Rapid clearance of Borrelia burgdorferi from the blood circulation.

BACKGROUND: Borrelia burgdorferi is a tick-borne spirochete that causes Lyme borreliosis (LB). After an initial tick bite, it spreads from the deposition site in the dermis to distant tissues of the host. It is generally believed that this spirochete disseminates via the hematogenous route. Borrelia persica causes relapsing fever and is able to replicate in the blood stream. Currently the exact dissemination pathway of LB pathogens in the host is not known and controversially discussed. METHODS: In this study, we established a strict intravenous infection murine model using host-adapted spirochetes. Survival capacity and infectivity of host-adapted B. burgdorferi sensu stricto (Bbss) were compared to those of B. persica (Bp) after either intradermal (ID) injection into the dorsal skin of immunocompetent mice or strict intravenous (IV) inoculation via the jugular vein. By in vitro culture and PCR, viable spirochetes and their DNA load in peripheral blood were periodically monitored during a 49/50-day course post-injection, as well as in various tissue samples collected at day 49/50. Specific antibodies in individual plasma/serum samples were detected with serological methods. RESULTS: Regardless of ID or IV injection, DNA of Bp was present in blood samples up to day 24 post-challenge, while no Bbss was detectable in the blood circulation during the complete observation period. In contrast to the brain tropism of Bp, Bbss spirochetes were found in ear, skin, joint, bladder, and heart tissue samples of only ID-inoculated mice. All tested tissues collected from IV-challenged mice were negative for traces of Bbss. ELISA testing of serum samples showed that Bp induced gradually increasing antibody levels after ID or IV inoculation, while Bbss did so only after ID injection but not after IV inoculation. CONCLUSIONS: This study allows us to draw the following conclusions: (i) Bp survives in the blood and disseminates to the host's brain via the hematogenous route; and (ii) Bbss, in contrast, is cleared rapidly from the blood stream and is a tissue-bound spirochete.

Tick-Borne Relapsing Fever in Southwest Colorado: A Case Report.

BACKGROUND: Tick-borne relapsing fever (TBRF) is a zoonosis caused by spirochetes of the genus Borrelia. The zoonosis is endemic in higher-elevation coniferous forests of the western United States. CASE REPORT: We discuss the case of a 44-year-old male residing in the San Juan Mountains of Western Colorado who presented with fever, myalgia, vomiting, and "violent chills" to an emergency department. Laboratory studies were notable for bandemia and thrombocytopenia with mild hyperbilirubinemia. Peripheral smear demonstrated multiple Borrelia spirochetes. The patient was treated with parenteral ceftriaxone and discharged with oral doxycycline therapy and recovered uneventfully. We discuss the clinical and epidemiological features of TBRF and the salient points for clinical diagnosis and management of this rare but important disease entity. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: TBRF is a rare and potentially life-threatening infectious process, which presents with nonspecific findings and often poses a diagnostic challenge. TBRF should be considered in the differential diagnosis for patients residing or vacationing in high-altitude forested areas in the western United States.

[Clinical and Laboratory Predictors for Forecasting the Outcomes of Ixodes Tick-Borne Borreliosis].

OBJECTIVE: Our aim was to identify the most informative clinical and laboratory predictors of chronicity of Ixodes tick-borne borreliosis in the acute phase of the disease based on the "optimal cut-off values" (COV) and the predicted probability of the outcomes. METHODS: A retrospective cohort controlled study was carried out. We used the technique of ROC-analysis to estimate the information content of the clinical and laboratory indicators in patients with Ixodes tick-borne borreliosis in the acute phase of the disease with erythemal (n =16), non-erythemal (n = 77) forms of Ixodes tick-borne borreliosis and co-infection with the tick-borne encephalitis (n = 68) for the prediction of the outcomes: recovery or chronization. RESULTS: A retrospective analysis of clinical and laboratory parameters recorded in the acute phase of the disease in 161 patients with chronic Ixodes tick-borne borreliosis. The calculations were performed for the informative clinical and laboratory prognostic predictors of the outcomes for the intervals above and below the COVvalues are defined probabilities of recovery or chronization of Ixodes tick-borne borreliosis. A general predictor of outcomes for all clinicalforms of the disease--the interleukin 8--was established: the probability of chronization after erythemal form is 100.0% at the level of its production over 107.89 pg/ml (AUC = 1.0), after non-erythemal form is 54.63 ± 0.23% at serum concentrations above 94.64 pg/ml (AUC = 0.770), after co-infection with the tick-borne encephalitis is 52.69 ± 0.27% at the level of interleukin 8 above 84.96 pg/ml (AUC = 0.780). CONCLUSION: The results of the study suggest the possibility of predicting the outcomes of infection in the acute phase, which allows to optimize the etiopathogenic therapy of the disease in a timely manner.

Neurocognitive functions and brain atrophy after proven neuroborreliosis: a case-control study.

BACKGROUND: Patients often report neurocognitive difficulties after neuroborreliosis (NB). The frequency and extent of cognitive problems in European patients have been studied incompletely. METHODS: Sixty patients received a neurological and neuropsychological work-up 6 months or longer after treatment for proven NB. Quality of life, psychiatric symptom load, and brain atrophy were measured. All results were compared with a group of 30 healthy control persons adapted for age, gender and education being serologically negative for Borrelia burgdorferi senso latu. A cognitive sum score and a global sum score including cognitive, psychological results and quality of life data was calculated for both groups. RESULTS: Patients after NB showed a lower (i.e. more impaired) score on the Scripps Neurological rating scale (SNRS), but the observed neurological deficits were generally mild (mean ± SD: 97.1 ± 4.7 vs. 99.1 ± 2.4, p = 0.02). The mean neuropsychological domain results of the NB group were all within the normal range. However, a lower performance was found for the frontal executive function z-values (mean ± SD -0.29 ± 0.60 vs. 0.09 ± 0.60; p = 0.0059) of NB patients. Comparing the global sum score (mean ± SD 11.3 ± 4.2 NB vs. 14.3 ± 2.9 control , p = 0.001) and the cognitive sum score of the NB group with those of the control group (mean ± SD -0.15 ± 0.42 NB vs. 0.08 ± 0.31 control , p = 0.0079), both differences were statistically different. The frequencies of impaired global sum scores and those of the pathological cognitive sum scores (p = 0.07) did not differ statistically. No significant differences were found for health-related quality of life (hrQoL), sleep, psychiatric symptom load, or brain atrophy. CONCLUSION: The mean cognitive functions of patients after proven NB were in the normal range. However, we were able to demonstrate a lower performance for the domain of frontal executive functions, for the mean cognitive sum score and the global sum score as a sign of subtle but measurable sequelae of neuroborreliosis. Brain atrophy is not a common consequence of neuroborreliosis.

A case of central sleep apnea strictly dependent upon REM-sleep.

Central sleep apnea (CSA) is characterized by the inability to generate regular breathing patterns as a result of the loss of metabolic drive and failure of respiratory muscle control. We present the case of a 54-year-old woman with a severe CSA strictly dependent upon REM-sleep. Extensive diagnostic workup excluded typical underlying causes and serological analysis revealed acute borreliosis infection. The severity of sleep apnea decreased after repeated polysomnographic studies without a specific therapy. CSA is usually associated with non-REM stages of slow-wave-sleep. This report illustrates the clinical presentation and diagnostic implications of an unusual case of a CSA strictly associated with REM-sleep. Anecdotally reports of severe respiratory failure in borreliosis indicate the potential of this infection to destabilize breathing control but the precise impact of the infection remains controversial. In our case, a relevant neuroborreliosis was not proven, since there were no other neurologic impairments and the patient refused studies of liquor fluid.

[Biochemical parameters of hepatobiliary system functions in viral hepatitis or ixodes tick-borne borreliosis concurrent with chronic opisthorchiasis].

The biochemical parameters of hepatobiliary system functions were studied in patients with opisthorchiasis and concomitant diseases, such as chronic viral hepatitis concurrent with chronic opisthorchiasis, as well as Ixodes tick-borne borreliosis in the presence of the same invasion. Although the magnitude ofbiochemical changes is not great in chronic opisthorchiasis or chronic viral hepatitis, the concomitance of these two diseases were ascertained to result in pronounced abnormalities, by demonstrating the exhaustion of spare capacities of the hepatobiliary system in parasitic invasion (or viral infection). When opisthorchiasis was concurrent with Ixodes tickborne borreliosis, some parameters under study differed from those in the groups of patients with monoinfections. Variance analysis showed that chronic opisthorchiasis had a great impact on carbohydrate and lipid metabolisms (glucose and cholesterol levels). The findings suggest that the formation of stable host-parasite relationships in chronic opisthorchiasis alters human metabolic processes and their compensatory capabilities.

Murine glia express the immunosuppressive cytokine, interleukin-10, following exposure to Borrelia burgdorferi or Neisseria meningitidis.

There is growing appreciation that resident glial cells can initiate and/or regulate inflammation following trauma or infection in the central nervous system (CNS). We have previously demonstrated the ability of microglia and astrocytes, resident glial cells of the CNS, to respond to bacterial pathogens by rapid production of inflammatory mediators. However, inflammation within the brain parenchyma is notably absent during some chronic bacterial infections in humans and nonhuman primates. In the present study, we demonstrate the ability of the immunosuppressive cytokine, interleukin-10 (IL-10), to inhibit inflammatory immune responses of primary microglia and astrocytes to B. burgdorferi and N. meningitidis, two disparate gram negative bacterial species that can cross the blood-brain barrier in humans. Importantly, we demonstrate that these organisms induce the delayed production of significant quantities of IL-10 by both microglia and astrocytes. Furthermore, we demonstrate that such production occurs independent of the actions of bacterial lipopolysaccharide and is secondary to the autocrine or paracrine actions of other glia-derived soluble mediators. The late onset of IL-10 production by resident glia following activation, the previously documented expression of specific receptors for this cytokine on microglia and astrocytes, and the ability of IL-10 to inhibit bacterially induced immune responses by these cells, suggest a mechanism by which resident glial cells can limit potentially damaging inflammation within the CNS in response to invading pathogens, and could explain the suppression of inflammation seen within the brain parenchyma during chronic bacterial infections.

Diversity of Ixodes-borne Borrelia species--clinical, pathogenetic, and diagnostic implications and impact on vaccine development.

Among Borrelia spirochetes carried by hard ticks belonging to the various Ixodes species, at least 10 species can be distinguished. Of these, Borrelia burgdorferi sensu stricto is involved in human Lyme borreliosis in North America and Europe, and Borrelia garinii and Borrelia afzelii in human disease in Europe and Asia. The pathogenetic significance of the other species is uncertain. Although some of the Borrelia species are restricted to certain tick species, Ixodes ricinus, the vector of Lyme borreliosis in Europe, can be infested by at least five different species, including all three pathogenic species. There is evidence that different Borrelia species are preferentially found in different hosts: In Europe, B. afzelii is frequently found in small mammals, whereas B. garinii and Borrelia valaisiana are often found in birds. This could very well be related to differential sensitivity of these species to complement-mediated bactericidal activity of different hosts. Borrelial complement regulator acquiring proteins, among them OspE or Erp proteins, bind to host factor H and related proteins, and this binding protects against activation of complement by the spirochetal surface. The binding is different for proteins originating from different species and is also depending on the host origin of factor H. In Europe, B. garinii is mainly found in neuroborreliosis, whereas in skin disease B. afzelii is more frequently found. The reason is unclear. The majority of human sera cross-react between proteins of different Borrelia species, but some sera react only with proteins from one of the species. This holds especially for reactivity with OspC. A vaccine against B. burgdorferi sensu stricto has been licensed, but was recently redrawn from the market because of commercial reasons. A vaccine protecting against all three pathogenic species is not yet available.

Delayed invasion of the kidney and brain by Borrelia crocidurae in plasminogen-deficient mice.

Borrelia crocidurae is an etiologic agent of relapsing fever in Africa and is transmitted to humans by the bite of soft ticks of the genus Ornithodoros. The role of the plasminogen (Plg) activation system for the pathogenicity of B. crocidurae was investigated by infection of Plg-deficient (plg(-/-)) and Plg wild-type (plg(+/+)) mice. No differences in spirochetemia were observed between the plg(-/-) and plg(+/+) mice. However, signs indicative of brain invasion, such as neurological symptoms and/or histopathological changes, were more common in plg(+/+) mice. Quantitative immunohistochemical analysis demonstrated infection of spirochetes in kidney interstitium and brain as soon as 2 days postinoculation. Lower numbers of extravascular spirochetes in plg(-/-) mice during the first days of infection suggested a less efficient invasion mechanism in these mice than in the plg(+/+) mice. The invasion of the kidneys in plg(-/-) mice produced no significant inflammation, as seen by quantitative immunohistochemistry of the CD45 common leukocyte marker. However, significant kidney inflammation was observed with infection in the plg(+/+) mice. In brain, inflammation was more severe in plg(+/+) mice than in plg(-/-) mice, and the numbers of CD45(+) cells increased significantly with duration of infection in the plg(+/+) mice. The results show that invasion of brain and kidney occurs as early as 2 days after inoculation. Also, Plg is not required for establishment of spirochetemia by the organism, whereas it is involved in the invasion of organs.

Tickborne infections as a cause of nonspecific febrile illness in Wisconsin.

Lyme disease, human granulocytic ehrlichiosis (HGE), and babesiosis are tickborne infections that are indigenous to Wisconsin. To assess their importance as a cause of nonspecific fever, we recruited patients with febrile illness at 10 clinics in northwestern Wisconsin from May through August of both 1997 and 1998. Eligible patients had a temperature >38.0 degrees C but no rash or other localizing source. Acute and convalescent serological tests were performed for Borrelia burgdorferi, Babesia microti, and Ehrlichia equi; polymerase chain reaction was performed to detect granulocytic Ehrlichia rDNA. Seventeen (27%) of 62 eligible patients had laboratory evidence of tickborne infection, including 7 (11%) with probable Lyme disease only, 8 (13%) with HGE only, and 2 (3%) with apparent coinfection. No patients with Babesia infection were identified. Patients with and without tickborne infection were similar with regard to age, sex, symptoms, history of tick bite, and outdoor exposure. The results suggest that tickborne infections are an important cause of nonspecific febrile illness during the tick season in northwestern Wisconsin.

Neuroborreliosis.

Neuroborreliosis, a manifestation of infection with the spirochete Borellia burgdorferi, has become the most frequently recognised arthropod-borne infection of the nervous system in Europe and the USA. The best criterion of an early infection with B. burgdorferi is erythema migrans (EM), but this is present in only about 40-60% of patients with validated borreliosis. Therefore use of the duration of the disease as a classification criterion for neuroborreliosis is increasing, the chronic form being distinguished from the acute when symptoms persist for more than 6 months. The diverse manifestations of neuroborreliosis require that it be included in the differential diagnosis of many neurological disorders. In Europe, meningopolyradiculoneuritis (Bannwarth's syndrome) represents the most common manifestation of acute neuroborreliosis, with the facial nerve being affected much more frequently than the other cranial nerves. Clinical symptoms affecting the central nervous system are rarely observed and then mostly in chronic courses. By far the most common manifestation of chronic neuroborreliosis is encephalomyelitis with spastic-ataxic disturbances and a disturbance of micturition. The current diagnosis of neuroborreliosis is a clinical one, which has to be confirmed by laboratory testing. In most patients, examination of the cerebrospinal fluid (CSF) reveals lymphocytic pleocytosis, damage to the blood-CSF-barrier and an intrathecal synthesis immunoglobulin (Ig) M, IgG, and sometimes IgA. Confirmation of a borrelial infection of the nervous system requires demonstration of an intrathecal synthesis of borrelial-specific antibodies in the CSF or detection of borrelial DNA in the CSF by polymerase chain reaction (PCR). There is no generally accepted therapeutic regime for the treatment of neuroborreliosis, but recent studies have shown ceftriaxone 2 g/day and cefotaxime 6 g/day to be effective in acute and chronic courses. Penicillin G 20 mega units/day and doxycycline 200 mg/day may be suitable for uncomplicated meningopolyneuritis, without involvement of the central nervous system. The durationof treatment--at least 2 weeks in the acute forms and 3 weeks in the chronic forms of neuroborreliosis--is very important for successful treatment. Corticosteroids are recommended only for patients with severe pain that does not respond to antibiotics an analgesics.

A mouse model of Borrelia meningitis after intradermal injection.

Both young and adult C3H/HeN mice developed meningitis within 3 weeks of intradermal inoculation with a newly identified uncultivable Borrelia species, an agent of human relapsing fever. Meningoencephalitis with perivascular infiltrates and plexitis developed at approximately 25 days after inoculation. Infiltrates were composed of B and plasma cells and monocytes. This model recreated the meningitis associated with spirochetal infections through an intradermal route of infection.

Reversal of Borrelia burgdorferi associated dilated cardiomyopathy by antibiotic treatment?

It is suggested that Borrelia burgdorferi infection could be associated with dilated cardiomyopathy (IDC). Stanek et al. were able to cultivate Borrelia burgdorferi from myocardial biopsy tissue of a patient with longstanding dilated cardiomyopathy. Here we present a study in which we examined the effect of standard antibiotic treatment on the left ventricular ejection fraction (LVEF) in patients with dilated cardiomyopathy associated with Borrelia burgdorferi infection. In this study we assessed the serum (IgG, IgM Elisa) and history of 46 IDC patients with specific regard to Borrelia burgdorferi infection (mean LVEF 30.4 +/- 1.3%, measured by cardiac catheterization and echocardiography with the length-area-volume method). All 46 patients received standard treatment for dilated cardiomyopathy: ACE inhibitors, digitalis, and diuretics. Eleven (24%) patients showed positive serology and a history of Borrelia burgdorferi infection; nine of these also had a typical history of tick bite and erythema chronicum migrans (ECM) and/or other organ involvement, and two had no recollection of tick bite or ECM but showed other Borrelia burgdorferi-associated disorders (neuropathy, oligoarthritis). These 11 patients with Borrelia burgdorferi infection received standard antibiotic treatment with intravenous ceftriaxone 2 g bid for 14 days. Six (55%) recovered completely and showed a normal LVEF after 6 months, three (27%) improved their LVEF, and two (18%) did not improve at all. This amounts to nine (82%) patients with recovery/improvement in the Borrelia burgdorferi group. The 35 patients who did not show positive serology or a history of Borrelia burgdorferi infection did not receive antibiotic treatment. In this group without Borrelia burgdorferi infection 12 (26%), showed recovery/improvement following the standard treatment of dilated cardiomyopathy (see earlier). Our results indicate that Borrelia burgdorferi infection could play a decisive role in the development of dilated cardiomyopathy, especially in a geographical region such as Graz, where Borrelia burgdorferi is endemic. While we are aware of the small number of Borrelia burgdorferi patients in this study, we nevertheless conclude that in a remarkable number of patients with signs of Borrelia burgdorferi infection, dilated cardiomyopathy could be reversed and LVEF improved.

Myocarditis in mice and guinea pigs experimentally infected with a canine-origin Borrelia isolate from Florida.

OBJECTIVE: To characterize the pathogenic potential of a unique Borrelia isolate obtained from a dog from Florida (FCB isolate). DESIGN: Prospective experimental infection. ANIMALS: 32 preweanling Swiss Webster mice and 12 adult male Hartley guinea pigs were injected intraperitoneally with 10(5) spirochetes. PROCEDURE: Mice were used as controls and blood recipients, and at 3- to 4-day intervals, 1 control mouse and 2 infected mice were necropsied, tissues were cultured, and a recipient mouse was inoculated with blood. Guinea pigs were randomized to 4 groups and inoculated intradermally with 10(0), 10(2), 10(3), or 10(4) spirochetes. For 48 days, clinical, hematologic, serologic, and microbiologic tests were performed on them, after which they were necropsied. RESULTS: In mice, spirochetemia was detectable between postinoculation days (PID) 3 and 13, and seroreactivity to homologous antigen was detectable during PID 10 through 31. Compared with control mice, infected mouse spleens were 2 to 3 times larger. Histologic lesions included lymphoid hyperplasia, neutrophilic panniculitis, epicarditis, and myocarditis, with intralesional spirochetes detected from PID 3 through 6. During PID 10 through 31, nonsuppurative epicarditis developed. Signs of illness and hematologic abnormalities were not observed in guinea pigs, despite isolating spirochetes from blood during PID 7 to 27. When necropsied on PID 48, histologic lesions included lymphoid hyperplasia and lymphocytic plasmacytic epicarditis. CONCLUSIONS: The FCB isolate causes spirochetemia, lymphoid hyperplasia, dermatitis, and myocardial injury in Swiss Webster mice and can be transmitted by blood inoculation. In Hartley guinea pigs, the isolate causes spirochetemia, lymphoid hyperplasia, and epicarditis. Documentation of disease in mice, guinea pigs, and, presumably, dogs raises the level of concern that the FCB isolate might be pathogenic for man and other animal species.

Does Lyme disease occur in the south?: a survey of emerging tick-borne infections in the region.

Lyme disease is the most common arthropod-borne infection in the United States. However, the risk of infection varies widely by geographic region. In the South, Borrelia burgdorferi has been identified in ticks and small mammals, but transmission of the agent to humans has not been documented. The Lyme disease-like disorder reported from the region may have another etiology.

Neuroborreliosis simulating a progressive stroke.

A 55-year-old man with an onset and course of neurological symptoms of a progressive stroke was found to have a CNS infection caused by the borrelia spirochete. Almost complete recovery was seen after intravenous infusion of bencylpenicillin. Elevated borrelia IgG antibody titers could be seen for long time after recovery. The possibility of an infection due to neuroborreliosis must be considered. If CT scan doesn't show any focal ischemic or hemorrhagic area further investigation with lumbar puncture is necessary in stroke patients.

CNS-borreliosis selectively affecting central motor neurons.

A patient is described having Borrelia burgdorferi spirochetal infection clinically affecting central motor neurons selectively and without any sensory impairment. Diagnosis was based on elevated B. burgdorferi IgG antibody titers in cerebrospinal fluid (CSF) and titer normalization at clinical recovery. This occurred promptly and was complete after penicillin treatment despite 14 months of progressive central nervous system (CNS) dysfunction, favouring the hypothesis of the presence of the organism within the CNS. CSF findings characteristic of neuroborreliosis were registered, including parallel occurrence of mononuclear pleocytosis, severe blood-brain barrier damage and marked CSF IgM index elevation of prolonged duration. Some earlier reports of CNS manifestations related to B. burgdorferi are reviewed.