen Lutheran Medical Center
1836 South Avenue
La Crosse, WI 54601

Borreliacidal Antibodies Against OspC: Implications For Vaccine Development
And Serodiagnosis
Steven M. Callister, Ph.D.

Borreliacidal or killing antibodies are produced after infection with Borrelia burgdorferi. These highly specific antibodies are produced in response to stimulation of the immune system by B. burgdorferi outer surface proteins (Osp), including OspA, OspB, OspC, and others. We recently confirmed the ability of OspC and other proteins to induce borreliacidal antibodies in vivo shortly after infection, while anti-OspA and anti-OspB borreliacidal antibodies are produced primarily during later stages of the illness. Detection of anti-OspC borreliacidal antibodies has implications for vaccine development and serodiagnosis.

Despite the presence of high concentrations of borreliacidal antibodies, Lyme disease spirochetes are often not eliminated. However, borreliacidal antibodies can provide protection from infection if they are present at high levels prior to challenge with B. burgdorferi. Anti-OspA borreliacidal antibodies are responsible for providing protection after vaccination with OspA. Vaccination with OspC has also been shown to provide protection against Lyme disease. However, anti-OspC borreliacidal antibodies have not previously been detected, leading to speculation that protection was due to other mechanisms. The ability of OspC to induce borreliacidal antibodies provides a possible explanation for the ability of OspC vaccination with to provide protection. In addition, serodiagnostic tests which detect borreliacidal antibodies can be sensitive and highly specific.

In a recent investigation, blinded CDC serum samples were analyzed for the presence of borreliacidal antibodies. High concentrations of borreliacidal antibodies were detected in 9 (70%) of 13 culture-defined early Lyme disease sera using an OspAB- B. burgdorferi isolate expressing high levels of OspC. In contrast, little or no borreliacidal antibodies were detected in 24 (96%) of 25 potential cross-reactive sera. In addition, detection of borreliacidal antibodies using this isolate will not be hindered by vaccination with the current OspA vaccine.

Potential Role of the UHB Gene Family of the Lyme Disease Spirochetes in Immune Evasion
Richard T. Marconi, Ph.D. & Shian Ying Sung (Ph.D. candidate)

Evidence suggests that the Lyme disease spirochetes evade destruction by the immune system in part through antigenic variation in outer surface proteins. While the vls gene family has been demonstrated to contribute to antigenic variation, the overall process is likely multi-factorial. We have conducted extensive analyses on a series of lipoprotein encoding genes that form a super gene family. All members of this gene family exhibit homology with each other, particularly in the N terminal region of their deduced amino acid sequences and are flanked at their 5' end by a conserved upstream, promoter carrying sequence element called the upstream homology box (UHB).

Hence we have designated this gene family as the UHB gene family. We have demonstrated that this gene family contains 3 distinct sub-families (ospE, ospF and pG groups). Members of these subfamilies exhibit significant variation. PCR analyses revealed the presence of highly polymorphic domains in the coding sequences of both the ospE and ospF sub-families. In the ospE related genes these variable domains are flanked by direct repeat elements (up to 38 bp) and computer analyses predict this domain to be hydrophilic, surface exposed, and antigenic. To determine if immune pressure drives rearrangement or sequence changes in the UHB flanked genes we have analyzed the stability of these genes over an infection period in mice of 2 months.

While plasmid composition changed over the course of infection, gross gene rearrangements in the ospE and ospF related genes were not detected through PCR analyses. We are currently sequencing the amplicons to determine if point mutations have arisen during the course of infection. In addition to the analyses outlined above we are also assessing the transcriptional expression of UHB flanked genes under different environmental conditions and are characterizing the humoral immune response to these proteins. The characterization of the UHB gene family among Bbsl species will prove important in attempts to decipher its role in the biology and pathogenesis of the Lyme disease spirochetes.

Novel Features of Rabbit Infection and Immunity in the Study of Lyme Disease
Michael A. Lovett, M.D., Ph.D.

No abstract available.

Borrelia burgdorferi Lipoproteins and the Control of Inflammation in Lyme Disease.
P. K. Murthy, V. A. Dennis, B. Lasater, and M. T. Philipp*

Borrelia burgdorferi lipoproteins are known to induce local and systemic production of proinflammatory cytokines such as IL-6, IL-1-beta and TNF-alpha in macrophage/monocytes. These cytokines have been implicated in the pathogenesis of Lyme disease.

We have reported that heat-killed B. burgdorferi spirochetes (Bb) and lipidated outer surface protein A (L-OspA) but not unlipidated OspA (U-OspA) are able to stimulate not only the production of inflammatory cytokines but also that of the anti-inflammatory cytokine IL-10 in peripheral blood mononuclear cells from uninfected humans and rhesus monkeys. Monocytes are the cells that transcribe both types of cytokines (Giambartolomei et al., Infect. Immun. 1999, 67, 140-147). We have now demonstrated, in a kinetic study, that in the monocytic cell line THP-1, stimulation with Bb, L-OspA, or LPS but not U-OspA induces the production of IL-10, IL-6 and IL-12 at about 8 h post-stimulation (PS). However, while the peak production of IL-10 occurred between 8 and 16 h PS, that of the other two cytokines took place much later, at 48 h PS. Recombinant IL-10 (rIL-10) added to L-OspA- or LPS-stimulated THP-1 cells completely inhibited IL-12 production using as little as 0.1 ng/ml of rIL-10. The inhibitory effect of rIL-10 on IL-6 production was dose dependent. The addition of anti-IL-10 antibody markedly enhanced IL-6 and IL-12 production.

These results show that IL-10 induced by B. burgdorferi lipoproteins can downregulate proinflammatory responses similarly induced by lipoproteins. They further suggest that IL-10 induced by the spirochete may contribute to control inflammation in Lyme disease and that exogenous rIL-10 might be therapeutically useful.

A Novel Toxin (Bb Tox 1) of Borrelia burgdorferi
Mark J. Cartwright, Ph.D.*, Suzanne E. Martin, Ph.D. and Sam T. Donta, M.D.

The mechanisms responsible for many of the symptoms of Lyme disease remain to be delineated. Because many of the symptoms involve the nervous system, we postulated that the Lyme spirochetes produce a toxin that interferes with normal neurophysiological function. We have identified and cloned a gene of B. burgdorferi which encodes a protein that is a neurotoxin.

Initially, degenerate primers were designed to highly conserved regions within various toxin groups. These primers were used for amplification of DNA extracted from B. burgdorferi strain 2591 to identify genes that express proteins analogous to existing toxins. Degenerate primers designed to the highly conserved catalytic domains of diphtheria and pertussis toxins yielded an amplification product. The product was cloned, sequenced, and subsequently identified in The Institute of Genomic Research (TIGR) database as BB0755, a 37 kD protein of unknown function. The full length gene for BB0755 was cloned, expressed and purified using epitope tags in the pET30a expression system, and the resultant recombinant protein renamed Bbtox1. Using the synthetic target agmantine, Bbtox1 exhibited ADP-ribosyltransferase activity. No ADP-ribosyltransferase activity was detected using elongation factor 2 as the target. In tissue culture, Bbtox1 affected the morphology (rounding) of Y1 mouse adrenal cells and C6 rat glial cells. Bbtox1 induced cell death in both Y1 and C6 cells. C6 glial cells responded to Bbtox1 in a dose and time dependent manner. Brefeldin A, an inhibitor of the trans-golgi network, accelerated the onset of action of Bbtox1 an Y1 adrenal cells.

The effects of Bbtox1 are consistent with a mechanism of action similar to that of botulinum C2 and other cytoskeletal toxins. Studies are underway to identify the cellular target of Bbtox1 and its role in Lyme Disease. In addition, a homologous gene in Treponema pallidum of undefined function is being analyzed to determine if it codes for a toxin similar to Bbtox1.

Quantitative Spirochetal DNA in Dog Tissue
Reinard K. Straubinger, D.V.M., Ph.D.

Background: B. burgdorferi is known to establish a persistent infection in the mammalian host. However, little is known about the number and the tissue preference of the spirochete. Quantification of B. burgdorferi organisms by culture or staining methods is either impossible or not practical. Current DNA amplification methods are labor intensive and only a limited number of samples can be processed.
Objective: Determine the absolute number of B. burgdorferi organisms by a new method of DNA amplification in a large number of canine tissue and buffy coat samples collected over a 500-day period.
Design: Sixteen specific-pathogen-free beagle dogs were infected with B. burgdorferi by tick challenge. Starting at day 120 after tick exposure, 12 dogs were treated with antibiotics for 30 consecutive days (4 dogs, azithromycin, 25 mg/kg daily, po; 4 dogs, ceftriaxone, 25 mg/kg, daily, iv; 4 dogs, doxycycline, 10 mg/kg, BID, po). The remaining four dogs received no antibiotic therapy. Over a 500-day period, blood samples were taken at two-week intervals and skin punch biopsy samples at monthly intervals. Twenty-five tissue samples were collected during necropsy. DNA of all samples was recovered by phenol/chloroform extraction. Detection and quantification of B. burgdorferi DNA was carried out in 96-well plates in an ABI7700 Sequence Detection System. Primers and a fluorescent-labeled probe designed to bind specifically to the ospA gene of B. burgdorferi strain N40 were used for DNA amplification and quantification. The intensity of fluorescent signal for test samples was compared to a standard curve, generated with DNA in a ten-fold dilution series of a known number of culture-derived low-passage B. burgdorferi organisms suspended in canine buffy coats.
Results: All 16 dogs became infected after tick challenge. In skin biopsy samples of untreated dogs, spirochete numbers peaked at day 60 post infection (< 4 ¥ 106 organisms per 100 ng extracted DNA) and decreased by 100- to 1000-fold during the following six months. Antibiotic treatment did not eliminate the infection, but reduced the number of spirochetes in skin tissue by a factor of 1000 or more. Buffy coat samples were rarely positive (1.6% of 576 buffy coat samples of all dogs). More than 500 days after infection, B. burgdorferi was detectable at low levels (102-104 organisms per 100 ng extracted DNA) in multiple tissue samples in all untreated dogs and in eight of 12 antibiotic-treated dogs. However, more tissue samples were positive in untreated dogs than in antibiotic-treated dogs.
Conclusions: This DNA detection system facilitates the precise and rapid quantification of B. burgdorferi in a large number of tissue and blood samples. Data generated with this technique provide evidence that during the first two months after infection the number of spirochetes increased in the skin of infected dogs and declined thereafter. Interestingly, peak numbers of organisms coincided with the development of the first clinical signs. Antibiotic treatment did not eliminate the infection but decreased the number of organisms.

Antimicrobial Agents that Target DNA Gyrase in Borrelia burgdorferi
D. Scott Samuels, Betsy J. Kimmell, Kendal M. Galbraith, and Christian H. Eggers

The only DNA topoisomerase that can catalyze the introduction of supercoiling into a DNA molecule is the prokaryotic enzyme DNA gyrase. DNA gyrase is an A2B2 tetramer: the A subunit binds DNA, generating a double-stranded break and then resealing it, while the B subunit uses ATP to drive the reaction. DNA gyrase is the target of several groups of antimicrobial agents. Coumarin antibiotics, including coumermycin A1, bind to the B subunit, blocking ATP binding and inhibiting enzyme activity. Fluoroquinolone antibiotics, such as ciprofloxacin, bind to the A subunit after it has generated the double-stranded break in DNA and prevents the resealing reaction. We have examined the effects of several DNA gyrase inhibitors on the cell growth and DNA conformation of B. burgdorferi . We found that B. burgdorferi is highly susceptible to growth inhibition and plasmid relaxation (loss of supercoiling) by coumermycin A1 treatment. Although coumermycin A1 is not a clinically useful antibiotic for a variety of reasons, we have used it to develop a genetic system for B. burgdorferi . We have shown that B burgdorferi is fairly resistant to ciprofloxacin, and another fluoroquinolone moxifloxacin, but more susceptible to the fluoroquinolones Bay-Y3118 and sparfloxacin. We will test other, more potent fluoroquinolone antibiotics, including trovafloxacin, clinafloxacin and sitafloxacin. Most recently we have used the fluoroquinolone antibiotics to map the sites on DNA where DNA gyrase (or the homologous enzyme topoisomerase IV) prefers to bind.

Update on Tick-Associated Human Histopathology
Paul H. Duray, M.D., Xiadu Guo, M.D., Ph.D.

Recent technical laboratory approaches have contributed to the understanding of human and mammalian tissue models in infections induced by tick vectors. PCR has been one of the major approaches due to the feasibility of appropriate infectious agent classification and linkage for a given histopathologic condition.

Tissue lesion classifications prior to PCR, tissue immunoblotting with quantitative protein analysis, and animal infection models were fraught with guess-work and supposition. Established and generally accepted histologic spectrum includes the inflammatory and fibroinflammatory dermal, adipose, and fascial tissue lesions, myositis, myocarditis, expansile skin erythematous dermatitis, synovitis with some joint erosion if recurrent, peripheral neuritis, autonomic gangliitis, ocular vitreitis, and some degree of lymphoreticular hyperplasia. Still unclear are the histopathologic lesions directly involved with Borrelia and Ehrlichia infections.

Recent studies have shown borrelial spirochetes to be directly present in the degenerative synovial surface deposits and in relatively high numbers as compared to the underlying sub-synovium in patients with Lyme synovitis prior to antibiotic therapy. We have now observed spirochete clustering in the hair follicle adventitial layer of lymphocytoma cutis-like lesions in humans and in erythema migrans-like lesions rabbit models. Lymphocytoma may be very rarely seen in U.S. cases of undiagnosed Borreliosis, but when present, spirochetes can be identified. Relapsing fever borrelia are linked to pleuritis and are demonstrable in the pleura of rodent models. Some lesions that extended experience permits decreasing links to Borrelia are lichen sclerosis of skin, plasmacytic panniculitis, and cutaneous vasculitis. Gaps in our knowledge will inevitably exist regards the important CNS questions.

Ehrlichiosis, Babesiosis, and Borreliosis
Edwin J. Masters, M.D.

Human granulocytic ehrlichiosis (HGE), Lyme borreliosis and Babesiosis are a clinical triad with a common tick vector, Ixodes scapularis. This triad occurs mainly in the Northeast and north central states. Human monocytic ehrlichiosis (HME); a new Babesiosis, MO1, and a borreliosis causing clinical erythema migrans are found in the lower Midwest and South.

Human babesiosis in the U.S. has been associated in the northeastern and upper midwestern states with Babesia microti and Ixodes scapularis ticks, in California and Washington State with WAI-type piroplasms and in the Southeast Missouri with a related but distinct intraerythrocytic piroplasm MO1. Human monocytic ehrlichiosis (HME) caused by Ehrlichia chaffeensis has been associated with Amblyomma americanum (lone star) ticks in the Midwest and phagocytophylia-like organism has been found in the upper Midwest and Northeast. Ehrlichiosis has also been recently found in California. Atypical Borrelia burgdorferi have been found in Missouri ticks and a new species, Borrelia lonestari, has been discovered in lone star ticks. Additionally, erythema migrans cases have been documented in the lower Midwest and other borrelia appearing spirochetes that stained with H5332 have been observed in lone star ticks. Furthermore, ticks simultaneously harboring Borrelia and Babesia as well as Borrelia and Ehrlichia have been reported.

Are there parallel paths of pathogenicity between lone star and Ixodes deer ticks? Geographic and temporal histories of the evolving knowledge and awareness of Babesiosis, Ehrlichiosis, and Lyme Disease are compared.

Given this history of the evolving geographic association of Borreliosis, Babesiosis and Ehrlichiosis (although different species or strains may be involved), when there is evidence for the presence of two of these ticks vectored illnesses, a high index of suspicion for the third is warranted, along with the possibility of co-infection.

Clinical and Pathogenetic Studies of HGE
J. Stephen Dumler, M.D.

Human granulocytic ehrlichiosis (HGE) is an acute febrile tick-borne zoonotic illness caused by obligate intracellular bacteria of the Ehrlichia phagocytophila group, that infect cells of myeloid derivation in mammalian hosts. Recent advances have improved understanding of bacterial and host components involved in HGE. In humans, fever, headache, myalgias, and malaise characterize HGE in most patients and involvement of the gastrointestinal and respiratory systems and skin is less frequent. Definite CNS involvement has not been documented. Laboratory abnormalities include thrombocytopenia, leukopenia, and elevations in serum hepatic aminotransferase activities. Most infections are asymptomatic or subclinical; however, a sepsis-like syndrome, adult respiratory distress syndrome, rhabdomyolysis, hemorrhage, peripheral neuropathies, severe opportunistic and nosocomial infections, and death may occur. Severity appears to be related to initial burden of the infectious agent and delays in diagnosis and treatment.

A chronic or persistent phase of HGE has not been documented, and co-infection with other tick-borne agents has not been proven to adversely affect outcome. Most patients recover rapidly in association with a TH1 response and high titers of antibodies. Animal models, especially horses, are good mimics of human disease; mice do not develop any clinical signs of disease and have TH2 responses, but do develop pathologic lesions similar to those observed in humans and other animal models. In vitro and experimental infections in horses and mice indicate that infection is established in myeloid precursors of bone marrow or other hematopoietic tissues and is mediated via ehrlichial MSP adhesins and leukocyte CD15-associated receptors, after which bacterial infection may control some host cell functions and responses. Later, infected neutrophils are released into the peripheral circulation and adhere to endothelial surfaces, particularly in the spleen, liver, and lung. In vitro, infected neutrophils secrete high levels of chemokines, but not proinflammatory cytokines.

Thus, the localized secretion of chemokines allows recruitment and activation of mononuclear inflammatory cells that in turn release proinflammatory cytokines and induce localized tissue injury. In mice, a kinetic relationship between ehrlichial burden, IFNK release, and pathologic index is observed, suggesting that E. phagocytophila bacteria drive a potentially deleterious inflammatory response but do not directly mediate substantial cell injury. Although not proven, it is suspected that poorly controlled proinflammatory cytokine release may be related to systemic manifestations and increased severity of disease. Continued study of the ehrlichiae and infected hosts will contribute greatly to our understanding of HGE and help to devise better management and treatment strategies.

Development of Tick Transmission Models for Infections with Borrelia, Babesia, and Ehrlichia
Edward M. Bosler, Ph.D.

Since I. scapularis is the vector for Borrelia burgdorferi, Babesia microti and the agent of Human Granulocytic Ehrlichiosis it stands to reason that a single tick is capable of harboring and transmitting multiple pathogens and that human co-infection may arise from a single tick bite. Our previous field data demonstrates that co-infection occurs in both mammals and ticks on Long Island. These data also indicate the need to establish laboratory tick-animal transmission models to study transfer of multiple pathogens.

We currently maintain infection in C3H mice with the three B. burgdorferi genospecies that cause human disease (B. burgdorferi sensu stricto, B. afzelli and B. garinii) via tick transmission. We
recently established pathogen infection profiles for the agents of HGE and Babesiosis in 4 inbred mouse strains when the organisms were singly inoculated at 2 dosages via 2 routes of inoculation. In the case of HGE infection three distinct patterns (self limiting, chronic and intermittent) emerged from the different mouse strains used. Patterns of B. microti infection were less defined and to produce consistent murine infection the organism had to first be "mouse adapted".

Non-infected larval ticks were fed on HGE infected mice as well as Babesia infected mice in order to obtain infected nymphs for subsequent tick to mouse transmission. HGE infection rates in nymphs ranged between 20-50% and appeared to be dependent on the host mouse strain. Currently only SCID mice appear to efficiently infect larval ticks with B. microti.

Vectors of B. Burgdorferi and Related Pathogens
John F. Anderson, Ph.D.

Ixodes scapularis in eastern United States and Ixodes pacificus in western United States are the primary vectors of Borrelia burgdorferi in the New World. The closely related species Ixodes ricinus and Ixodes persulcatus are the main vectors in the Old World. All four tick species feed on blood three times in their lives, and all feed on many different types of host (lizards, birds, and mammals). All feed on humans as larvae, nymphs, and adults, but most humans acquire infections of Borrelia burgdorferi in eastern United States from bites of nymphal I. scapularis. Nymphs normally need to be attached for 40 or more hours for Borrelia to be transferred from the tick to its host. Most humans acquire their infections in late spring and early summer when nymphs actively seek hosts. The continued increase in numbers of I. scapularis is related to the continued increase in abundance of the white-tailed deer, the primary host animal for the adult tick.

We have been identifying ticks sent in by citizens and testing them for the presence of Borrelia burgdorferi since 1990. Sixteen species have been identified of which 13 were off humans and six were not native to Connecticut. The most common species received were I. scapularis, Dermacentor variabilis, and Amblyomma americanum. Of the 25,463 I. scapularis tested by culture, IFA, or PCR, 5226 or 22% were infected with B. burgdorferi. Ticks attach to humans literally from head to toe; therefore it is important for humans to examine themselves thoroughly for attached ticks and to remove them promptly.

Personal and Property Prevention Against Lyme Disease
Kirby C. Stafford III, Ph.D.

Objectives: Lyme disease is considered primarily a peridomestic disease. The use of acaricides, vegetative management, deer exclusion, and the acaricidal treatment of deer were evaluated for the control of the tick, Ixodes scapularis, at residential landscapes in Lyme and Old Lyme, Connecticut.

Methods: A survey of tick control practices by licensed pesticide applicators was conducted. Various combinations of landscape modifications and pesticides were tested at residential home sites from 1995-1998. Trials of USDA-patented, pesticide self-application deer feeders ('4-posters') were begun in 1997 with monitoring of corn consumption and usage of the devices by deer. The abundance of questing ticks was measured for all studies at both treatment and control sites.

Results: The pesticides carbaryl, chlorpyrifos, and cyfluthrin were the most widely used materials for tick control in 1994 and 1995. The experimental trials found that synthetic pyrethroid insecticides generally reduced nymphal tick abundance by over 90%. Clearing leaf litter and wood chip barriers at the lawn perimeter can reduce nymphal abundance by an average of 42% - 88%. Certain combinations of natural pyrethrin, piperonyl butoxide, and insecticidal soap or silicon dioxide can reduce tick abundance by 71% - 97%, although some combinations of these materials were less effective and produced more variable results. Over 90% of the local deer population were observed utilizing the '4-posters' during the first year of the study, although usage declined in fall 1998 with competing food sources (i.e. acorns).

Conclusions: Acaricides are extremely effective for the control of I. scapularis and some less toxic materials may offer an alternative to synthetic chemicals for tick control at individual homes. On a larger scale, the acaricidal treatment of at least 90% of the local deer population could potentially reduce tick abundance community-wide, but the treatment regime will need to be improved.

The Work-up of Suspected Lyme Disease
Anthony Lionetti, M.D.

Perhaps one of the greatest stumbling blocks to the accurate and consistent diagnosis of Lyme Borreliosis has been the relative failure of the clinical laboratory in confirmation of disease. This is based on the biology of the causative organism, Borrelia burgdorferi and issues in laboratory performance. These issues will be discussed in detail, as well as their impact on clinical research and individual patient management.

Attendees will learn the elements of the History and Physical Examination which may assist them in the diagnosis of the patient with suspected Lyme Borreliosis. Emphasis will be placed on the Differential Diagnosis including Fibromyalgia and Chronic Fatigue Syndrome.

A diagnostic algorithm incorporating the History and Physical examination, along with the use of Special Studies and the Clinical Laboratory will be presented.

Neuropsychiatric Lyme Disease in Children and Adults
Brian Fallon, M.D.*, Felice Tager, Ph.D. Ron Rykiel, Ph.D.
Columbia University, New York State Psychiatric Institute, and the Jackson School District, NJ

While encephalopathy is not recognized in the CDC's Surveillance Case Definition of Lyme disease, cognitive disturbance due to Lyme Disease is common in adults and accounts for much of the long-term disability. Psychiatric disturbances, such as changes in mood, anxiety, paranoia, mania, psychosis, also may emerge during Lyme disease, in some cases as a reaction to having a serious disabling illness and, in other cases, as an organically induced disorder which improves when appropriate antibiotic treatment is given. Recently, published reports indicate that children also may have severe neuropsychiatric problems related to Lyme disease. This talk will review current knowledge about neuropsychiatric Lyme disease in adults and children, focusing upon one recent controlled study of neuropsychiatric problems in children with Lyme disease.

Methods 22 children with Lyme disease and 27 healthy age- and sex-matched controls between the ages of 8 and 18 were recruited. Measures of psychopathology included the Child Behavior Checklist (parent and child form), the DuPaul Attention Deficit Hyperactivity Disorder Rating Scale, the Child Depression Inventory, and a comprehensive neuropsychiatric symptom checklist. In addition, parents and children with Lyme disease were interviewed using the Diagnostic Interview Schedule for Children to obtain DSM Axis I disorders.

Results The children with Lyme disease were ill for over 3 years (mean 39.9 months). The mean time between symptom onset and diagnosis was 10.5 months. Nearly two-thirds had received IV antibiotics in addition to oral antibiotic treatment. Among the ongoing symptoms endorsed by over 70% of the Lyme children, the majority were neuropsychiatric (irritability, rage reactions, mood swings, depression, headache, poor concentration, memory loss) and systemic (fatigue, arthralgias, insomnia). Each symptom was reported significantly more frequently by the Lyme sample than the controls. 50% of the children with Lyme disease reported suicidal ideation and 9% reported having made a suicide gesture. After controlling for multiple comparisons, the Lyme children had significantly more anhedonia (CDI), more inattentiveness (DuPaul), and more internalization and externalization (CBCL). On the DISC child interviews, the most common diagnoses were disturbances of: mood (major depression 55%, systhymia 15%); fear (panic disorder 20%, separation anxiety disorder 20%, overanxious disorder 20%); cognition (Attention Deficit Hyperactivity Disorder 25%); and behavior (Oppositional Defiant Disorder 25%, Conduct Disorder 20%).

Discussion These results suggest that neuropsychiatric problems occur among children with chronic Lyme disease, particularly since the majority of parents reported that these neuropsychiatric problems were new-onset after contracting Lyme Disease. The frequency rates of neuropsychiatric disorders are not generalizable to all children with chronic Lyme disease given the likelihood of referral bias affecting our study. Nevertheless, these findings should alert clinicians and educators to the need to consider Lyme disease when faced with a child from a Lyme endemic area who has new onset neuropsychiatric and systemic symptoms.

Fibromyalgia, Lyme Disease, and Gulf War Syndrome
Sam T. Donta, M.D.

Ever since the realization that Lyme Disease can exist in a chronic form, there has been an increasing awareness of the relationship of chronic Lyme Disease to other multi-symptom disorders such as fibromyalgia and chronic fatigue. These chronic multi-symptom disorders, including the newest member, Persian Gulf War Illness, share as their major features fatigue, musculoskeletal pain, and neurocognitive dysfunction. On clinical grounds, there is little basis to separate or distinguish one disorder form the other.

This presentation will review some of the epidemiologic features of the chronic multi-symptom disorders, the clinical symptoms, and possible etiologies. Using chronic Lyme Disease as a model, approaches to the diagnosis and management of the multi-symptom disorders will be suggested.

Monitoring Lyme Disease in the Community - First Sentinel Health Site
Daniel Cameron, M.D., M.P.H.

Hypothesis: New and innovative designs are necessary if we are ever to improve the understanding of chronic Lyme disease.

Design: This sentinel health site is set in a private medical practice in Mt. Kisco, Westchester County, New York, USA, an area hyperendemic for Lyme disease. This sentinel health site evaluated a consecutive case series cohort (n=1181) and followed the cohort prospectively. 962 patients were evaluated and treated for Lyme disease from June 1997 to February 1999. 219 patients (19%) were evaluated, observed, but not treated, thus not included in this analysis.

Results:
1) The majority of the 962 treated patients (83%) presented with chronic Lyme disease, the remaining 17% with an erythema migrans rash.
2) Only 123 patients (13%) presented with a positive ELISA with Western Blot confirmation.
3) The treatment success for an initial presentation of chronic Lyme disease was 80%.
4) The prevalence of relapses was 54%.
5) The one year incidence of a relapse was 19%.
6) The success rate of retreating the first relapse was 85%.

Conclusions: This sentinel health site easily affords a timely response to current research questions. When examined using a sentinel health site a high proportion of chronic Lyme disease is revealed, most not able to be confirmed with a positive Western Blot. Most Chronic Lyme disease can be successfully treated but the success is tempered by the high prevalence and incidence of relapses. If a relapse occurs, a relapse can successfully respond to re-treatment.

Professor of Medicine
Professor of Physiology and Experimental Medicine
Division of Rheumatology
George Washington University Medical Center
2150 Pennsylvania Avenue, Suite 5-405
Washington, DC 20037

Update from the NEMC/NYMC Extramural Chronic Lyme Study
Arthur Weinstein, M.D.

No abstract available.

Update from the NIH Intramural Chronic Lyme Disease Study
Adriana R. Marques, M.D.

The mechanism(s) underlying persistent signs and symptoms of disease, despite the administration of what is currently considered to be adequate antibiotic therapy, is one of the most pressing and controversial issues regarding Lyme disease today. Our clinical protocol is designed to study the cause of persistent symptoms in patients with Lyme disease, and the interactions between the Borrelia burgdorferi and the immune system. The protocol permits us to assemble a well-characterized cohort of patients with presumed chronic Lyme disease and relevant controls, including asymptomatic seropositive controls; volunteers who have recovered from Lyme disease; patients with multiple sclerosis; and healthy volunteers. These patients are being extensively evaluated in a cross-sectional study. Patients who are found to have laboratory markers of persistent infection by study criteria are offered treatment with intravenous ceftriaxone, and followed prospectively over the course of one year. At this point, we have enrolled and evaluated 45 patients and controls in this protocol. The protocol has served as the basis for multiple parallel lines of investigation that are being developed in collaboration with scientists both inside and outside the NIH. Lines of investigation include evaluation of both currently available test for the diagnosis of B. burgdorferi infection and development of new approaches to assess persistence of infection in our cohort, as well as studies of possible autoimmune mechanisms involved in chronicity of the disease.

Chronic Fatigue Syndrome and Post Lyme Disease
Lauren Krupp, M.D.

Objective: 1) To compare clinical findings in Post Lyme Syndrome, Chronic Fatigue Syndrome and Recovered Lyme.

2) To provide an update of the NIH STPO-LD treatment study.

Methods: Self-report fatigue and mood measures, psychiatric interviews, cognitive testing in PLS (n=40), CFS (n=25), recovered Lyme (N=14).

Results: 84% of PLS meet criteria for CFS. However, mild-moderate cognitive deficits are present in both groups, but are more prominent in PLS. PLS and CFS have an elevated lifetime prevalence of psychiatric disorders compared to recovered Lyme patients.

The initial 40 subjects enrolled in the STOP-LD double blind placebo controlled clinical trial show clinical findings similar to other PLS groups studied. 80% have EM and 20% have late manifestations without EM. 57% had a lifetime history of psychiatric disorder. 63% had mild or moderate cognitive impairment.

Conclusion: The clinical trial should provide important data on treatment approaches for this persistently symptomatic patient group.

Ziracin: A Novel Antibiotic against Bb
Charles S. Pavia, Ph.D.

A novel antibiotic, ziracin, was tested for its ability to inhibit growth, in vitro, of the Lyme disease spirochete B. burgdorferi (Bb) and to cure C3H mice of an acute Bb infection. For the in vitro experiments, the MICs (based on =90% growth inhibition) and the MBCs (100% killing) for ziracin were compared with those for penicillin (Pen) and ceftriaxone (Ctx). Selected Bb strains (3 reference strains: B31, 297 and CA287; and 27 recent patient isolates) were cultured in a micro-dilution system in the presence of various concentrations of the 3 antibiotics. Each test well of a microtiter plate contained one-half of one million Bb, with or without antibiotic, in a final volume of 0.2 ml of BSK media. The antibiotics were diluted in BSK media and added at various concentrations (0.01-10.0 µg/ml). After incubating the sealed plates at 35-37°C for 24-48 hours, MICs were determined based on direct microscopic counts of the number of live, motile Bb visualized using phase-contrast microscopy. An MBA was considered to be the lowest concentration of antibiotic in which no bacteria survived or could be detected following subculture. This was done by taking Bb micro-cultures that had been inhibited by =90% (based on MIC test results), and then adding these into separate culture tubes containing fresh BSK support media lacking any antibiotics. These culture tubes were incubated for up to one week and subsequently analyzed for any growth based on microscopic observations. Our results showed that for both the Bb reference strains and the patient isolates, the MICs ranged from 0.1-0.5 µg of ziracin per mil, 0.5-2.0 µg of Pen per mil, and 0.1-.25 µg of Ctx per ml. For these same Bb strains, the MBCs (in µg/ml) for ziracin ranged mostly from 0.2-0.5, for Pen the range was 1.0-4.0, and for Ctx it was 0.2-0.5. For the in vivo studies, separate groups of C3H mice were infected intradermally with 100.00 Bb. Seven to 10 days later, mice were given daily doses of ziracin (50 mg/kg/bw) i.p., for 5 days. The treated mice were sacrificed 2 days later and extract cultures of their urinary bladders were prepared in BSK media. No Bb organisms grew out of these extract cultures, whereas Bb was isolated from extract cultures of matched, infected control mice not treated with ziracin. These data suggest that ziracin may be a possible therapy for Lyme disease since it has better or nearly equal in vitro and in vivo inhibitory activity against Bb relative to two other antibiotics that are frequently used for the treatment of Lyme disease.

The Role of Cognitive Remediation in Brain Injured Patients and its Potential Relevance to Chronic Lyme Encephalopathy
Leo J. Shea III, Ph.D.

Studies have demonstrated that patients with brain injury have greater rates of functional recovery when they receive systematic multimodal therapy. A major part of such a system is the application of cognitive remediation to diagnosed cognitive deficits.

The overall goal of cognitive remediation is the amelioration of acquired cognitive deficits through: an informational and educational process which commences with early diagnosis, followed by discrete and highly specific neuropsychological testing; a detailed explanation of the nature and functional impact of the neurocognitive/behavioral deficits, focused on increasing patient awareness; encouraging patient flexible/malleability to the remediation process; assisting patient learning, mastering and habituating of specific compensatory strategies to improve daily functioning; increasing patient acceptance of the changes occasioned by the illness and valuing the
"present self".

Initial cases studies with Lyme Disease patients indicate that, as with other acquired brain injured
patients, systematic application of cognitive remediation process holds promise for increased daily functioning.

Chronic Lyme Disease
Kenneth Liegner, M.D., P.C.

1) Thorough evaluation to confirm diagnosis of chronic Lyme disease and assess for possible additional conditions (including co-infections) which may interfere with response to treatment and recovery.

2) Antibiotic therapy is mainstay of treatment. Simplest, safest and least expensive regiment that works, is preferred.

3) Intravenous antibiotic therapy usually reserved for patients not responding to intensive oral antibiotics. Most patients requiring intravenous antibiotics, and particularly requiring prolonged intravenous therapy, have neurolgic involvement.

4) Duration of treatment determined by clinical response.

5) Improved methods of treatment for chronic Lyme disease are needed.

The New Lyme Disease
Joseph J. Burrascano, Jr., M.D.

I propose we redefine what we have been calling Lyme. A huge body of research and clinical experience has demonstrated the nearly universal phenomenon in Lyme patients of co-infection with multiple tick-borne pathogens. Studies have shown that concurrent Borrelial and Ehrlichial and/or Babesial infections result in a change in a patient's individual clinical presentation, with different symptoms, atypical signs, decreased reliability of standard diagnostic tests, and most importantly, the unexpected creation of chronic, persistent forms of each of these infections. As time goes by, I am convinced that more pathogens will be found.

Therefore, "Lyme Disease", as we had come to know it, probably represents a mixed infection. This may explain the discrepancy between laboratory study of pure Borrelia infections, and what front line physicians have been seeing for years in real patients.

It is still early in our efforts to sort out clinical features of the individual pathogens in the co-infected patient, but trends are emerging. We need a better understanding of the pathogenesis of these illnesses in the mammalian host, how they interact in a co-infected host, and better diagnostic tools that include direct detection of all potential tick-borne microbes.

I propose we refer to the general clinical symptom complex as "Lyme Disease", and name the separate entities as Lyme Borreliosis (LB) Babesial infections as "Piroplasmosis" and the Ehrlichia species as "Ehrlichiosis"

Chronic Lyme Disease: A Symptom Complex of Multiple Co-Infections: New Diagnostic & Treatment Protocols
Richard I. Horowitz, M.D.

Background: Chronic Lyme disease must be seen in the light of multiple tick borne diseases, including HME, HGE, and Babesiosis. New diagnostic and treatment protocols may effectively help patients with chronic ongoing symptomatology.

Diagnosis: Lyme disease is primarily a clinical diagnosis. A 38 question questionnaire (Burrascano '95) is routinely administered to patients on initial screening. Specific attention is paid to the gestalt of symptoms including fatigue, headaches, stiff neck, migratory arthralgias and paresthesias that come and go, neuro-cognitive difficulties, and new psychiatric disturbances. Initial testing includes a Lyme Elisa, IgM & IgG Western Blot, HME, HGE & Babesiosis testing by IFA, with CBC, SMA24, TFT's, B12-folate-MMA + homocysteine testing if neuro-cognitive defects exist, and a ESR, ANA and RF depending on clinical circumstances. Diagnosis depends upon the gestalt of clinical symptoms, supported by positive antibody testing. Presumptive evidence of a tick borne disorder is made if any of the above antibody tests are low level positive, specially if the 23, 31, 34, 39 +93 bands are present on the Western Blot. Difficult diagnostic cases have Lyme urine antigen testing, Lyme multiplex PCR testing, and Babesia PCR + RNA analysis done through Igenex laboratories, Palo Alto, California. A clinical trial of antibiotics for presumptive Lyme disease yielding a Jarish-Herxheimer reaction helps to confirm the diagnosis.

Treatment: All of the 3 major tick borne illnesses are addressed with combination therapy employed to both target intracellular pathogenicity and prevent resistance. Antibiotics are rotated according to their clinical effectiveness, and include Amoxicillin and Probenecid, Ceftin, Suprax, and Doxycycline or Minocycline, in combination with a macrolide (Clarithromycin or Azithromycin). Patients are evaluated monthly and given a % of normal, reviewing initial symptoms. For symptom plateau or worsening symptoms, higher doses of antibiotics or switching regimens is helpful. Bicillin is a useful alternative to failed oral regimens, or in severely ill patients. IV medication is used as a last resort unless severe neurological defects or 3rd degree heart block exists at the onset. A new treatment protocol effective in resistant cases of Lyme disease is the use of Metronidazole for several months duration. Although Jarish-Herxheimer flares are frequent initially, many patients have shown clinical improvement within the 1st several weeks including decreased fatigue, arthralgias, and neuro-cognitive defects. Plaquenil is added for resistant arthritis or in patients with a positive ANA and evidence of immune hyper-reactivity. Treatment for Babesiosis has also become an important element in curing chronic disease in the upper Hudson Valley, NY, as co-infection rates are high. A full diagnostic work up for Babesiosis including IFA/PCR and RNA analysis is essential in chronic patients as smears are often negative.

Although Cleocin + Quinine and the newer regimen of Mepron + Zithromax may be helpful, relapse rates are high and new data has shown that the addition of high dose trimethoprim-sulfamethoxazole is extremely beneficial in elimination parasitemia. All patients are placed on sugar free yeast free diets with probiotics to prevent yeast overgrowth, with vitamin mineral supplementation. All Lyme treatment regimens are continued until the patient is 2 months symptom free.

Treatment Roundtable

No Abstract Available