Summary of the fourth international symposium on lyme borreliosis

367 SPECIAL ARTICLE SUMMARY OF THE FOURTH INTERNATIONAL SYMPOSIUM ON LYME BORRELIOSIS zyxwv zyxwvut zyxwvuts LEONARD H. SIGAL The IV International Conference on Lyme Borreliosis was held June 18-21, 1990 in Stockholm and was attended by over 460 participants from 28 countries. Selected presentations from the meeting will be published later this year as a supplement to the Scandinavian Journal of Infectious Diseases; the proceedings of the first three meetings are also available (1-3). A summary of the large body of information reported, divided into nine broad categories, is presented herein. Terminology The following new nomenclature was proposed for Lyme borreliosis/Lyme disease. Early localized disease would be defined by the presence of erythema chronicum migrans (ECM) or lymphadenosis benigna cutis, with or without lymphadenopathy or other symptoms or signs. Early disseminated disease would be defined by the presence of multiple ECM or acute neurologic, cardiac, or articular findings. Chronic disease would be defined by the presence of acrodermatitis chronica atrophicans, tertiary neuroborreliosis, or arthritis, persisting or relapsing for at least 6 months. From the Departments of Medicine and Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey, and the Lyrne Disease Center, Robert Wood Johnson Medical School, New Brunswick, New Jersey. Leonard H. Sigal, MD: Assistant Professor, University of Medicine and Dentistry of New Jersey, and Director, Lyrne Disease Center. Address reprint requests to Leonard H. Sigal, MD, 1 Robert Wood Johnson Place-MEB 484, New Brunswick, NJ 089030019. Submitted for publication August 10, 1990; accepted in revised form November 6, 1990. Geographic distribution/epidemiology The geographic distribution of Lyme disease is expanding to areas of the US contiguous to those where cases were reported earlier, and increasing numbers of cases have also been reported in many parts of Europe (from Spain to Russia, the Baltic to the Balkans), in Japan, and in China. Subclinical infection (asymptomatic seropositivity) was reported frequently from Sweden, Italy, Switzerland, The Netherlands, and the US. This must be considered when one ascribes a clinical condition to Lyme disease: Seropositivity does not necessarily indicate causality. The question of whether all asymptomatic seropositive individuals should be treated has not received adequate study, although many clinicians routinely prescribe a 1-month regimen of oral antibiotics. Lyme disease continues to be endemic in several specific geographic areas, with the site of exposure often being near the patient’s home. New Ixodid species of ticks, in addition to those previously recognized as vectors of Lyme disease, have been identified as potential vectors, and the geographic distribution of Zxodes dammini is spreading in some areas. With the use of polymerase chain reaction (PCR) techniques, Borrelia burgdorjeri has been identified in the US in museum tick specimens dating back to the 1940’s, suggesting the presence of the organism in the New World for at least 50 years. In the summary of the workshop on Methods for the Control of Lyme Borreliosis Vectors, it was suggested that the best way to avoid the disease is to take personal precautions by knowing and avoiding high-risk areas, wearing proper clothing, and properly using tick repellent or acaricide. Widespread use of zyxwvut Arthritis and Rheumatism, Vol. 34, No. 3 (March 1991) SIGAL 368 acaricides, host management, and modification of habitat in high-risk areas are experimental at this time, but might be of use in an integrated program in these areas. certain cells. The organisms may exert a direct toxic effect on certain cells. The organism crosses endothelial cell layers by passage through intercellular junctions or through the cells. In an animal model, B burgdorferi has been shown to cross the blood-brain barrier within 48 hours of inoculation. The organism may reside deep within collagen fibers, which may explain its persistence in tissues. Changes in surface antigens, or in vivo down-regulation or modification of surface antigens, may explain how the organism evades the immune system. B burgdorferi can cause modification of local tissue and of the immune response by eliciting cytokines; production of interleukin-6 and tumor necrosis factor were described in one poster. Vasculitis has been demonstrated in peripheral neuropathy biopsy specimens, and it may contribute to tissue damage in Lyme disease. Autoimmunity may occur in Lyme disease. Patients with neurologic damage have serum antibodies to human axons; this reactivity can be absorbed by incubation of the serum with B burgdorferi. Crossreactivity between the organism’s flagellin and a human axonal protein (p67) was found by use of a monoclonal antibody to flagellin, H9724; H9724 also binds to normal human axons. In another reported study, H9724 bound to a number of human tissues, including Schwann cells and synovial cytoskeleton. The complement component C3dk/C3e cross-reacts with the 66-kd and 73-kd immunodominant proteins, suggesting that a complex interaction between B burgdorferi and complement may play a role in Lyme disease. The HLA linkage of Lyme disease was discussed in two lectures. DR2 and/or DR4 were found more often in patients with chronic, rather than brief, arthritis, and the presence of DR4 was associated with antibiotic failure. The proposed DR2/4 linkage supports the contention that certain individuals may mount an autoreactive response, even after the organism has been killed. A study from Europe, however, did not identify the same DR2 or DR4 linkages. z zyxwvut zyxwvutsrq Clinical manifestations/pregnancy It now seems likely that the neurologic and rheumatologic manifestations of infection with B burgdorferi are quite similar in Europe and North America. A review of Lyme carditis pointed out that the heart block may resolve spontaneously, but also summarized cases of heart block not responding to antibiotics. Reflex sympathetic dystrophy was reported as a possible manifestation of Lyme disease, occurring after painful radiculopathy, but also as the first manifestation of presumed Lyme disease. Cases of interstitial, focal nodular, and inclusion body myositis attributed to B burgdorferi were reported; silver stain revealed the organism in 2 of 4 muscle specimens studied, although B burgdorferi was not grown from any of the 5 specimens cultured. Audiovestibular dysfunction and intraocular disease (choroiditis, neuroretinitis, and retinal vasculitis) possibly due to B burgdorferi were described. In the latter study, all 10 of the patients’ sera contained IgG anti-B burgdorferi antibodies, and 5 of the 10 were IgM positive. Asymptomatic central nervous system infection, evidenced by the presence of intrathecal antibodies in patients with facial palsy and of lymphocytic pleocytosis in patients with isolated ECM, may be relatively frequent. The question of the effects of Lyme disease on pregnancy has caused concern. However, recent studies suggest that there is little, if any, risk of fetal damage due to Lyme disease. In a report of 6 pregnant women with Lyme disease, all delivered healthy babies, a finding that is consistent with most anecdotal reports. A large prospective survey failed to identify an increased risk of congenital malformation in the infants of seropositive mothers. Pediatric neurologists surveyed in an area in which Lyme disease is endemic did not identify any neurologic disorders attributable to congenital Lyme disease. Immunopathogenesis The pathogenesis of tissue damage in Lyme disease is likely due to many mechanisms. B burgdorferi adheres nonspecifically to many cell types, and live organisms may exert a direct toxic effect on Diagnostic tests Recent studies have demonstrated that serologic testing for Lyme disease (technique or antigen preparation) is not standardized. The value of T cell proliferative responses in diagnosing Lyme disease has been questioned. Antibody-capture enzyme-linked immunosorbent assay (ELISA) was reported as effective in identifying specific antibodies in the cerebro- LYME BORRELIOSIS SYMPOSIUM zyxwv 369 zyxwvutsr zyx z spinal fluid, especially early in Lyme disease. IgA detected by this assay is a sensitive measure of intrathecal antibody production. An inhibition ELISA using monoclonal antibodies to increase accuracy was discussed. Higher levels of a n t i 4 burgdorferi antibodies in the cerebrospinal and synovial fluid as compared with blood helps to establish this infection as the cause of the local inflammation. Concentration of antigenspecific T cells in synovial fluid is also useful in diagnosing Lyme arthritis. False seropositivity was reported in patients with endocarditis, rheumatoid arthritis, systemic lupus erythematosus, and mumps meningitis. Western blot is useful in differentiating true-positive from falsepositive ELISA results. The debate continues about what are the optimal ELISA conditions. Serologic results differ depending on the strain of organism, the antigenic preparation, and antigenic variation during culture of B burgdorferi. The presence of serum antibodies to a 39-kd protein may represent a valuable new marker for active infection. The value of T cell responses in diagnosing Lyme disease remains uncertain, but results may be improved by the use of antigen-primed macrophages as antigen-presenting cells or of autologous serum in culture. Reports of preliminary studies indicated that PCR is an effective technique for identifying B burgdorferi. Of particular note, PCR detected DNA from the organism in the synovial fluid of 6 patients with Lyme arthritis; none of the 17 control fluids gave an unequivocally positive result with both of the primers used (osp A and osp B). PCR also detected B burgdorferi in the urine of 2 patients with ECM. The Symposium on Diagnostic Tests in Lyme Borreliosis summary states that measurement of urinary antigen is a controversial new test, whose efficacy and accuracy have not yet been established. Test kits that are currently available have not been standardized or fully tested for sensitivity or specificity. nous penicillin G in another study. Both cefotaxime and ceftriaxone were effective in the treatment of Lyme neurologic disease. A 3-center study compared amoxicillin and intravenous penicillin in children with Lyme arthritis; at least 17% of the patients in each group failed to respond within 3 months or experienced recurrent joint disease. Synovectomy has been found to be effective in many patients whose arthritis has not responded to antibiotics. Two reports from the US and one from Europe confirmed the very small risk of seroconversion (09%), and the even lower incidence of symptomatic disease (0-3%), after known tick bite. A prospective study of single-dose doxycycline prophylaxis for tick bites is not yet complete; preliminary results suggest that the drug is well tolerated but that the risk of infection is very low even without prophylaxis. Therapy/ prophylaxis Animal models are useful in understanding the potential role of protective antibodies in Lyme disease. Serum from infected hamsters plus complement can kill B burgdorferi, and protective antibodies persist in hamsters for up to a year after initial infection. In mice, initial infection suppresses the development of spirochetemia upon subsequent challenge with B burgdorferi. Monoclonal antibodies to outer surface proteins A and B were protective in scid mice. The role of individual cloned borrelial antigens as candidate vaccines is being evaluated in a mouse model of Public awareness/anxiety/false diagnosis In endemic areas, misinformation and anxiety about possible complications of Lyme disease are prevalent. Serologic tests are often misused and misinterpreted, a particular problem in patients whose symptoms are vague. Many patients are misdiagnosed as having Lyme disease and are given prolonged antibiotics for “atypical” infection. In one reported study, 13 of 30 patients with endocarditis had positive ELISA results for Lyme disease. In only 1 of these patients was there antecedent or present Lyme disease; in 4,the Lyme serologic result caused a delay in making the real diagnosis. The majority of patients seen at a Lyme disease referral center did not have Lyme disease as the cause of their symptoms. Many had been subjected to multiple unnecessary courses of antibiotics. Fibromyalgia may occur after or during Lyme disease. zyxw zyxwvutsrq Reports of therapeutic trials included the following findings: Amoxicillin is effective for treating ECM and for preventing progression of Lyme disease; doxycycline and amoxicillin plus probenecid are equally effective for treating ECM; and intravenous ceftriaxone may be preferable to oral penicillin for the treatment of patients with early, severe disease. In one study of Lyme meningoencephalitis, oral doxycycline was effective; doxycycline was equivalent to intrave- Animal models 370 zyxwvutsr SIGAL zyxwvutsrq zyxwvutsrqp Lyme disease. Myocarditis and myositis in a mouse model, pancarditis in BALB/c mice, and inflammation of multiple organs, including heart and joints, in scid mice were reported. B burgdorferi organism Cloned B burgdorferi proteins are being evaluated for use in the development of better diagnostic tests and vaccines. The mechanisms of tissue adherence, penetration, and destruction may become clear as knowledge of the molecular biology of the organism becomes available. B burgdorferi changes surface proteins after in vivo passage in mice or ticks. DNAcontaining, nuclease-resistant vesicles are shed by the organism, which may represent a genetic exchange system. Different strains of the organism can be classified using restriction fragment length polymorphism. Conclusion In the 15 years since Lyme disease was first described, much has been learned about the causative organism, its vectors, and the clinical manifestations and pathogenesis of the infection. We look forward to the fifth International Symposium, to be held in Washington, DC, in 2-3 years, at which time more answers will become available. ACKNOWLEDGMENTS I am grateful to Drs. Eva Asbrink, Alan Barbour, Jorge Benach, Durland Fish, Elliot Frank, John Halperin, Russell Johnson, Alan Kaell, Steven Luger, Stephen Malawista, Thomas Mather, Robert Nadelman, Thomas Schwan, and Christine Williams for helpful discussions about the Fourth International Conference on Lyme Borreliosis. zyxwv REFERENCES 1 . International Symposium on Lyme Disease. Yale J Biol Med 57:445-705, 1984 2 . Second International Symposium on Lyme Disease and Related Disorders. Zentralbl Bakteriol Mikrobiol Hyg [A] 263:1-495, 1986 3. Third International Symposium on Lyme Disease and Related Disorders. Ann NY Acad Sci 539:l-513, 1988