RESUMEN
Lyme borreliosis, caused by Borrelia burgdorferi sensu lato, is the most common tickborne disease. Its neuronal form, neuroborreliosis, comprises 3 to 38% of borreliosis cases in Europe. Borrelia outer surface proteins and virulence factors, OspE and BBK32, have been previously reported to help cause infection by promoting attachment to human host epithelial cells and evading complement attack. We assessed the serological responses to BBK32 and OspE in 19 individuals diagnosed with neuroborreliosis to see whether antibodies that could both target the bacteria and neutralize the virulence mechanisms on the microbial surface emerge. Results evaluate levels of total protein, IgG and the chemokine CXCL13, a determinant for B-cell recruitment during neuroinflammation, in patients' cerebrospinal fluid samples. Antibody levels against BBK32 and OspE correlated with those against VlsE, a well-characterized diagnostic serological marker of the disease. A dual serological profile of the patients was observed. K-means clustering split the cohort into two discrete groups presenting distinct serological and CNS responses. One group contained young patients with low levels of anti-BBK32 and OspE antibodies. The other group showed stronger responses, possibly following prolonged infections or reinfections. Additionally, we assessed anti-ganglioside antibodies that could cause autoimmunity or complement dysregulation but observed that they did not correlate with neuroborreliosis in our patient cohort. The dual nature of antibody responses against the virulence factors BBK32 and OspE in neuroborreliosis patients may suggest the necessity of repeated exposures for efficient immune responses. Better protection could be achieved if the virulence factors were formulated into vaccines.
Asunto(s)
Anticuerpos Antibacterianos , Antígenos Bacterianos , Proteínas de la Membrana Bacteriana Externa , Borrelia burgdorferi , Neuroborreliosis de Lyme , Humanos , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/sangre , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Proteínas de la Membrana Bacteriana Externa/inmunología , Persona de Mediana Edad , Femenino , Masculino , Adulto , Anciano , Borrelia burgdorferi/inmunología , Antígenos Bacterianos/inmunología , Factores de Virulencia/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Quimiocina CXCL13/sangre , Quimiocina CXCL13/inmunología , Proteínas Bacterianas/inmunología , Formación de Anticuerpos/inmunologíaRESUMEN
The purpose of this study was to describe the epidemiology of Lyme neuroborreliosis (LNB) in Kalmar County, in southern Sweden, between 2008 and 2019, and to analyse the relationship between the LNB incidence and climate factors. Data containing cerebrospinal fluid (CSF) cell counts and borrelia CSF/serum antibody index results was received from the departments of clinical chemistry and microbiology at Kalmar County hospital. For this study, we defined LNB as a case with a positive borrelia antibody CSF/serum index and CSF leukocytes > 5 × 106/L. Climate data including mean temperature, humidity and precipitation covering Kalmar County was collected from the Swedish Meteorological and Hydrological Institute. A total of 5051 paired serum-CSF samples from 4835 patients were investigated of which 251 laboratory LNB cases were found. The average annual LNB incidence in Kalmar County 2008-2019 was 8.8 cases per 100,000 inhabitants. Positive relationships were observed between mean temperature and LNB incidence (p < 0.001) as well as precipitation and LNB incidence (p = 0.003), both with a one calendar month delay. The results suggest an association between climate factors such as mean temperature and precipitation and LNB incidence, presumably through increased/decreased human-tick interactions. This calls for increased awareness of LNB in both the short perspective after periods of warmth and heavy precipitation as well as in a longer perspective in relation to possible climate change. Further studies with larger study groups, covering other geographical areas and over longer periods of time are needed to confirm these findings.
Asunto(s)
Técnicas de Laboratorio Clínico/métodos , Neuroborreliosis de Lyme/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Borrelia , Niño , Preescolar , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina M/sangre , Inmunoglobulina M/líquido cefalorraquídeo , Incidencia , Lactante , Recién Nacido , Neuroborreliosis de Lyme/líquido cefalorraquídeo , Neuroborreliosis de Lyme/epidemiología , Neuroborreliosis de Lyme/inmunología , Masculino , Persona de Mediana Edad , Suero , Suecia , Adulto JovenRESUMEN
BACKGROUND: Cerebrospinal fluid (CSF) oligoclonal bands (OCB) occur in chronic or post-acute phase of inflammatory diseases of the central nervous system. OBJECTIVE: To determine whether CSF OCB in patients with neuroborreliosis (NB) are specific for borrelia burgdorferi senso lato. METHODS: We performed isoelectric focusing followed by immunoblotting in CSF of 10 NB patients and 11 controls (7 patients with multiple sclerosis, 2 patients with neuromyelitis optica spectrum disease, 1 patient with dementia and 1 patient with monoclonal gammopathy). Immunoblotting was performed using an uncoated as well as a borrelia antigen pre-coated nitrocellulose membrane (NCM). OCB were counted by visual inspection and photometric analysis. OCB were compared between uncoated und pre-coated NCM both in the NB and control group. For validation purposes inter-assay precision was determined by calculating the coefficient of variation (CV). RESULTS: Borrelia-specific OCB were found in the CSF of 9 NB patients and in none of the control subjects resulting in a sensitivity of 90% and a specificity of 100%. Number of NB specific OCB were 11±7 bands by photometric analyses compared to 9±5 bands by visual inspection. Validation experiments revealed an inconsistent inter-assay precision between visual and photometric analyses (NB uncoated: visual 28% versus photometric 14%, control subject uncoated: visual 16% versus photometric 24%). CONCLUSIONS: In CSF samples with positive OCB, Borrelia-specific bands were detected in almost all NB patients and in none of the control subjects. Inconsistent inter-assay precision may be explained by a poor comparability of visual and photometric approach.
Asunto(s)
Borrelia burgdorferi/inmunología , Líquido Cefalorraquídeo/inmunología , Líquido Cefalorraquídeo/microbiología , Neuroborreliosis de Lyme/líquido cefalorraquídeo , Neuroborreliosis de Lyme/inmunología , Bandas Oligoclonales/líquido cefalorraquídeo , Bandas Oligoclonales/inmunología , Adulto , Antígenos Bacterianos/inmunología , Estudios de Casos y Controles , Estudios Transversales , Demencia/inmunología , Femenino , Humanos , Immunoblotting/métodos , Neuroborreliosis de Lyme/microbiología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/microbiología , Neuromielitis Óptica/inmunología , Paraproteinemias/inmunología , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
Neutrophils are first responders of antimicrobial host defense and sterile inflammation, and therefore, play important roles during health and disease [...].
Asunto(s)
COVID-19 , Trampas Extracelulares , Inmunidad Innata , Neuroborreliosis de Lyme , Neutrófilos , Animales , Humanos , Antiinflamatorios/uso terapéutico , Ensayos Clínicos como Asunto , COVID-19/inmunología , COVID-19/virología , Desoxirribonucleasa I/uso terapéutico , Diabetes Mellitus/inmunología , Diabetes Mellitus/patología , Trampas Extracelulares/efectos de los fármacos , Trampas Extracelulares/inmunología , Inflamación , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/microbiología , Neuroborreliosis de Lyme/patología , Malaria Falciparum/inmunología , Malaria Falciparum/parasitología , Malaria Falciparum/patología , Meningitis Viral/inmunología , Meningitis Viral/patología , Meningitis Viral/virología , Infarto del Miocardio/inmunología , Infarto del Miocardio/patología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/patología , Obesidad/inmunología , Obesidad/patología , Proteínas Recombinantes/uso terapéuticoRESUMEN
Lyme borreliosis (LB) is caused by Borrelia burgdorferi and infection may lead to not only a large variety of clinical manifestations but also a subclinical outcome. The aim of the present study was to investigate if there is a constitutional difference in complement activation between individuals with previous subclinical Lyme borreliosis (SB) and patients previously diagnosed with Lyme neuroborreliosis (LNB).Lepirudin plasma for activation studies was collected from 60 SB individuals and from 22 patients pre-diagnosed with LNB. The plasma was incubated with live Borrelia spirochetes of two strains (complement sensitive B. garinii Lu59 and complement resistant B. afzelii ACA1).Complement factor C3 was measured in non-activated lepirudin plasma with immune-nephelometry and C3a and sC5b-9 generated during complement activation were measured by enzyme-linked immunosorbent assay.We found that the complement sensitive Lu59 induced higher complement activation than the complement resistant ACA1 when measuring activation products C3a and sC5b-9 in SB and LNB patients, p < 0.0001. No significant difference was found between SB and LNB patients in systemic levels of C3. Furthermore, SB individuals generated a higher activation of C3 cleavage to C3a (C3a/C3 ratio) than LNB patients after activation with ACA1, p < 0.001, but no significant differences were found in response to Lu59. In conclusion, Lu59 induced higher complement activation than ACA1 and individuals with previous SB showed increased generation of C3a compared with patients with previous LNB. In our study population, this mechanism could lead to less elimination of spirochetes in LNB patients and thereby be a factor contributing to the clinical outcome.
Asunto(s)
Activación de Complemento , Enfermedad de Lyme/inmunología , Neuroborreliosis de Lyme/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Infecciones Asintomáticas , Borrelia burgdorferi , Complemento C3/análisis , Humanos , Enfermedad de Lyme/complicaciones , Neuroborreliosis de Lyme/complicaciones , Neuroborreliosis de Lyme/diagnóstico , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Commercial cellular tests are used to diagnose Lyme borreliosis (LB), but studies on their clinical validation are lacking. This study evaluated the utility of an in-house and a commercial enzyme-linked immunosorbent spot (ELISpot) assay for the diagnosis of Lyme neuroborreliosis (LNB). Prospectively, peripheral blood mononuclear cells (PBMCs) were isolated from patients and controls and analysed using an in-house Borrelia ELISpot assay and the commercial LymeSpot assay. B. burgdorferi B31 whole cell lysate and a mixture of outer surface proteins were used to stimulate the PBMCs and the numbers of interferon-gamma-secreting T cells were measured. Results were evaluated using receiver operating characteristic (ROC) curve analysis. Eighteen active and 12 treated LNB patients, 10 healthy individuals treated for an early (mostly cutaneous) manifestation of LB in the past and 47 untreated healthy individuals were included. Both assays showed a poor diagnostic performance with sensitivities, specificities, positive and negative predictive values ranging from 44.4-66.7%, 42.0-72.5%, 21.8-33.3% and 80.5-87.0%, respectively. The LymeSpot assay performed equally poorly when the calculation method of the manufacturer was used. Both the in-house and the LymeSpot assay are unable to diagnose active LNB or to monitor antibiotic treatment success.
Asunto(s)
Borrelia burgdorferi/inmunología , Ensayo de Immunospot Ligado a Enzimas/métodos , Leucocitos Mononucleares/inmunología , Neuroborreliosis de Lyme/diagnóstico , Adulto , Anciano , Antibacterianos/uso terapéutico , Borrelia burgdorferi/efectos de los fármacos , Borrelia burgdorferi/fisiología , Células Cultivadas , Femenino , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/microbiología , Enfermedad de Lyme/tratamiento farmacológico , Enfermedad de Lyme/inmunología , Enfermedad de Lyme/microbiología , Neuroborreliosis de Lyme/tratamiento farmacológico , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/microbiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROC , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/microbiología , Resultado del TratamientoRESUMEN
To evaluate occurrence and extent of CSF CXCL13 elevations beyond Lyme neuroborreliosis, we investigated CXCL13 in an unselected patient cohort with neuroinflammatory disease. From March 2016 to March 2017, 180 in-patients with CSF pleocytosis were categorized into following groups: pyogenic CNS infections, aseptic meningoencephalitis, neuroimmunological diseases, and reactive pleocytosis. We provide evidence that CXCL13 elevation occurs at variable extent in the majority of neuroinflammatory diseases. The exact role of CXCL13 in CSF is elusive, but the broad occurrence in neuroinflammation points at CNS immune activation, which is not exclusive for LNB.
Asunto(s)
Quimiocina CXCL13/líquido cefalorraquídeo , Neuroborreliosis de Lyme/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimiocina CXCL13/fisiología , Femenino , Humanos , Leucocitosis/líquido cefalorraquídeo , Leucocitosis/inmunología , Neuroborreliosis de Lyme/inmunología , Masculino , Meningoencefalitis/líquido cefalorraquídeo , Meningoencefalitis/inmunología , Persona de Mediana Edad , Adulto JovenRESUMEN
Neutrophils operate as part of the innate defence in the skin and may eliminate the Borrelia spirochaete via phagocytosis, oxidative bursts, and hydrolytic enzymes. However, their importance in Lyme neuroborreliosis (LNB) is unclear. Neutrophil extracellular trap (NET) formation, which is associated with the production of reactive oxygen species, involves the extrusion of the neutrophil DNA to form traps that incapacitate bacteria and immobilise viruses. Meanwhile, NET formation has recently been studied in pneumococcal meningitis, the role of NETs in other central nervous system (CNS) infections has previously not been studied. Here, cerebrospinal fluid (CSF) samples from clinically well-characterised children (N = 111) and adults (N = 64) with LNB and other CNS infections were analysed for NETs (DNA/myeloperoxidase complexes) and elastase activity. NETs were detected more frequently in the children than the adults (p = 0.01). NET presence was associated with higher CSF levels of CXCL1 (p < 0.001), CXCL6 (p = 0.007), CXCL8 (p = 0.003), CXCL10 (p < 0.001), MMP-9 (p = 0.002), TNF (p = 0.02), IL-6 (p < 0.001), and IL-17A (p = 0.03). NETs were associated with fever (p = 0.002) and correlated with polynuclear pleocytosis (rs = 0.53, p < 0.0001). We show that neutrophil activation and active NET formation occur in the CSF samples of children and adults with CNS infections, mainly caused by Borrelia and neurotropic viruses. The role of NETs in the early phase of viral/bacterial CNS infections warrants further investigation.
Asunto(s)
Infecciones del Sistema Nervioso Central/inmunología , Trampas Extracelulares/metabolismo , Neutrófilos/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Infecciones del Sistema Nervioso Central/metabolismo , Quimiocinas CXC/líquido cefalorraquídeo , Quimiocinas CXC/metabolismo , Niño , Preescolar , Trampas Extracelulares/fisiología , Femenino , Humanos , Neuroborreliosis de Lyme/líquido cefalorraquídeo , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/metabolismo , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Neutrófilos/patologíaRESUMEN
Neutrophils are crucial mediators of host defense that are recruited to the central nervous system (CNS) in large numbers during acute bacterial meningitis caused by Streptococcus pneumoniae. Neutrophils release neutrophil extracellular traps (NETs) during infections to trap and kill bacteria. Intact NETs are fibrous structures composed of decondensed DNA and neutrophil-derived antimicrobial proteins. Here we show NETs in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis, and their absence in other forms of meningitis with neutrophil influx into the CSF caused by viruses, Borrelia and subarachnoid hemorrhage. In a rat model of meningitis, a clinical strain of pneumococci induced NET formation in the CSF. Disrupting NETs using DNase I significantly reduces bacterial load, demonstrating that NETs contribute to pneumococcal meningitis pathogenesis in vivo. We conclude that NETs in the CNS reduce bacterial clearance and degrading NETs using DNase I may have significant therapeutic implications.
Asunto(s)
Líquido Cefalorraquídeo/citología , Trampas Extracelulares/microbiología , Evasión Inmune , Meningitis Neumocócica/inmunología , Neutrófilos/inmunología , Streptococcus pneumoniae/inmunología , Adolescente , Adulto , Anciano , Animales , Grupo Borrelia Burgdorferi/inmunología , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/microbiología , Líquido Cefalorraquídeo/inmunología , Líquido Cefalorraquídeo/microbiología , Desoxirribonucleasa I/administración & dosificación , Modelos Animales de Enfermedad , Trampas Extracelulares/efectos de los fármacos , Trampas Extracelulares/inmunología , Femenino , Humanos , Neuroborreliosis de Lyme/líquido cefalorraquídeo , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/microbiología , Masculino , Meningitis Neumocócica/líquido cefalorraquídeo , Meningitis Neumocócica/tratamiento farmacológico , Meningitis Neumocócica/microbiología , Meningitis Viral/líquido cefalorraquídeo , Meningitis Viral/inmunología , Persona de Mediana Edad , Neutrófilos/microbiología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/administración & dosificación , Punción Espinal , Streptococcus pneumoniae/aislamiento & purificación , Hemorragia Subaracnoidea/líquido cefalorraquídeo , Adulto JovenRESUMEN
About 5-20% of the general population in endemic areas have seroprevalence for anti-borrelial antibodies. Previous studies have shown a high rate of 25-97% of persisting anti-borrelial antibodies in patients with treated Lyme neuroborreliosis (LNB) at follow-up. These studies used immunoblots with antigens from whole-cell sonicates, which could be less specific than modern recombinant antigens. We assessed the seroprevalence of anti-borrelial antibodies in serum from patients with definite LNB and healthy controls with a line immunoblot using highly specific recombinant antigens. We retrospectively identified patients with treated definite LNB who were treated at the Medical Center-University of Freiburg. Serum from LNB patients at a mean follow-up period of 4.9 years (SD: 3.3) and serum from healthy controls were assessed for anti-borrelial antibodies with a line immunoblot with recombinant antigens. A total of 45 patients with definite LNB and 40 healthy controls were included. Ten LNB patients (22.7%) had persisting antibodies (IgG and/or IgM) in serum at follow-up. Serum samples from six healthy controls (15%) were positive for anti-borrelial antibodies (IgG and or IgM). Prevalence of positive IgM or IgG antibodies showed no statistically significant difference between LNB patients at follow-up and healthy controls (IgM p = 0.32, IgG p = 0.54). Immunoblot reactivity patterns at follow-up in LNB patients did not have statistically significant differences from healthy controls. The discrepancy regarding earlier studies reporting higher amounts of LNB patients with persisting antibodies could be due to a higher specificity of the antigens used in recombinant immunoblots compared to other immunoblots (e.g., whole-cell sonicates). The results of our study should be replicated in a larger prospective multi-center study.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/inmunología , Borrelia/inmunología , Neuroborreliosis de Lyme/epidemiología , Adulto , Anciano , Western Blotting , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/microbiología , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/inmunología , Estudios Retrospectivos , Sensibilidad y Especificidad , Estudios SeroepidemiológicosRESUMEN
BACKGROUND: Infection with Borrelia burgdorferi sensu lato complex (B. b. sl) spirochetes can cause Lyme borreliosis, manifesting as localized infection (e.g. erythema migrans) or disseminated disease (e.g. Lyme neuroborreliosis). Generally, patients with disseminated Lyme borreliosis will produce an antibody response several weeks post-infection. So far, no case of neuroborreliosis has been described with persistently negative serology one month after infection. CASE PRESENTATION: We present a patient with a history of Mantle cell lymphoma and treatment with R-CHOP (rituximab, doxorubicine, vincristine, cyclofosfamide, prednisone), with a meningo-encephalitis, who was treated for a suspected lymphoma relapse. However, no malignant cells or other signs of malignancy were found, and microbial tests did not reveal any clues, including Borrelia serology. He did not recall being bitten by ticks, and a Borrelia PCR on CSF was negative. After spontaneous improvement of symptoms, he was discharged without definite diagnosis. Several weeks later, he was readmitted with a relapse of symptoms of meningo-encephalitis. This time however, a Borrelia PCR on CSF was positive, confirmed by two independent laboratories, and the patient received ceftriaxone upon which he partially recovered. Interestingly, during the diagnostic process of this exceptionally difficult case, a variety of different serological assays for Borrelia antibodies remained negative. Only P41 (flagellin) IgG was detected by blot and the Liaison IgG became equivocal 2 months after initial testing. CONCLUSIONS: To the best of our knowledge this is the first case of neuroborreliosis that is seronegative on repeated sera and multiple test modalities. This unique case demonstrates the difficulty to diagnose neuroborreliosis in severely immunocompromised patients. In this case, a delay in diagnosis was caused by broad differential diagnosis, an absent known history of tick bites, negative serology and the low sensitivity of PCR on CSF. Therefore, awareness of the diagnostic limitations to detect Borrelia infection in this specific patient category is warranted.
Asunto(s)
Huésped Inmunocomprometido , Neuroborreliosis de Lyme , Linfoma de Células del Manto , Humanos , Neuroborreliosis de Lyme/complicaciones , Neuroborreliosis de Lyme/inmunología , Linfoma de Células del Manto/complicaciones , Linfoma de Células del Manto/tratamiento farmacológico , MasculinoRESUMEN
Tick-borne encephalitis (TBE) is widely prevalent on the Eurasian continent, including Japan, but four cases of TBE have been reported in Japan. To inspect unconfirmed TBE cases in Japan, we conducted a retrospective seroepidemiological study of a total of 158 samples from 81 meningoencephalitis patients suspected as Lyme disease. Two serum samples from one patient showed neutralizing antibodies against TBE virus. The patient with severe and progressive encephalitis had a history of tick bite in Hokkaido in 2012. These results demonstrated that tick-borne encephalitis virus (TBEV) case was actually unconfirmed in Japan. Further seroepidemiological surveys are required to identify unconfirmed TBEV infections to consider the pros and cons of introducing specific countermeasures including vaccination in Japan.
Asunto(s)
Vectores Arácnidos/virología , Virus de la Encefalitis Transmitidos por Garrapatas/inmunología , Encefalitis Transmitida por Garrapatas/diagnóstico , Garrapatas/virología , Anciano de 80 o más Años , Animales , Anticuerpos Antivirales/sangre , Diagnóstico Diferencial , Encefalitis Transmitida por Garrapatas/sangre , Encefalitis Transmitida por Garrapatas/inmunología , Encefalitis Transmitida por Garrapatas/virología , Humanos , Japón , Neuroborreliosis de Lyme/sangre , Neuroborreliosis de Lyme/diagnóstico , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/microbiología , MasculinoRESUMEN
The aims of the study were to determine and compare the concentration of CXCL13 in cerebrospinal fluid (CSF) of patients with Lyme neuroborreliosis (LNB) and various other neurological disorders applying a Luminex based assay and ELISA, and to find factors associated with CXCL13 concentration. CSF samples obtained from four clinically well-defined groups of patients (proven LNB, suspected LNB, tick-borne encephalitis (TBE), and aseptic meningitis/meningoencephalitis other than TBE) - 25 samples per group - were analyzed. The performance of the Luminex recomBead CXCL13 assay (Microgen, Neuried, Germany) and ELISA (Euroimmun, Lübeck, Germany) was assessed by receiver operating characteristics. CXCL13 cut-off values were presented as functions of CSF lymphocyte/monocyte counts. Demographic variables, CSF findings, and history of erythema migrans were assessed as possible predictors for CXCL13 CSF concentrations by a general linear model. The calculated cut-off values determined by the maximum of the Youden index were >131â¯pg/mL for recomBead and >259â¯pg/mL for the ELISA. RecomBead showed a sensitivity of 88% (68.8-97.5%) and a specificity of 94% (83.5-98.7%). For the ELISA the corresponding values were 84% (63.9-95.5%) and 98% (89.4-99.9%). The CXCL13 concentration positively correlated with CSF lymphocyte/monocyte count and Borrelia-specific intrathecal antibody index (pâ¯<â¯0.05). High CXCL13 concentrations were only found in the group with proven LNB. CXCL13 levels above cut-off value were established in some patients with viral meningitis/meningoencephalitis but were not detected in patients with suspected LNB without pleocytosis. Applying a linearized cut-off of the CXCL13 concentration in the CSF which is dependent on the CSF cell count is a novel approach in the laboratory diagnosis of LNB.
Asunto(s)
Borrelia/inmunología , Quimiocina CXCL13/líquido cefalorraquídeo , Neuroborreliosis de Lyme/diagnóstico , Neuroborreliosis de Lyme/inmunología , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Adulto , Anticuerpos Antibacterianos/líquido cefalorraquídeo , Anticuerpos Antibacterianos/inmunología , Quimiocina CXCL13/inmunología , Técnicas de Laboratorio Clínico/instrumentación , Técnicas de Laboratorio Clínico/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Separación Inmunomagnética/métodos , Neuroborreliosis de Lyme/líquido cefalorraquídeo , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/diagnóstico , Curva ROC , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: The utility of cerebrospinal fluid (CSF) CXCL13 for diagnosis of acute Lyme neuroborreliosis (LNB) has been debated and the test is not yet routinely performed. This study's aim was to evaluate its overall diagnostic accuracy through meta-analysis. METHODS: Electronic searches in PubMed MEDLINE and Web of Science were performed to identify relevant articles published before January 2018. A summary receiver operating characteristic curve and an optimal cut-off were estimated modelling multiple cut-offs. Publication bias was evaluated using a funnel plot and the associated regression test. RESULTS: A total of 18 studies involving 618 individuals with acute LNB and 2326 individuals with other neurological disorders meeting the eligibility criteria were identified. The pooled sensitivity for CSF CXCL13 was 89% (95% CI 85%-93%) and the pooled specificity was 96% (95% CI 92%-98%), using the identified optimal cut-off value of 162 pg/mL. There was marked heterogeneity between studies, caused by differences in the designs of the study populations and age distribution. The optimal cut-off in the seven studies with a cross-sectional design was 91 pg/mL (sensitivity 96%, 95% CI 92%-98%; specificity 94%, 95% CI 86%-97%) and in the 11 case-control studies it was 164 pg/mL (sensitivity 85%, 95% CI 78%-91%; specificity 95%, 95% CI 90%-98%). CSF CXCL13 values above the optimal cut-off level (determined in this meta-analysis) were also detectable in some other central nervous system disorders, namely neurosyphilis and central nervous system lymphoma. CONCLUSIONS: Our meta-analysis shows that CSF CXCL13 has the potential to become a useful adjunct in the diagnosis of acute LNB.
Asunto(s)
Quimiocina CXCL13/líquido cefalorraquídeo , Neuroborreliosis de Lyme/diagnóstico , Enfermedad Aguda , Adulto , Biomarcadores/líquido cefalorraquídeo , Borrelia burgdorferi/inmunología , Estudios de Casos y Controles , Quimiocina CXCL13/inmunología , Niño , Estudios Transversales , Exactitud de los Datos , Ensayo de Inmunoadsorción Enzimática/métodos , Humanos , Neuroborreliosis de Lyme/líquido cefalorraquídeo , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/microbiología , Curva ROC , Juego de Reactivos para Diagnóstico , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Determinants of a subclinical course of Lyme borreliosis (LB) remain largely unknown. The aim of this study was to assess the extent, sex and age profiles of subclinical Borrelia seroconversion in a LB endemic area in Sweden and to map blood cellular Borrelia-specific immune marker patterns in individuals with a previous subclinical LB course compared with patients previously diagnosed with Lyme neuroborreliosis (LNB). METHODS: A large group of 1113 healthy blood donors was screened for multiple IgG anti-Borrelia antibodies and asked to complete a health inquiry regarding previous LB. A group of subjects with anti-Borrelia-specific IgG antibodies but no previous history of LB (subclinical LB, nâ¯=â¯60) was identified together with 22 cases of previous LNB. Whole Borrelia spirochetes, strains B. afzelii ACA1 and B. garinii Ip90, were used for ex vivo whole blood stimulations, whereas outer surface protein enriched fractions of the same strains were used for stimulation of peripheral blood mononuclear cells (PBMCs). An extensive panel of immune markers was analysed in the supernatants after stimulation using multiplex bead arrays, and Borrelia-specific secretion was determined by subtracting the spontaneous secretion. RESULTS: A total of 125/1113 blood donors reported previous clinical LB. In contrast, 66 donors denied previous LB but showed multiple IgG anti-Borrelia antibodies; these were defined as subclinical subjects, of whom 60 were available for further studies. The subclinical subjects consisted of significantly more men and had a younger age compared with the LNB patients (pâ¯≤â¯0.01). Discriminant analysis revealed a distinct pattern of sex, age and PBMC B. garinii-specific levels of IL-10, IL-17A and CCL20 discriminating subclinical subjects from LNB patients. CONCLUSIONS: This study confirms that subclinical Borrelia seroconversion is common in south-eastern Sweden. The findings further suggest that male sex, younger age together with B. gariniii induced levels of IL-10, IL-17A and CCL20 may be associated with a subclinical course.
Asunto(s)
Infecciones Asintomáticas/epidemiología , Biomarcadores/sangre , Citocinas/inmunología , Enfermedad de Lyme/diagnóstico , Enfermedad de Lyme/inmunología , Neuroborreliosis de Lyme/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/farmacología , Borrelia/química , Borrelia/inmunología , Citocinas/análisis , Citocinas/metabolismo , Femenino , Humanos , Inmunoglobulina G/sangre , Leucocitos Mononucleares/efectos de los fármacos , Enfermedad de Lyme/epidemiología , Neuroborreliosis de Lyme/diagnóstico , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/microbiología , Masculino , Persona de Mediana Edad , Seroconversión , Factores Sexuales , Suecia/epidemiología , Adulto JovenRESUMEN
BACKGROUND: The accuracy of the Lyme multiplex assay for the diagnosis of neuroborreliosis in horses is unknown. HYPOTHESIS/OBJECTIVES: To describe Lyme multiplex results in horses with a postmortem diagnosis of neuroborreliosis. The hypothesis was that paired serum and cerebrospinal fluid (CSF) results and a CSF : serum ratio would allow differentiation of horses with neuroborreliosis from those with other neurologic diseases. ANIMALS: Ninety horses that had neurologic examinations, serum and CSF Lyme multiplex analyses, and postmortem examination of the nervous system performed. METHODS: Retrospective study. Data collected included signalment, ante- and postmortem diagnoses, and serum and CSF Lyme multiplex results. The CSF : serum ratio was calculated by dividing CSF median fluorescent intensity (MFI) by serum MFI for each result. RESULTS: Ten horses had a final diagnosis of neuroborreliosis, 70 were diagnosed with other neurologic diseases, and 10 had no neurologic disease. Not all horses with neuroborreliosis had positive results: 4/10 had at least 1 positive serum result, 5/10 had at least 1 positive CSF result, and 3/10 had at least 1 CSF result 4-fold higher than the corresponding serum result. Results were similar for the 70 horses with other neurologic diseases: 53% had at least 1 positive serum result, 50% had at least 1 positive CSF result, and 16% had at least 1 CSF result 4-fold higher than the corresponding serum result. CONCLUSIONS AND CLINICAL IMPORTANCE: Positive Lyme multiplex results were common in horses with neurologic diseases and did not adequately differentiate horses with neuroborreliosis from horses with other disorders.
Asunto(s)
Antígenos Bacterianos/sangre , Antígenos Bacterianos/líquido cefalorraquídeo , Borrelia burgdorferi/inmunología , Enfermedades de los Caballos/inmunología , Neuroborreliosis de Lyme/veterinaria , Animales , Enfermedades de los Caballos/diagnóstico , Caballos , Inmunoensayo/métodos , Inmunoensayo/veterinaria , Neuroborreliosis de Lyme/diagnóstico , Neuroborreliosis de Lyme/inmunología , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/veterinaria , Estudios Retrospectivos , Estudios SeroepidemiológicosRESUMEN
Background: Lyme encephalopathy, characterized by nonspecific neurobehavioral symptoms including mild cognitive difficulties, may occur in patients with systemic Lyme disease and is often mistakenly attributed to central nervous system (CNS) infection. Identical symptoms occur in many inflammatory states, possibly reflecting the effect of systemic immune mediators on the CNS. Methods: Multiplex immunoassays were used to measure serum and cerebrospinal fluid (CSF) cytokines in patients with or without Lyme disease to determine if there are specific markers of active CNS infection (neuroborreliosis), or systemic inflammatory mediators associated with neurobehavioral syndromes. Results: CSF CXCL13 levels were elevated dramatically in confirmed neuroborreliosis (n = 8), less so in possible neuroborreliosis (n = 11) and other neuroinflammatory conditions (n = 44). Patients with Lyme (n = 63) or non-Lyme (n = 8) encephalopathy had normal CSF findings, but had elevated serum levels of interleukins 7, 17A, and 17F, thymic stromal lymphopoietin and macrophage inflammatory protein-α. Conclusions: CSF CXCL13 is a sensitive and specific marker of neuroborreliosis in individuals with Borrelia-specific intrathecal antibody production. However, it does not distinguish individuals strongly suspected of having neuroborreliosis, but lacking confirmatory intrathecal antibodies, from those with other neuroinflammatory conditions. Patients with mild cognitive symptoms occurring during acute Lyme disease, and/or after appropriate treatment, have normal CSF but elevated serum levels of T-helper 17 markers and T-cell growth factors, which are also elevated in patients without Lyme disease but with similar symptoms. In the absence of CSF abnormalities, neurobehavioral symptoms appear to be associated with systemic inflammation, not CNS infection or inflammation, and are not specific to Lyme disease.
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Encefalopatías/inmunología , Encefalopatías/microbiología , Quimiocina CXCL13/líquido cefalorraquídeo , Factores Inmunológicos , Neuroborreliosis de Lyme/inmunología , Adulto , Anticuerpos Antibacterianos/sangre , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Borrelia , Quimiocina CCL3/sangre , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Femenino , Humanos , Técnicas para Inmunoenzimas , Interleucina-17/sangre , Interleucina-7/sangre , Neuroborreliosis de Lyme/diagnóstico , Masculino , Persona de Mediana Edad , Linfopoyetina del Estroma TímicoRESUMEN
Some patients with a history of Borrelia burgdorferi infection develop a chronic symptomatology characterized by cognitive deficits, fatigue, and pain, despite antibiotic treatment. The pathogenic mechanism that underlines this condition, referred to as post-treatment Lyme disease syndrome (PTLDS), is currently unknown. A debate exists about whether PTLDS is due to persistent infection or to post-infectious damages in the immune system and the nervous system. We present the case of a patient with evidence of exposure to Borrelia burgdorferi sl and a long history of debilitating fatigue, cognitive abnormalities and autonomic nervous system issues. The patient had a positive Western blot for anti-basal ganglia antibodies, and the autoantigen has been identified as γ enolase, the neuron-specific isoenzyme of the glycolytic enzyme enolase. Assuming Borrelia own surface exposed enolase as the source of this autoantibody, through a mechanism of molecular mimicry, and given the absence of sera reactivity to α enolase, a bioinformatical analysis was carried out to identify a possible cross-reactive conformational B cell epitope, shared by Borrelia enolase and γ enolase, but not by α enolase. Taken that evidence, we hypothesize that this autoantibody interferes with glycolysis in neuronal cells, as the physiological basis for chronic symptoms in at least some cases of PTLDS. Studies investigating on the anti-γ enolase and anti-Borrelia enolase antibodies in PTLDS are needed to confirm our hypotheses.
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Borrelia burgdorferi/enzimología , Borrelia burgdorferi/inmunología , Enfermedad de Lyme/inmunología , Fosfopiruvato Hidratasa/inmunología , Adulto , Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/química , Antígenos Bacterianos/genética , Autoanticuerpos/sangre , Autoinmunidad , Borrelia burgdorferi/patogenicidad , Reacciones Cruzadas , Epítopos de Linfocito B/química , Epítopos de Linfocito B/genética , Epítopos de Linfocito B/inmunología , Glucólisis/inmunología , Humanos , Enfermedad de Lyme/etiología , Enfermedad de Lyme/microbiología , Neuroborreliosis de Lyme/etiología , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/microbiología , Masculino , Modelos Inmunológicos , Imitación Molecular/inmunología , Fosfopiruvato Hidratasa/química , Fosfopiruvato Hidratasa/genética , Conformación ProteicaRESUMEN
BACKGROUND: Cerebrovascular complications of Lyme neuroborreliosis (LNB) are poorly documented in the paediatric population. METHODS: We performed a retrospective analysis from prospectively registered cases of acute ischemic stroke (AIS) from the Swiss NeuroPaediatric Stroke Registry (SNPSR) from 2000 to 2015. Only cases with serologically confirmed LNB were included. In addition, a literature review on paediatric stroke cases secondary to Lyme neuroborreliosis in the same time frame was performed. RESULTS: 4 children out of 229 children with arterial ischemic childhood stroke and serologically confirmed LNB were identified in the SNPSR giving a global incidence of 1.7%. Median age was 9.9 years. A prior history of tick bites or erythema migrans (EM) was reported in two cases. Clinical presenting signs were suggestive of acute cerebellar/brainstem dysfunction. On imaging, three children demonstrated a stroke in the distribution of the posterior inferior cerebellar artery. The remaining fourth child had a "stroke-like" picture with scattered white matter lesions and a multifocal vasculitis with prominent basilar artery involvement. Lymphocytic pleocytosis as well as intrathecal synthesis of Borrelia burgdorferi antibodies were typical biological features. Acute intravenous third generation cephalosporins proved to be effective with rapid improvement in all patients. No child had recurrent stroke. Data from the literature concerning eight patients gave similar results, with prominent posterior circulation stroke, multifocal vasculitis and abnormal CSF as distinctive features. CONCLUSIONS: Lyme Neuroborreliosis accounts for a small proportion of paediatric stroke even in an endemic country. The strong predilection towards posterior cerebral circulation with clinical occurrence of brainstem signs associated with meningeal symptoms and CSF lymphocytosis are suggestive features that should rapidly point to the diagnosis. This can be confirmed by appropriate serological testing in the serum and CSF. Clinicians must be aware of this rare neurological complication of Lyme disease that demands specific antibiotic treatment.
Asunto(s)
Neuroborreliosis de Lyme/epidemiología , Sistema de Registros , Accidente Cerebrovascular/epidemiología , Antibacterianos/uso terapéutico , Anticuerpos Antibacterianos/líquido cefalorraquídeo , Cefalosporinas/uso terapéutico , Niño , Comorbilidad , Femenino , Humanos , Incidencia , Neuroborreliosis de Lyme/tratamiento farmacológico , Neuroborreliosis de Lyme/inmunología , Masculino , Estudios Retrospectivos , Suiza/epidemiologíaRESUMEN
BACKGROUND: Despite a well-described symptomatology, treatment delay and sequelae are common in patients with Lyme neuroborreliosis (LNB). The aim of this study was to contribute to the knowledge about the symptomatology and epidemiology of LNB. METHODS: We conducted a retrospective study of all LNB cases verified by a positive Borrelia intrathecal antibody index test performed at the Department of Microbiology, Odense University Hospital, Denmark, from 1995 through 2014. RESULTS: The study included 431 patients; 126 were children. The mean incidence was 4.7 per 100 000 inhabitants per year. The median delay from neurological symptom debut to first hospital contact was 20 days and significantly longer for patients with symptom debut in the winter/early spring. The most common clinical symptoms were painful radiculitis (65.9%), cranial nerve palsy (43.4%), and headache (28.3%). A total of 30.6% were seen in >1 hospital department, and 85.6% were admitted during their course of treatment. Serum Borrelia immunoglobulin M and immunoglobulin G at the time of positive Borrelia intrathecal antibody index test were negative in 67 patients (15.5%). We found a median treatment delay of 24 days, with no improvement in our 20-year study period. Residual symptoms following treatment were found in 28.1% of patients, and risk of residual symptoms was significantly associated with delay from symptom debut to initiation of treatment. CONCLUSIONS: The association between treatment delay and residual symptoms and the lack of improvement in treatment delay during the study period highlight the need for standardized diagnostic routines and a better follow-up for LNB patients. Our findings disprove that all patients with LNB develop positive serum Borrelia antibodies within 6 weeks after infection.