The pain of "chronic Lyme disease": moving the discourse in a different direction

About 30% of the population of the United States suffers from acute or chronic pain, often of unknown cause. Among this group might be included patients with symptoms claimed to be caused by a poorly defined condition called "chronic Lyme disease" in which chronic pain is a major contributor. Since there is no evidence to indicate that chronic Lyme disease is due to a persistent infection and that extended antibiotic therapy is beneficial and safe, this condition should not be viewed solely as an infectious disease problem. Rather, it should be considered within the context of a broad-based, multidisciplinary approach to determining the cause of chronic pain per se and developing more effective strategies for its treatment as outlined in a recent report on pain issued by the Institute of Medicine.     

The burgeoning molecular genetics of the Lyme disease spirochaete

Lyme disease is the most commonly reported vector-borne disease in North America and Europe, yet we know little about which components of the causative agent, Borrelia burgdorferi, are critical for infection or virulence. Molecular genetics has provided a powerful means by which to address these topics in other bacterial pathogens. Certain features of B. burgdorferi have hampered the development of an effective system of genetic analysis, but basic tools are now available and their application has begun to provide information about the identities and roles of key bacterial components in both the tick vector and the mammalian host. Increased genetic analysis of B. burgdorferi should advance our understanding of the infectious cycle and the pathogenesis of Lyme disease.     

The clinical spectrum and treatment of Lyme disease

Lyme disease was recognized as a separate entity because of close geographic clustering of affected children in Lyme, Connecticut, with what was thought to be juvenile rheumatoid arthritis. It then became apparent that Lyme disease is a complex, multisystem disorder. The illness usually begins in summer with erythema chronicum migrans and associated symptoms (stage 1). Weeks to months later, some patients develop neurologic or cardiac abnormalities (stage 2), and weeks to years later, many patients develop intermittent attacks of arthritis (stage 3), which may become chronic, with erosion of cartilage and bone. Patients with severe and prolonged illness have an increased frequency of the B-cell alloantigen, DR2. For patients with early Lyme disease, tetracycline appears to be the most effective drug, then penicillin, and finally erythromycin. High-dose intravenous penicillin is effective for the later stages of the disease.     

Cellular immune findings in Lyme disease

From 1981 through 1983, we did the first testing of cellular immunity in Lyme disease. Active established Lyme disease was often associated with lymphopenia, less spontaneous suppressor cell activity than normal, and a heightened response of lymphocytes to phytohemagglutinin and Lyme spirochetal antigens. Thus, a major feature of the immune response during active disease seems to be a lessening of suppression, but it is not yet known whether this response plays a role in the pathophysiology of the disease.     

Chemokines and Toll-like receptors in Lyme disease pathogenesis

Lyme disease is a tick-transmitted inflammatory disorder, caused by the spirochete Borrelia burgdorferi (Bb). Recent discoveries cast new light on Bb dissemination and the ensuing pathogenesis of inflammation. Although the strong proinflammatory Bb lipoproteins have been implicated in the induction of inflammation, they do not seem to act exclusively through Toll-like receptor (TLR) engagement. In fact, mice that are deficient for MyD88, a component of the TLR signaling pathway, manifest similar or increased recruitment of cells into Bb-infected tissues. By contrast, the absence of the chemokine receptor CXCR2 results in reduced inflammation. Overall, these findings highlight the complexity of Lyme disease pathogenesis and identify chemokine pathways as novel therapeutic targets for the control of Bb-induced inflammation.     

Lyme disease spirochaetes possess an aggrecan‐binding protease with aggrecanase activity

Connective tissues are the most common area of colonization for the Lyme disease spirochaete Borrelia burgdorferi. Colonization is aided by the interaction between numerous bacterial adhesins with components of the extracellular matrix (ECM). Here we describe a novel interaction between B. burgdorferi and the major ECM proteoglycan found in joints, aggrecan. Using affinity chromatography and mass spectrometry we identify two borrelial aggrecan‐binding proteins: the known ECM ligand Bgp (BB0588) and an uncharacterized protease BbHtrA (BB0104). Proteinase K studies demonstrate that BbHtrA is surface exposed. Immunoblots using sera from patients with both early and late Lyme disease establish that BbHtrA is expressed during human disease, immunogenic, and conserved in the three major Lyme disease spirochaete species. Consequences of the interaction between aggrecan and BbHtrA were examined by proteolysis assays. BbHtrA cleaves aggrecan at a site known to destroy aggrecan function and which has been previously observed in the synovial fluid of patients with Lyme arthritis. These data demonstrate that B. burgdorferi possess aggrecan‐binding proteins which may provide the organism with additional capability to colonize connective tissues. Moreover, our studies provide the first evidence that B. burgdorferi possess proteolytic activity which may contribute to the pathogenesis of Lyme arthritis.     

Epidemiological and clinical features of 1,149 persons with Lyme disease identified by laboratory-based surveillance in Connecticut

Laboratory-based surveillance of Lyme disease in Connecticut during 1984 and 1985 identified 3,098 persons with suspected Lyme disease; 1,149 were defined as cases. Lyme disease incidence in Connecticut towns ranged from none to 1,407 cases per 100,000 population in 1985. A comparison of 1985 data with data from 1977 epidemiologic studies indicated that incidence increased by 129 percent to 453 percent in towns previously known to be endemic for Lyme disease and that Lyme disease had spread northward into towns thought to be free of Lyme disease in 1977. Children aged five to 14 years had the highest incidence. Of persons with Lyme disease, 83 percent had erythema migrans, 24 percent had arthritis, 8 percent had neurologic sequelae, and 2 percent had cardiac sequelae. The distribution of symptoms was age-dependent: case-persons less than 20 years old were almost twice as likely to have arthritis than older case-persons (35 percent versus 18 percent). Of persons with arthritis, 92 percent of those less than 20 years of age, compared to 68 percent of older persons, did not have antecedent erythema migrans. We conclude that Lyme disease is increasing in incidence and geographic distribution in Connecticut. Of those with Lyme disease, children may be more likely than adults to develop arthritis and have it as their first major disease manifestation.     

Activists decry physician disinterest in Lyme disease during Vancouver conference.

Although it was well advertised, few Canadian physicians attended a recent conference on Lyme disease in Vancouver. The apparent lack of interest upsets the president of the Lyme Borreliosis Society, who says many patients have been misdiagnosed, mistreated or untreated and "are now chronically disabled." Interestingly, the disease seems to be much more common in the US than Canada. In New York State, for instance, more than 26,000 cases have been diagnosed, but in nearby Ontario the total is only 200.     

The gene for glycogen-storage disease type 1b maps to chromosome 11q23.

Glycogen-storage disease type 1 (GSD-1), also known as "von Gierke disease," is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase) activity. There are four distinct subgroups of this autosomal recessive disorder: 1a, 1b, 1c, and 1d. All share the same clinical manifestations, which are caused by abnormalities in the metabolism of glucose-6-phosphate (G6P). However, only GSD-1b patients suffer infectious complications, which are due to both the heritable neutropenia and the functional deficiencies of neutrophils and monocytes. Whereas G6Pase deficiency in GSD-1a patients arises from mutations in the G6Pase gene, this gene is normal in GSD-1b patients, indicating a separate locus for the disorder in the 1b subgroup. We now report the linkage of the GSD-1b locus to genetic markers spanning a 3-cM region on chromosome 11q23. Eventual molecular characterization of this disease will provide new insights into the genetic bases of G6P metabolism and neutrophil-monocyte dysfunction.     

Pros and cons of a prion-like pathogenesis in Parkinson's disease

Background  

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder which affects widespread areas of the brainstem, basal ganglia and cerebral cortex. A number of proteins are known to accumulate in parkinsonian brains including ubiquitin and α-synuclein. Prion diseases are sporadic, genetic or infectious disorders with various clinical and histopathological features caused by prion proteins as infectious proteinaceous particles transmitting a misfolded protein configuration through brain tissue. The most important form is Creutzfeldt-Jakob disease which is associated with a self-propagating pathological precursor form of the prion protein that is physiologically widely distributed in the central nervous system.     

Preparation and purification of recombinant outer surface protein A (rOspA) of Borrelia burgdorferi sensu stricto and Borrelia afzelii

The recombinant Outer surface protein A (rOspA) from Borrelia burgdorferi is a possible immunogen for protection of infected humans and animals against development of Lyme borreliosis (Lyme disease), a chronic tick-borne disease characterised by diverse dermatologic, neurologic, rheumatic, and cardiac manifestations. For several years, research and development have been directed towards a vaccine for the prevention of this debilitating disease. Numerous animal studies demonstrate that pre-existing antibodies against the outer surface proteins of B. burgdorferi can prevent infection and disease caused by this organism. In this communication, using recombinant DNA technology, genes from B. burgdorferi sensu stricto and B. afzelii were inserted into E. coli-expression vectors and the rOspA were produced. Our aim was to obtain rOspA protein in a purity and quantity desirable for immunization of experimental animals. rOspA is currently the most developed, molecularly-defined vaccine candidate for the prevention of Lyme borreliosis.     

Taxonomy of the Lyme disease spirochetes.

Morphology, physiology, and DNA nucleotide composition of Lyme disease spirochetes, Borrelia, Treponema, and Leptospira were compared. Morphologically, Lyme disease spirochetes resemble Borrelia. They lack cytoplasmic tubules present in Treponema, and have more than one periplasmic flagellum per cell end and lack the tight coiling which are characteristic of Leptospira. Lyme disease spirochetes are also similar to Borrelia in being microaerophilic, catalase-negative bacteria. They utilize carbohydrates such as glucose as their major carbon and energy sources and produce lactic acid. Long-chain fatty acids are not degraded but are incorporated unaltered into cellular lipids. The diamino amino acid present in the peptidoglycan is ornithine. The mole % guanine plus cytosine values for Lyme disease spirochete DNA were 27.3-30.5 percent. These values are similar to the 28.0-30.5 percent for the Borrelia but differed from the values of 35.3-53 percent for Treponema and Leptospira. DNA reannealing studies demonstrated that Lyme disease spirochetes represent a new species of Borrelia, exhibiting a 31-59 percent DNA homology with the three species of North American borreliae. In addition, these studies showed that the three Lyme disease spirochetes comprise a single species with DNA homologies ranging from 76-100 percent. The three North American borreliae also constitute a single species, displaying DNA homologies of 75-95 percent. Lyme disease spirochetes and Borrelia exhibited little or no DNA homology (0-2 percent) with the Treponema or Leptospira. Plasmids were present in the three Lyme disease spirochetes and the three North American borreliae.     

Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease

To fight, flee or hide are the imperatives of long-term survival by an infectious microbe. Active immune suppression, induction of immune tolerance, phase and antigenic variation, intracellular seclusion, and incursion into immune privileged sites are examples of survival strategies of persistent pathogens. Here we critically review the supporting evidence for possible stratagems utilized by Borrelia burgdorferi, the spirochete that causes Lyme disease, to persist in the mammalian host.     

The role of lizards in the ecology of Lyme disease in two endemic zones of the northeastern United States

We examined the role of lizards in the ecology of Lyme disease in New York and Maryland. We collected data on vector tick infestations, measured lizard "realized" reservoir competence for the Lyme disease spirochete Borrelia burgdorferi, and estimated lizard population density. These data were incorporated into a model that predicts a host's ability to influence the prevalence of B. burgdorferi in the tick population, a primary risk factor in the epidemiology of Lyme disease. Published data on other northeastern hosts were included in the model to provide a reference for interpreting the importance of lizards as hosts. The model results indicate that 5-lined skinks (Eumeces fasciatus) are dilution hosts, capable of reducing infection prevalence in the tick population by 10.7-51.5 percentage points, whereas eastern fence lizards (Sceloporus undulatus) are not dilution hosts in the areas studied. Owing to moderate burdens of larval ticks, relatively high population densities, and reservoir incompetence, E. fasciatus may play an important role in the ecology of Lyme disease by reducing vector infection prevalence and associated human risk of infection.     

Lyme disease in northwestern coastal California.

To determine the incidence of physician-diagnosed Lyme disease in an endemic area of California, an active surveillance program was implemented in Lake, Mendocino, Sonoma, and southern Humboldt counties. More than 200 medical care providers were called monthly for their list of suspected cases of Lyme disease. Pertinent information was abstracted from the medical record of each patient. Of 153 cases of possible early Lyme disease ascertained from July 1991 to December 1992, 37% consisted of physician-diagnosed erythema migrans. Only 58% of erythema migrans rashes were at least 5 cm in diameter. An additional 43 patients had suspicious rashes not classified as erythema migrans. Of 166 patients with possible late-stage Lyme disease, 31% had specific clinical symptoms and 75% had a positive serologic test. With an incident case defined as physician-diagnosed erythema migrans of at least 5 cm in diameter, the annual incidence of Lyme disease in northwestern coastal California according to active surveillance only was 5.5 per 100,000. The rate of Lyme disease in California is substantially lower than that in the Atlantic northeastern United States. Many suspected cases of Lyme disease in this endemic area do not meet surveillance criteria, which are intentionally restrictive. Although some of the illnesses not meeting surveillance criteria may be due to infection with Borrelia burgdorferi, it appears that Lyme disease is being overdiagnosed in this area.     

Epidemiologic features of Lyme disease in New York

During 1982, surveillance identified 207 cases of Lyme disease in New York State. Cases were clustered in two geographic areas, eastern Long Island and northern Westchester counties. Symptoms and signs of Lyme disease in cases were consistent with previous reports, with erythema chronicum migrans (ECM) being the most frequently (77 percent) reported sign of disease. Facial palsy was reported in a surprisingly high 18 percent of cases. Of 160 cases whose sera were submitted for Lyme spirochete specific IgG antibody testing, 112 (70 percent) had titers greater than or equal to 64, while 88 (55 percent) had titers greater than or equal to 128. Positive titers were not associated with any single sign or symptom of disease, but were significantly associated with symptom onset or tick bite occurring during the three-month period of June, July, and August. We conclude that the incidence of Lyme disease in New York is much higher than previously recognized. In addition, our data suggest that a serologic test for Lyme-spirochete IgG antibody lacks sensitivity, but can be useful in confirming the diagnosis of Lyme disease when antibody titers are high.     

Immune responsiveness during disease progression from acute rheumatic fever to chronic rheumatic heart disease

Streptococcus pyogenes causes pharyngitis in school age children, which if left untreated causes acute rheumatic fever (ARF) that later progress toward rheumatic heart disease (RHD). The pathogenesis of this disease and its progression as post infectious squeal is not well understood. In this study, percentages of CD4(+) and CD8(+) T-cells were compared among patients of ARF, RHD and Chronic RHD using flow cytometer. The production of Th1/Th2 cytokines from serum and endothelial cells of damaged and normal heart valves was also analyzed using flow cytometer. Results showed an inverse proportion of CD4(+) and CD8(+) T-cell numbers in ARF and RHD patients. Cytokine assay demonstrated a switch-over from Th1 to Th2 type, as the disease progressed. We observed significantly high IL-6 in ARF patients and high TNF-α in early RHD patients which allowed us to construct a hypothesis, that, during initial infection phase, lot of antibodies are produced (via IL-6) and TNF-α has a role in disease progression and tissue damage during RHD phase.     

Gestational attenuation of Lyme arthritis is mediated by progesterone and IL-4

Infection of different strains of laboratory mice with the agent of Lyme disease, Borrelia burgdorferi, results in arthritis, the severity of which has been correlated with the dominance of Th1 cytokines. In this study, we demonstrate that changes in B. burgdorferi-specific immunologic responses associated with pregnancy can alter the outcome of Lyme arthritis in mice. Whereas nonpregnant female C3H mice consistently developed severe Lyme arthritis, pregnant mice had a marked reduction in arthritis severity that was associated with a slight reduction in IFN-gamma and markedly increased levels of IL-4 production by B. burgdorferi-specific T cells. Similar reductions in arthritis severity and patterns of cytokine production were observed in nonpregnant, progesterone-implanted mice. Ab neutralization of IL-4 in progesterone-implanted mice resulted in severe arthritis. Our results are consistent with the known shift toward Th2 cytokine expression at the maternal-fetal interface, and are the first to show a pregnancy-related therapeutic effect in an infectious model.     

Frameworks for risk communication and disease management: the case of Lyme disease and countryside users

Management of zoonotic disease is necessary if countryside users are to gain benefit rather than suffer harm from their activities, and to avoid disproportionate reaction to novel threats. We introduce a conceptual framework based on the pressure-state-response model with five broad responses to disease incidence. Influencing public behaviour is one response and requires risk communication based on an integration of knowledge about the disease with an understanding of how publics respond to precautionary advice. A second framework emphasizes how risk communication involves more than information provision and should address dimensions including points-of-intervention over time, place and audience. The frameworks are developed by reference to tick-borne Lyme borreliosis (also known as Lyme disease), for which informed precautionary behaviour is particularly relevant. Interventions to influence behaviour can be directed by knowledge of spatial and temporal variation of tick abundance, what constitutes risky behaviour, how people respond to information of varying content, and an understanding of the social practices related to countryside use. The frameworks clarify the response options and help identify who is responsible for risk communication. These aspects are not consistently understood, and may result in an underestimation of the role of land-based organizations in facilitating appropriate precautionary behaviour.