Treatment of Lyme borreliosis

Borrelia burgdorferi sensu lato is the causative agent of Lyme borreliosis in humans. This inflammatory disease can affect the skin, the peripheral and central nervous system, the musculoskeletal and cardiovascular system and rarely the eyes. Early stages are directly associated with viable bacteria at the site of inflammation. The pathogen-host interaction is complex and has been elucidated only in part. B. burgdorferi is highly susceptible to antibiotic treatment and the majority of patients profit from this treatment. Some patients develop chronic persistent disease despite repeated antibiotics. Whether this is a sequel of pathogen persistence or a status of chronic auto-inflammation, auto-immunity or a form of fibromyalgia is highly debated. Since vaccination is not available, prevention of a tick bite or chemoprophylaxis is important. If the infection is manifest, then treatment strategies should target not only the pathogen by using antibiotics but also the chronic inflammation by using anti-inflammatory drugs.     

Lyme borreliosis situation in North Africa

Many epidemiological studies were conducted for studying Lyme borreliosis (LB) which represents a new global public health problem. It is now the most common vector-borne disease in Europe and North America. The causative agent Borrelia burgdorferi sl is a bacterial species complex comprising 12 delineated and named species. In North Africa, few studies based on clinical and serological features, have suggested that LB could occur. Indeed, recent studies conducted in Tunisia, Algeria and Morocco have showm that Ixodes ricinus is present in cooler and humid area of these regions. These studies also revealed that this species is a vector of B. burgdorferi sl with high prevalence of infection. Using IFI and PCR tests, the mean rate of Borrelia-infection ranged from 50 to 60% in I. ricinus adult collected in Tunisia and Morocco and from 30 to 40% in nymphs; in contrast, the prevalence in larvae is less than 2.5%. Several strains of B. burgdorfer were isolated from adult and nymph I ricinus collected in Tunisia and Morocco. The identification of these strains and DNAs directly extracted from Ixodes was done by PCR-RFLP and sequence analysis. The results showed that B. lusitaniae (genotypes Poti B2 and Poti B3) is the predominant species circulating in I. ricinus in Tunisia and Morocco, B. garinii and B. burgdorferi ss and B lusitaniae were also present but very rare. These results provide the evidence for the existence of B. burgdorferi sl in North Africa; however, the impact of LB in the human population seem to be negligible and the seroprevalence of Borrelia in forest workers (considered as population at high risk) in Tunisia is less than 4%.     

Microbiological and serological diagnosis of Lyme borreliosis

In Europe, Lyme borreliosis is caused by Borrelia burgdorferi sensu stricto, B. afzelii, B. garinii and the recently described species B. spielmanii. For the development of diagnostic tools, the heterogeneity of the causative agents must be considered. The serological diagnosis should follow the principle of a two-step procedure: a sensitive enzyme-linked immunosorbent analysis as the first step, followed by immunoblot (IgM and IgG) if reactive. The sensitivity and standardization of immunoblots have been enhanced by the use of recombinant antigens instead of whole cell lysates. Improved sensitivity has resulted from the use of recombinant proteins primarily expressed in vivo (e.g. VlsE) and the combination of homologous proteins from different strains (e.g. DbpA). At present, detection rates for serum antibodies are 20-50% in localized, 70-90% in disseminated early and nearly 100% in late disease. Detection of the borreliae by culture or PCR should be confined to specific indications. The best results are obtained from skin biopsies (50-70% with culture or PCR) and synovial tissue or fluid (50-70% with PCR). Cerebrospinal fluid is positive in only 10-30%. Methods that are not recommended for diagnostic purposes include antigen tests in body fluids, PCR of urine and lymphocyte transformation tests.     

DNA persistence after treatment of Lyme borreliosis

One hundred twenty-four patients—53 with neuroborreliosis, 48 with erythema migrans, and 23 with Lyme arthritis—were tested in a prospective study for the presence of the DNA of Borrelia burgdorferi sensu lato in plasma, cerebrospinal fluid (CSF), urine, and synovial fluid by nested polymerase chain reaction (PCR). Specific DNA was detected using five amplification systems simultaneously: three targeted chromosomal genes encoding 16S rDNA, flagellin, and p66; and two plasmid sequences of OspA and OspC. Patients were examined clinically and by PCR before and after treatment and again after 3 and 6 months. Before treatment, the specific DNA was detected in 78 patients (62.9 %). Forty-one neuroborreliosis patients were DNA-positive (77.4 %), with CSF positivity in 26 patients, urine in 25, and plasma in 16. Twenty-six erythema migrans patients were DNA-positive (54.2 %), with plasma positivity in 18 cases and urine in 14. Eleven Lyme arthritis cases (47.8 %) were DNA positive (six in urine, five in plasma, and four in synovial fluid). The frequency of PCR positives was comparable in CSF and urine, and it was lower by approximately 50 % in plasma. Specific DNA was also found in a significant number of patients in later testing periods: 48 patients after treatment, 29 patients after 3 months, and 6 patients after 6 months. The prolonged PCR positivity was not explainable by persistent infection according to the clinical manifestations of the disease. Possible explanations of the problem are discussed.     

Fundamental processes in the evolutionary ecology of Lyme borreliosis

The evolutionary ecology of many emerging infectious diseases, particularly vector-borne zoonoses, is poorly understood. Here, we aim to develop a biological, process-based framework for vector-borne zoonoses, using Borrelia burgdorferi sensu lato (s.l.), the causative agent of Lyme borreliosis in humans, as an example. We explore the fundamental biological processes that operate in this zoonosis and put forward hypotheses on how extrinsic cues and intrinsic dynamics shape B. burgdorferi s.l. populations. Additionally, we highlight possible epidemiological parallels between B. burgdorferi s.l. and other vector-borne zoonotic pathogens, including West Nile virus.     

Review The ecology of ticks transmitting Lyme borreliosis

The main vectors of Borrelia burgdorferi sensu lato, the cause of Lyme borreliosis, are ixodid ticks of the Ixodes persulcatus species complex. These ticks, which occur throughout the northern temperate zone, have very similar life cycles and ecological requirements. All are three-host ticks, with the immature stages mainly parasitizing small to medium-sized mammals and birds and the adult females parasitizing large mammals such as deer, cattle, sheep and hares. The host-seeking stages show a distinct seasonality, which is regulated by diapause mechanisms and there appear to be major differences in this respect between the Old World and New World species. Most cases of human borreliosis are transmitted in the summer by the nymphal stages, with the exception of the Eurasian species, I. persulcatus, in which the adult females are mainly responsible. The ticks acquire the spirochaetes from a wide variety of mammals and birds but large mammals do not seem to be infective, so that t icks that feed almost exclusively on large mammals, for example in some agricultural habitats, are rarely infected. The greatest tick infection prevalences occur in deciduous woodland harbouring a diverse mix of host species and the diversity of the different genospecies of B. burgdorferi s.l. is also greatest in such habitats. There is evidence that these genospecies have different host predilections but, apart from the fact that I. persulcatus does not seem to be infected by B. burgdorferi sensu stricto, they do not seem to be adapted to different tick strains or species. © Rapid Science Ltd. 1998     

Lyme borreliosis in central Italy (1995-1998)

From January 1995 to July 1998, 340 serum samples collected in Central Italy from patients clinically suspected of having Lyme borreliosis were investigated. All samples were tested for the presence of antibodies to B. burgdorferi by Elisa. The Elisa positive samples were subjected to further tests by Western Blot for confirmation. Out of 340 patients, 13 (3.8%) proved to be B. burgdorferi positive, while 9 (2.6%) were found to have Lyme disease with seroprevalence being higher in these latter than that of blood donors from Central Italy. Our results indicate that Lyme borreliosis is present in Central Italy. A comparison between Italian and European studies reveals that Lyme disease is still underestimated in Italy, the main reason being that a monitoring system for the study of Lyme borreliosis was only established in 1990.     

Cutting edge: T cell-mediated pathology in murine Lyme borreliosis

Even in the absence of an appropriate model or direct evidence, T cells have been hypothesized to exacerbate the manifestations of Lyme disease. To define definitely the role of T cells in Lyme disease, the course of disease in immunocompetent and B cell-deficient mice was compared. By 8 wk postinoculation, immunocompetent mice resolved both carditis and arthritis, whereas foci of myocarditis and severe destructive arthritis characterized disease of B cell-deficient mice. Cell transfer experiments using infected B6-Rag1 knock out mice demonstrated that: 1) innate immunity mediated the initial sequelae of infection, 2) transferring both naive T cells and B cells induced resolution of carditis and arthritis, 3) infected mice reconstituted with T cells developed myocarditis and severe destructive arthritis, and 4) CD4+ T cells were responsible for the observed immune-mediated pathology. These data demonstrate directly the deleterious effect of T cells in Lyme disease.     

Lyme borreliosis: host responses to Borrelia burgdorferi.

The chronic inflammatory condition that develops after infection by B. burgdorferi is a complex process resulting from host responses to a limited number of organisms. Amplification mechanisms driven by potent proinflammatory molecules, i.e., IL-1, may explain the vigorous response to a paucity of organisms. Spirochete dissemination to distant locations involves adherence to and penetration across endothelium and may be facilitated by host responses that increase vessel permeability. The apparent lack of tissue tropism in Lyme disease is reflected in the organism's ability to adhere to different eucaryotic cell types in vitro and the wide distribution of B. burgdorferi in various organs of infected humans and experimentally infected animals. While phagocytosis and complement activation have been observed in vitro, the specific immune response that develops in humans is inefficient in eradicating the organisms, which may possess some mechanism(s) to evade this response. There is significant evidence for host autoreactivity based on antigenic cross-reactivity between the 41-kDa flagellar subunit and stress proteins of the spirochetes and endogenous host cell components. Although the outer surface proteins appear to be suitable candidates as targets for vaccination in animal studies, fundamental differences in the immune response to spirochetal components may preclude their use in humans.     

Cytogenetic aberrations in peripheral blood mononuclear cells in acute Lyme borreliosis patients

Cytogenetic aberrations are known to be caused by biological mutagenic factors, including both intracellular parasites, such as viruses, and some extracellular infectious agents, including bacteria, protozoa, and helminthes. The present study is aimed at investigating the cytogenetic status of acute Lyme borreliosis (LB) patients. As a result of the present study, a peripheral blood mononuclear cell culture of acute LB patients demonstrated a significantly higher frequency of lymphocytes with cytogenetic aberrations of the aneugenic type, such as polyploidy, hypoploidy, or endoreduplication, as well as of the clastogenic type, such as chromatid and chromosomal breaks accompanied by the inhibition of proliferative responses to mitogens and an increase in the elimination of genetically abnormal cells by apoptosis compared to the control.     

Serodiagnosis of Lyme borreliosis with bead based immunoassays using multiplex technology

The serological diagnosis of Lyme borreliosis is accomplished by the detection of IgG and IgM antibodies specific for relevant antigens of the spirochetal pathogen Borrelia burgdorferi. Instead of the usual enzyme immune assay for screening and the Western blot technique for confirmation, bead based multiplex assays with multiple simultaneously performed distinct reactions can provide quick, automatically derived and reliable results in a single run by flow cytometer technology. The broad analytical dynamic range of assay signals and the high sensitivity and specificity of the multiplex formats allow even for a reliable use in CSF based analyses for antibody specificity index in supposed neuroborreliosis. Fluorescence intensity of the bead based reactions can be transformed into quantified values as U/ml, either for each single antigen or summed up for a group of relevant key antigens. Additionally or alternatively distinct reactions of single bead populations can be transformed to Western blot band equivalents. Internal and external quality controls with the multiplex systems show characteristic data equivalent to the conventional assay formats, so that the advantages of the multiplex assays are ready for use in the routine diagnostic laboratory.     

Associations of HLA DR and DQ molecules with Lyme borreliosis in Latvian patients

ABSTRACT: BACKGROUND: Many autoimmune diseases are associated with variants of HLA genes such as those encoding the MHC complex. This correlation is not absolute, but may help in understanding of the molecular mechanism of disease. The purpose of this study was to determine HLA-DR,-DQ alleles in Latvian patients with Lyme borreliosis and control (healthy) persons. Case patients and control subjects were similar in age, gender and ethnic heritage and differed only as regards the presence of Borrelia burgdorferi infection. The study included 20 patients with clinical stage - erythema migrans and 25 control (healthy) persons. HLA genotyping was performed by PCR with sequence-specific primers. RESULTS: The results show difference in HLA-DRB1 alleles distribution between patients and control subjects. The frequencies of HLA-DRB1 *04 (OR 8.65; p<0.022) and HLA-DRB1 *17 (03) (OR 7.00; p<0.048) were increased in the Lyme disease patients. And the frequency of allele DRB1*13 (OR 0.13; p<0.033) was lower in Borreliosis patients and higher in control group. But, significant differences in frequencies of HLA-DQ alleles we did not detect. CONCLUSIONS: HLA predisposition to Lyme borreliosis appears not to be limited to HLA molecules, but some HLA-DR alleles also have a significant influence, and, may have implications in our understanding of pathogenesis of this disease. In particular, HLA-DRB1*04 and DRB1 *17 (03) may contribute to the Lyme borreliosis development in Latvian population KEYWORDS: Lyme borreliosis, HLA alleles, PCR.     

Lyme borreliosis in Lithuania: its prevalence, clinical picture and treatment efficacy

In 1988 Lyme borreliosis (LA) was diagnosed in 376 patients in Lithuania, including 101 patients who had the first stage of circular migrating erythema. Of this latter group, in 40 patients (39.6%) specific antibodies to the causative agent of LB were detected. All 101 patients were intensively treated with antibiotics for 10-14 days. The effectiveness of treatment was evaluated 4-5 months later. Information was collected only on 90 patients, including 82 patients who had undergone treatment. Complete convalescence was achieved in 52 cases (63.4%). 20 more persons considered themselves to be practically healthy. But in 10 patients (12.2%) the development of the disease continued, among them in 6 patients who stopped the prescribed course of treatment on their own accord. Out of 8 patients who had not yet even started to undergo treatment, 5 patients had signs of the manifest progress of the disease. Besides, information on the incubation period of the disease, its seasonal character, the characteristic features of erythema and concomitant symptoms in presented.