Acute Tick-borne Encephalitis Research Articles

Dysregulation of the kynurenine pathway is related to persistent cognitive impairment in tick-borne encephalitis.

Tick-borne encephalitis (TBE) patients frequently suffer cognitive and neuropsychiatric sequelae, which may be severe and long-lasting. The underlying mechanisms remain poorly understood, but likely involve dysregulation of immunological and neuroinflammatory processes. Here, we investigated the activity of the kynurenine pathway (KP), an immunologically induced set of enzymes generating neuroactive metabolites via degradation of the amino acid tryptophan and their correlation with the cognitive performance in TBE patients. KP metabolite concentrations were measured in serum and cerebrospinal fluid (CSF) samples from patients taken during hospitalization for acute TBE (n = 87) and a control group (n = 12) by UPLC/MS-MS. At two follow-up occasions, 6 and 18 months after hospital discharge, additional serum samples were obtained from TBE patients and their cognitive performance was evaluated by the Matrics Consensus Cognitive Battery. Relative to controls, TBE patients exhibited a robust induction of the KP in both the central nervous system and peripheral blood during the acute phase of the disease, with drastic elevations of the neuroactive QUIN and KYNA in CSF. KP activity remained significantly elevated in serum of TBE patients at the 6- and 18-month follow-ups. Several inverse associations between cognitive performance and measurements of KP activity recorded in both CSF and serum were found by rank correlation analysis. Further, via ROC analysis, serum rKT was found to be an accurate predictor of impaired overall cognition (<35 T-score) 6 months after acute TBE (AUC 0.79, CI 0.64-0.93, p < 0.01 for rKT measured during acute TBE; AUC 0.68, CI 0.50-0.86, p < 0.05 for rKT measured at 6 months). We have found evidence of both acute and chronic dysregulation of KP activity in TBE patients, which correlated with degree of cognitive impairment at long-term follow-up. Our findings suggest that KP metabolites may serve as biomarkers for TBE-related cognitive sequelae, and more broadly, that the KP may offer avenues for development of novel treatments.

Evaluating peripheral blood lymphocyte subset composition and lipopolysaccharide-induced cytokine secretory activity in mononuclear leukocyte cultures from patients with febrile and meningeal forms of tick-borne encephalitis

Introduction.Multiple studies on immune response in patients with various clinical forms of tick-borne encephalitis (TBE) have shown conflicting results. The study aim was to estimate the changes in peripheral blood lymphocyte subset counts and activity of spontaneous and lipopolysaccharide (LPS)-stimulated cytokine production in the mononuclear leukocyte cultures in patients with febrile and meningeal acute TBE.Materials and methods.Groups 1 and 2 included 16 and 12 patients with febrile and meningeal acute TBE, respectively. The control group included 13 healthy donors. Hemogram and T-lymphocyte, T-helper cell, T-cytotoxic and NK cell counts were analyzed by flow cytometry at week 1 of the disease as well as the spontaneous and LPS-stimulated secretion levels of TNFα, IL-1β, IL-6, IL-10, IL-8, and MCP-1 were assessed by ELISA in the supernatants of mononuclear cell cultures twice: during hospitalization and two weeks later. Statistical analysis was performed by the Mann–Whitney U-test, and Wilcoxon test.Results.Group 2 demonstrated significant decrease in spontaneous and/or LPS-stimulated levels of proinflammatory cytokines IL-1β, IL-6, MCP-1, and TNFα, but showed higher IL-8 level as compared with Group 1. In addition, spontaneous and/or LPS-induced levels of IL-6 and TNFαin Group 2 did not significantly differ from the controls, which presumably also indicated the suppression of their production. In contrast, spontaneous and/or LPS-induced levels of IL-1β, IL-6, MCP-1, and TNFαin Group 1 were higher than in the controls. The spontaneous IL-10 level in the patients from both groups were higher than in the controls. Peripheral blood lymphocyte and T-cytotoxic T-lymphocyte counts in both groups of TBE patients were lower than in the controls. There was significant increase in neutrophil counts, decrease in NK cell count in Group 2 as compared to the patients with a milder febrile form.Conclusion.Meningeal acute TBE patients was presumably associated with inadequate immune response with NK cell deficiency, T-cell dysfunction, increased neutrophil count in the peripheral blood and impaired pro-inflammatory cytokine production related to innate immune response.

Tick-borne encephalitis: A comprehensive review of the epidemiology, virology, and clinical picture.

Tick-borne encephalitis virus (TBEV) is a flavivirus commonly found in at least 27 European and Asian countries. It is an emerging public health problem, with steadily increasing case numbers over recent decades. Tick-borne encephalitis virus affects between 10,000 and 15,000 patients annually. Infection occurs through the bite of an infected tick and, much less commonly, through infected milk consumption or aerosols. The TBEV genome comprises a positive-sense single-stranded RNA molecule of ∼11 kilobases. The open reading frame is>10,000 bases long, flanked by untranslated regions (UTR), and encodes a polyprotein that is co- and post-transcriptionally processed into three structural and seven non-structural proteins. Tick-borne encephalitis virus infection results in encephalitis, often with a characteristic biphasic disease course. After a short incubation time, the viraemic phase is characterised by non-specific influenza-like symptoms. After an asymptomatic period of 2-7days, more than half of patients show progression to a neurological phase, usually characterised by central and, rarely, peripheral nervous system symptoms. Mortality is low-around 1% of confirmed cases, depending on the viral subtype. After acute tick-borne encephalitis (TBE), a minority of patients experience long-term neurological deficits. Additionally, 40%-50% of patients develop a post-encephalitic syndrome, which significantly impairs daily activities and quality of life. Although TBEV has been described for several decades, no specific treatment exists. Much remains unknown regarding the objective assessment of long-lasting sequelae. Additional research is needed to better understand, prevent, and treat TBE. In this review, we aim to provide a comprehensive overview of the epidemiology, virology, and clinical picture of TBE.

Nature of pathological changes on magnetic resonance imaging of the CNS in patients with focal forms of acute tick-borne encephalitis

Introduction. Tick-borne encephalitis (TBE) is a widespread natural focal viral neuroinfection in Russia and the Sverdlovsk region. The high level of morbidity, leading to disability, and the annual registration of focal forms and lethal cases determine the relevance of the search for early differential diagnostic criteria for acute tickborne encephalitis (TBE). A promising direction in the early diagnosis of TBE is acquired by magnetic resonance imaging (MRI).The aim of the study was to study the features of the MRI picture in patients with focal forms of TBE.Material and methods. The study included 38 patients with focal forms of OKE who were treated in the neurological department of Sverdlonsk regional clinical hospital № 1 since 2009 to 2019.Results. In the acute period of focal forms of TBE, pathological changes of an inflammatory nature during MRI of the CNS were more often detected in the cerebral hemispheres (mainly in the white matter) in 40.4 % and subcortical structures in 36.8 %, in the brainstem in 16.7 %, less often in 6.1 % – in the region of the cerebellum and spinal cord. Bilateral nature and combined lesions of the CNS structures were detected 2 times more often. Discussion A detailed analysis of the localization and nature of MRI changes in the CNS in patients with severe focal forms of the disease, in contrast to single descriptions of the MRI picture of TBE according to the literature, made it possible to identify combined lesions of the frontal and parietal lobes characteristic of TBE in combination with pathological changes in the region of the thalamus and basal ganglia.Conclusion. Identification of typical MRI changes in the CNS in patients with a clinical picture of viral encephalitis in the spring-summer period contributes to the early diagnosis of a severe course of TBE.

Neurological disease suspected to be caused by tick-borne encephalitis virus infection in 6 horses in Switzerland.

Reports on acute tick-borne encephalitis virus (TBEV) infections with signs of neurologic disease in horses are limited. To describe the epidemiological, clinical, and laboratory findings of suspected acute TBEV infections in 6 horses. Six horses originating from TBEV endemic regions of Switzerland were presented to equine hospitals with acute onset of neurologic disease between 2011 and 2019. Retrospective case series. Horses with acute onset of signs of neurologic disease that were subjected to clinical and microbiological examinations to rule out infectious diseases affecting the central nervous system. All horses exhibited acute signs of neurologic disease including ataxia and proprioceptive deficits. Horses tested positive for TBEV using virus neutralization test and samples were further tested for TBEV-specific IgM. The presence of TBEV-specific IgM antibodies was confirmed in 5 horses (cases 1-5, Laboratory Unit [LU] values ranging from 30 to 56). One horse (case no. 6) with an LU value just below the test threshold (LU=22.3) was also included under the hypothesis that the horse was transitioning from acute to chronic infection. All horses originated from areas where humans with confirmed tick-borne encephalitis reported to have been bitten by ticks. Acute TBEV infection should be a differential diagnosis in horses with signs of neurologic disease and originating from TBEV endemic areas. The establishment of harmonized diagnostic criteria would help to overcome the diagnostic challenges associated with TBEV and other Flavivirus infections in horses.

Serum and cerebrospinal fluid phosphorylated neurofilament heavy subunit as a marker of neuroaxonal damage in tick-borne encephalitis.

Extensive axonal and neuronal loss is the main cause of severe manifestations and poor outcomes in tick-borne encephalitis (TBE). Phosphorylated neurofilament heavy subunit (pNF-H) is an essential component of axons, and its detection in cerebrospinal fluid (CSF) or serum can indicate the degree of neuroaxonal damage. We examined the use of pNF-H as a biomarker of neuroaxonal injury in TBE. In 89 patients with acute TBE, we measured CSF levels of pNF-H and 3 other markers of brain injury (glial fibrillary acidic protein, S100B and ubiquitin C-terminal hydrolase L1) and compared the results to those for patients with meningitis of other aetiology and controls. Serum pNF-H levels were measured in 80 patients and compared with findings for 90 healthy blood donors. TBE patients had significantly (P<0.001) higher CSF pNF-H levels than controls as early as hospital admission. Serum pNF-H concentrations were significantly higher in samples from TBE patients collected at hospital discharge (P<0.0001) than in controls. TBE patients with the highest peak values of serum pNF-H, exceeding 10 000 pg ml-1, had a very severe disease course, with coma or tetraplegia. Patients requiring intensive care had significantly higher serum pNF-H levels than other TBE patients (P<0.01). Elevated serum pNF-H values were also observed in patients with incomplete recovery (P<0.05). Peak serum pNF-H levels correlated positively with the duration of hospitalization (P=0.005). Measurement of pNF-H levels in TBE patients might be useful for assessing disease severity and determining prognosis.

Acute tick-borne encephalitis during pregnancy – An alarming combination

We report on a pregnant patient who contracted tick-borne encephalitis (TBE) during her second trimester in an endemic region in Southern Germany. The patient presented with typical symptoms including fever and headache, and TBE infection was confirmed by positive blood and cerebrospinal fluid (CSF) testing. During acute infection there was no evidence of pregnancy complications, and the mother recovered well. We performed a clinical follow-up examination of both mother and child eight months after the diagnosis of TBE, which revealed no signs of sequelae.This case study presents rare evidence of TBE infection during pregnancy and may provide guidance for both physicians as well as mothers-to-be dealing with TBE.

Monitoring of cytogenetic instability by micronuclei assay of both immunocompetent and non-immunocompetent cells in tick-borne encephalitis patients depending on variants of glutathione-S-transferase genes in the genotype

Aim of this study was to study the dynamics of the frequency of cytokinesis-blocked T-lymphocytes with micronuclei in peripheral blood and the frequency of buccal micronucleated epithelium cells for a period of half a year in patients with acute tick-borne encephalitis, depending on burden of active and inactive variants of glutathione-S-transferase genes (GSTM1 and GSTT1) in the patient's genotype. We carried out micronucleus assay in immunocompetent and non-immunocompetent cells in 54 patients with acute tick-borne encephalitis and 35 healthy persons (control) residing in the Tomsk and Tyumen regions. To analyze the frequency of cytokinesis-blocked micronucleated T-lymphocytes was used venous peripheral blood as material for phytohemagglutinin-stimulated cultures, and to study the frequency of buccal micronucleated cells, samples of the buccal mucous membrane epithelial cells were obtained. To carried out both techniques of micronucleus assay, cytological preparations were prepared, which were stained using the Giemsa or Felgen methods. The material for the study was obtained repeatedly during admission of patients to treatment, and also after 1 week, 1, 3 and 6 months. Polymerase chain reaction was used to analyze the alleles of the GSTM1 and GSTT1 genes. As a result of this analysis was found a significant increase in the frequency of micronucleated cells in tick-borne encephalitis patients compared with the control group. In addition, the frequency of cytokinesis-blocked micronucleated T-lymphocytes was increased significantly higher than the one of micronucleated buccal cells. The most significant and prolonged increase in the frequency of micronucleated cells was associated with the mutant inactive variants of the genes GSTM1 (0/0) and GSTT1 (0/0). In the patients with burden the inactive forms of these genes, the cytogenetic instability of the cytokinesis-blocked blood T-lymphocytes could persist for up to six months. In case of buccal cells, the frequency of micronucleated cells was close to the one in the control group as early as 1-3 months after a course of treatment. Conclusion. It was found that the most increased and prolonged frequency of cytogenetically instable cells persisted in cytokinesis-blocked T-lymphocytes of peripheral blood of patients with tick-borne encephalitis who were carriers of the genotype with inactive variants of both GSTM1 (0/0) and GSTT1 (0/0 ) glutathione-S-transferase genes.

Monitoring of cytogenetic effects in tick-borne encephalitis patients with type 2 diabetes mellitus, depending on polymorphism of glutathione-S-transferase genes

BACKGROUND: Tick-borne encephalitis (TBE) is an acute viral disease with activation of oxidative stress and increasing in cytogenetic instability. Clinical symptoms of infectious diseases usually more severe in patients with type 2 diabetes mellitus (DM2), especially in the case of burden in the genotype of mutant variants of glutathione-S-transferase genes GSTM1 and GSTT1.&#x0D; AIMS: The aim of this study was to study the dynamics of the frequency of micronucleated cells in patients with acute TBE with concomitant DM2, depending on the burden of active and inactive variants of glutathione-S-transferase genes (GSTM1 and GSTT1) in the patients genotype.&#x0D; MATERIALS AND METHODS: Totally, samples to make micronucleus assay were obtained from 138 patients with febrile illness of acute TBE, 64 of whom were diagnosed with concomitant DM2 (groups 3 and 4). As control groups, 57 healthy individuals (control 1) and 61 patients with DM2 (control 2) were examined. The samples of buccal cells for the micronucleus assay were repeatedly obtained from the individuals on the first day of admission, and also after 1 week, 1, 3 and 6 months. Polymerase chain reaction was used to analyze the variants of the GSTM1 and GSTT1 genes.&#x0D; RESULTS: On the first days of the disease, significant increases in the frequency of micronucleated buccal cells were determined in all TBE patients as compared to controls 1 and 2 (P0.001). Significant increases in the frequency of micronucleated buccal cells was revealed in groups 3 and 4 of the TBE patients who were carriers of inactive variants of the GSTM1(0) and GSTT1(0) genes, as compared to the subgroup of TBE patients with active variants of these genes (P0.001). In all subgroups of TBE patients with concomitant DM2, the frequencies of micronucleated cells were significantly higher than in the subgroups of TBE patients without DM2 (P0.001). Study of the dynamics of the frequency of micronucleated buccal cells, as compared to the control, demonstrated that the highest and long-lasting (within 6 months) cytogenetical effects were maintained in the group of TBE patients with genotype GSTM1(0)/GSTT1 (0) and concomitant DM2.&#x0D; CONCLUSION: The most prolonged and highest increases in the frequencies of cytogenetically instable cells were determined in the group of acute TBE patients with concomitant DM2 who were carriers of the genotype with inactive variants of both GSTM1(0) and GSTT1(0) glutathione-S-transferase genes.

A Sensitive Nano Luciferase Immune Complex Assay System for Highly Sensitive and Specific Detection of Antibodies Against Tick-Borne Encephalitis Virus.

Tick-borne encephalitis virus (TBEV) can cause fever, headache, neurological disorders, and/or peripheral flaccid paralysis; therefore, it is a major threat to public health. A rapid, sensitive, and simple method for detecting anti-TBEV antibodies is needed urgently to determine infection and for vaccine evaluation. Here, a luciferase-based immunocomplex assay system (Luc-IC) was developed to detect TBEV antibodies. The system is based on a reporter Nano luciferase (NLuc) that is co-expressed as a fusion protein with viral envelope domain III (ED3) in COS7 cells. The cell supernatant was used directly to detect antigen without the need for a purification step. This simple procedure effectively improved the sensitivity of the assay. Sera from 50 patients with an acute tick-borne encephalitis infection were tested to determine the sensitivity of the NLuc-IC assay. Furthermore, 62 sera from individuals infected with Japanese encephalitis virus, West Nile virus, yellow fever virus, dengue virus, or Zika virus were also tested to determine specificity. The results demonstrated that the assay was 100% sensitive and 100% specific for TBEV antibodies. Thus, this very simple NLuc-IC assay is potentially useful for rapid and accurate diagnosis of TBEV infection in both humans and animals.

Infectious diseases causing autonomic dysfunction.

To review infectious diseases that may cause autonomic dysfunction. Review of published papers indexed in medline/embase. Autonomic dysfunction has been reported in retrovirus (human immunodeficiency virus (HIV), human T-lymphotropic virus), herpes viruses, flavivirus, enterovirus 71 and lyssavirus infections. Autonomic dysfunction is relatively common in HIV-infected patients and heart rate variability is reduced even in early stages of infection. Orthostatic hypotension, urinary dysfunction and hypohidrosis have been described in tropical spastic paraparesis patients. Varicella zoster reactivation from autonomic ganglia may be involved in visceral disease and chronic intestinal pseudo-obstruction. Autonomic and peripheral nervous system dysfunction may happen in acute tick-borne encephalitis virus infections. Hydrophobia, hypersalivation, dyspnea, photophobia, and piloerection are frequently observed in human rabies. Autonomic dysfunction and vagal denervation is common in Chagas disease. Neuronal depopulation occurs mainly in chagasic heart disease and myenteric plexus, and megacolon, megaesophagus and cardiomyopathy are common complications in the chronic stage of Chagas disease. Parasympathetic autonomic dysfunction precedes left ventricle systolic dysfunction in Chagas disease. A high prevalence of subclinical autonomic neuropathy in leprosy patients has been reported, and autonomic nerve dysfunction may be an early manifestation of the disease. Autonomic dysfunction features in leprosy include anhidrosis, impaired sweating function, localised alopecia ,and reduced heart rate variability. Urinary retention and intestinal pseudo-obstruction have been described in Lyme disease. Diphtheritic polyneuropathy, tetanus and botulism are examples of bacterial infections releasing toxins that affect the autonomic nervous system. Autonomic dysfunction may be responsible for additional morbidity in some infectious diseases.

Autonomic and peripheral nervous system function in acute tick-borne encephalitis.

ObjectivesTick‐borne encephalitis (TBE) is an emerging flaviviral zoonosis in Central and Eastern Europe. TBE can present as meningitis, meningoencephalitis, or meningoencephalomyelitis. Dysfunction of the autonomic (ANS) and peripheral motoric and sensory nervous system (PNS) might contribute to acute and long‐term complications. We aimed to examine, whether the ANS and PNS are affected in acute TBE.MethodsFourteen patients with acute TBE, 17 with diabetic polyneuropathy (d‐PNP), and 30 healthy controls (HC) were examined in our single‐center, prospective study. ANS and PNS function was assessed by time‐ and frequency‐domain parameters of the heart rate (HR) variability at rest and deep respiration, and by sural and tibial nerve neurography. Primary endpoint was the HR variability at rest measured by root mean square of the successive differences (RMSSD). Autonomic symptoms and quality of life (QoL) were assessed by questionnaires.ResultsTick‐borne encephalitis patients had a lower RMSSD at rest (TBE 13.1 ± 7.0, HC 72.7 ± 48.3; P < 0.001) and deep respiration (TBE 42.8 ± 27.0, HC 109.7 ± 68.8; P < 0.01), an increased low‐frequency to high‐frequency power component ratio at rest (TBE 4.0 ± 4.0, HC 0.8 ± 0.5; P < 0.001), and a higher minimal heart rate at rest (TBE 85.4 ± 7.0, HC 69.5 ± 8.5; P < 0.001), all similar to patients with d‐PNP, indicating sympathovagal imbalance with increased sympathetic activation. Compared to HC, sural and tibial nerve conduction velocities and action potential amplitudes were reduced, ANS symptoms were more frequent, and QoL was lower in patients with TBE.ConclusionsThe ANS and to a lesser degree the PNS are affected by acute TBE, which could potentially contribute to short‐ and long‐term morbidity.

Investigation of coagulation behavior using Rotational Thromboelastometry (Rotem®) in patients with neuroinfectious diseases

Background: European tick-borne encephalitis (TBE) commonly presents with neurological disturbances, whereas primary psychiatric manifestations are rare. Aim: To report a case of acute TBE presenting as major depressive episode. Case report: A 72-year-old man had been suffering from fatigue, poor appetite and tremor of the left hand for 2 weeks. Progression of these symptoms made him believe that he had acquired an incurable and fatal disorder. He repeatedly noted in his diary that 'the end is not far off”. Generalized weakness and fluctuating level of consciousness lead to examination at the Neurologic Department. His psychiatric medical history was unremarkable. Brain MRI, EEG and laboratory examination was normal. Diminished drive, dysthymia, hopelessness and suicidal ideation were found on mental state exam. Diagnosed with major depression he was hospitalized in the psychiatric ward. One day later, he developed a generalized seizure and lab findings supported the diagnosis of European TBE (CSF: 13 cells/μL; protein 60 mg/dL; positive TBE-IgM in serum and CSF). Depressive symptoms declined gradually with a combination of psychotherapy, mirtazapin and sertralin. The tremor responded well to propanolol and was seen as unrelated to TBE. He was discharged home 30 days from admission with minimal residual fatigue and low dose mirtazapin. Conclusion Acute life-threatening psychiatric manifestations can be the predominant presenting but successfully treatable feature of TBE. We conclude that awareness for this condition should be raised in endemic regions and high-level of suspicion for encephalitis maintained with the occurrence of seizures or focal-neurological deficits in acute psychiatric conditions.

Tick-borne encephalitis presenting as major depressive episode: a case report

Background: European tick-borne encephalitis (TBE) commonly presents with neurological disturbances, whereas primary psychiatric manifestations are rare. Aim: To report a case of acute TBE presenting as major depressive episode. Case report: A 72-year-old man had been suffering from fatigue, poor appetite and tremor of the left hand for 2 weeks. Progression of these symptoms made him believe that he had acquired an incurable and fatal disorder. He repeatedly noted in his diary that 'the end is not far off”. Generalized weakness and fluctuating level of consciousness lead to examination at the Neurologic Department. His psychiatric medical history was unremarkable. Brain MRI, EEG and laboratory examination was normal. Diminished drive, dysthymia, hopelessness and suicidal ideation were found on mental state exam. Diagnosed with major depression he was hospitalized in the psychiatric ward. One day later, he developed a generalized seizure and lab findings supported the diagnosis of European TBE (CSF: 13 cells/μL; protein 60 mg/dL; positive TBE-IgM in serum and CSF). Depressive symptoms declined gradually with a combination of psychotherapy, mirtazapin and sertralin. The tremor responded well to propanolol and was seen as unrelated to TBE. He was discharged home 30 days from admission with minimal residual fatigue and low dose mirtazapin. Conclusion Acute life-threatening psychiatric manifestations can be the predominant presenting but successfully treatable feature of TBE. We conclude that awareness for this condition should be raised in endemic regions and high-level of suspicion for encephalitis maintained with the occurrence of seizures or focal-neurological deficits in acute psychiatric conditions.

Analysis of serum levels of cytokines, chemokines, growth factors, and monoamine neurotransmitters in patients with tick-borne encephalitis: identification of novel inflammatory markers with implications for pathogenesis.

Tick-borne encephalitis (TBE) is a leading human neuroinfection in Europe and northeastern Asia. However, the pathophysiology of TBE is not understood completely. This study sought to determine the specific serum mediators that are associated with acute TBE. The levels of 30 cytokines, chemokines, and growth factors were measured in serum samples from 87 patients with clinically and serologically confirmed acute TBE and from 32 control subjects using the Cytokine Human Magnetic 30-Plex Panel for the Luminex platform. Serum levels of the monoamine neurotransmitters serotonin, dopamine, and noradrenaline were measured via enzyme-linked immunosorbent assay. TBE virus infection elicited increased levels of the pro-inflammatory cytokines interleukin (IL)-6, IL-8, and IL-12. TBE patients had higher IL-12:IL-4 and IL-12:IL-10 ratios than control patients, reflecting the global pro-inflammatory cytokine balance. Serum levels of the monoamine neurotransmitters serotonin, dopamine, and noradrenaline were significantly lower in TBE patients than in the control group. Most interestingly, increased levels of hepatocyte growth factor and vascular endothelial growth factor were observed in TBE patients; these proteins may be novel and mechanistically important inflammatory biomarkers of TBE.

Specificity and dynamics of effector and memory CD8 T cell responses in human tick-borne encephalitis virus infection.

Tick-borne encephalitis virus (TBEV) is transferred to humans by ticks. The virus causes tick-borne encephalitis (TBE) with symptoms such as meningitis and meningoencephalitis. About one third of the patients suffer from long-lasting sequelae after clearance of the infection. Studies of the immune response during TBEV-infection are essential to the understanding of host responses to TBEV-infection and for the development of therapeutics. Here, we studied in detail the primary CD8 T cell response to TBEV in patients with acute TBE. Peripheral blood CD8 T cells mounted a considerable response to TBEV-infection as assessed by Ki67 and CD38 co-expression. These activated cells showed a CD45RA-CCR7-CD127- phenotype at day 7 after hospitalization, phenotypically defining them as effector cells. An immunodominant HLA-A2-restricted TBEV epitope was identified and utilized to study the characteristics and temporal dynamics of the antigen-specific response. The functional profile of TBEV-specific CD8 T cells was dominated by variants of mono-functional cells as the effector response matured. Antigen-specific CD8 T cells predominantly displayed a distinct Eomes+Ki67+T-bet+ effector phenotype at the peak of the response, which transitioned to an Eomes-Ki67-T-bet+ phenotype as the infection resolved and memory was established. These transcription factors thus characterize and discriminate stages of the antigen-specific T cell response during acute TBEV-infection. Altogether, CD8 T cells responded strongly to acute TBEV infection and passed through an effector phase, prior to gradual differentiation into memory cells with distinct transcription factor expression-patterns throughout the different phases.

Tick-borne encephalitis: A review of epidemiology, clinical characteristics, and management.

Tick-borne encephalitis is an infection of central nervous system caused by tick-borne encephalitis virus transmitted to humans predominantly by tick bites. During the last few decades the incidence of the disease has been increasing and poses a growing health problem in almost all endemic European and Asian countries. Most cases occur during the highest period of tick activity, in Central Europe mainly from April to November. Tick-borne encephalitis is more common in adults than in children. Clinical spectrum of the disease ranges from mild meningitis to severe meningoencephalitis with or without paralysis. Rare clinical manifestations are an abortive form of the disease and a chronic progressive form. A post-encephalitic syndrome, causing long-lasting morbidity that often affects the quality of life develops in up to 50% of patients after acute tick-borne encephalitis. Clinical course and outcome vary by subtype of tick-borne encephalitis virus (the disease caused by the European subtype has milder course and better outcome than the disease caused by Siberian and Far-Easter subtypes), age of patients (increasing age is associated with less favorable outcome), and host genetic factors. Since clinical features and laboratory results of blood and cerebrospinal fluid are nonspecific, the diagnosis must be confirmed by microbiologic findings. The routine laboratory confirmation of the tick-borne encephalitis virus infection is based mainly on the detection of specific IgM and IgG antibodies in serum (and cerebrospinal fluid), usually by enzyme-linked immunosorbent assay. There is no specific antiviral treatment for tick-borne encephalitis. Vaccination can effectively prevent the disease and is indicated for persons living in or visiting tick-borne encephalitis endemic areas.

Tick-borne encephalitis in Bulgaria, 2009 to 2012

For the last 60 years, only a few cases of tick-borne encephalitis (TBE) have been detected in Bulgaria. Considering the remarkable increase in TBE morbidity in Europe over the past two decades, we conducted a study of TBE among patients with acute viral meningitis who were hospitalised in Bulgaria during 2009 to 2012. A total of 86 patients with viral meningitis of unknown aetiology during this period were tested. Acute TBE was confirmed in three of these patients. The last TBE case was detected in October 2012; the other two were diagnosed in 2009. To the best of our knowledge, these three patients are the first confirmed TBE cases reported in Bulgaria. The risk of TBE is underestimated in Bulgaria due to the low awareness of medical doctors.

Tick‐borne encephalitis in Latvia 1973–2009: epidemiology, clinical features and sequelae

To report a 37-year observational experience in Latvia relating the incidence of human tick-borne encephalitis (TBE) and its clinical manifestations, to the field abundance of ticks. Tick abundance was measured by standard flagging techniques. Incidence of human tick-borne disease was derived from Public Health reporting data. Clinical and follow-up data were determined from hospital cohorts from 1973 to 2009. Two TBE incidence peaks in the mid-1970s and the 1990s correlated with increased field abundance of ticks. Increased human TBE in the 1970s was associated with higher field abundance of both Ixodes ricinis and I. Persulcatus. The 1990s peak was particularly associated with I. ricinus, the species predominating in western/central Latvia, and with other factors, including changed agricultural land usage. Proportions of patients with meningitic or focal forms of TBE were similar in the two outbreaks and the intervening periods. Meningeal irritation occurred in 90%, altered consciousness in 19%, ataxia in 34%, seizures in 9%, bulbar features in 2-3% and limb weakness in 15% with shoulder amyotrophy predominating in 5%. Annual mortality varied from 0 to 1.3% and was not related to the overall incidence of TBE. Follow-up for 1-13 years of a cohort of 100 patients revealed long-term sequelae in over 50%, more commonly in those suffering focal forms of acute TBE. Clinical features and mortality of the 1970s and 1990s TBE outbreaks were similar and did not point to a change in virulence.

Tick-borne Encephalitis Among US Travelers to Europe and Asia 2000–2009

Tick-borne encephalitis virus (TBEV) is the most common arbovirus transmitted by ticks in Europe. Approximately 10,000 cases of tick-borne encephalitis (TBE) are reported annually in Europe and Russia. Although TBE is endemic in parts of China, information regarding its incidence is limited. TBEV is closely related to Powassan virus (POWV), another tick-borne flavivirus that is a rare cause of encephalitis in North America and Russia; TBEV and POWV can cross-react in serologic tests. Before 2000, two cases of TBE in North American travelers to Europe were reported. State health officials or clinicians send specimens from patients with unexplained encephalitis to CDC as part of routine surveillance and diagnostic testing. CDC recently reviewed all 2000-2009 laboratory records to identify cases of TBE among U.S. travelers; the five cases identified are summarized in this report. All five cases had TBEV or POWV immunoglobulin M (IgM) antibodies in serum and were confirmed as acute TBE cases by plaque-reduction neutralization tests against both viruses. All four patients who had traveled to Europe or Russia had biphasic illnesses (a common feature of TBE) and made nearly complete recoveries. The fifth patient, the first reported case of TBE in a U.S. traveler to China, had a monophasic illness with severe encephalitis and neurologic sequelae. Health-care providers should be aware of TBE, should counsel travelers about measures to reduce exposure to tick bites, and should consider the diagnosis of TBE in travelers returning from TBE-endemic countries with meningitis or encephalitis.