Severe Tick-borne Encephalitis Research Articles

Autoantibodies neutralizing type I IFNs underlie severe tick-borne encephalitis in ∼10% of patients.

Tick-borne encephalitis (TBE) virus (TBEV) is transmitted to humans via tick bites. Infection is benign in >90% of the cases but can cause mild (<5%), moderate (<4%), or severe (<1%) encephalitis. We show here that ∼10% of patients hospitalized for severe TBE in cohorts from Austria, Czech Republic, and France carry auto-Abs neutralizing IFN-α2, -β, and/or -ω at the onset of disease, contrasting with only ∼1% of patients with moderate and mild TBE. These auto-Abs were found in two of eight patients who died and none of 13 with silent infection. The odds ratios (OR) for severe TBE in individuals with these auto-Abs relative to those without them in the general population were 4.9 (95% CI: 1.5-15.9, P < 0.0001) for the neutralization of only 100 pg/ml IFN-α2 and/or -ω, and 20.8 (95% CI: 4.5-97.4, P < 0.0001) for the neutralization of 10 ng/ml IFN-α2 and -ω. Auto-Abs neutralizing type I IFNs accounted for ∼10% of severe TBE cases in these three European cohorts.

Clinical characteristics and factors affecting disease severity in hospitalized tick-borne encephalitis patients in Norway from 2018 to 2022

PurposeTo describe the clinical characteristics and factors associated with disease severity in a Norwegian cohort of hospitalized patients with tick-borne encephalitis (TBE).MethodsThis observational multicenter study included hospitalized patients with TBE in the endemic area in the southeastern region of Norway from 2018 to 2022. Clinical signs and findings from laboratory tests, EEG, CT and MRI scans were recorded. Patient characteristics were compared among those with mild, moderate, and severe TBE, and factors associated with disease severity were identified.ResultsNearly all eligible patients were included in the final cohort (153/189 participants, 81%). The median age was 56 years, 63% were men, and 7% were vaccinated against TBE; no participants were fully vaccinated. TBE presented as mild (meningeal) disease in 31% of patients and as moderate or severe (encephalitic) disease in 54% and 14% of patients, respectively. We found that 46% of the patients had a monophasic course, 64% had hyponatremia, and 7% presented with central nervous system (CNS) symptoms without pleocytosis in cerebrospinal fluid (CSF). Dysesthesia, a symptom previously not described, was reported in 10% of the patients. Most objective findings were related to the CNS. Preexisting comorbidities, CRP and CSF protein levels were predictors of more severe disease.ConclusionThis novel presentation of a large Norwegian cohort supports TBE as a serious disease in the southeastern region of Norway. The majority of hospitalized patients presented with encephalitis, and fewer presented with meningitis. Comorbidities, CRP and CSF protein levels were associated with more severe disease.Trial registrationProsjekt #2,296,959 – The Norwegian Tick-borne Encephalitis Study – NOTES. Acute phase characteristics and long-term outcomes. – Cristin.

Long-term neurological and neurocognitive impairments after tick-borne encephalitis in Lithuania - a prospective study

Background The aim of this study was to characterise long-term neurological and neurocognitive sequelae after tick-borne encephalitis (TBE) in adults. Methods 98 prospective consecutive TBE patients, classified by disease severity, were included. Immediate outcomes were evaluated with Glasgow Outcome Scale (GOS) and Rankin Scale (RS). After 6 and 18 months, long-term disability was evaluated using Modified Rankin Scale (MRS) and neurocognitive assessment was performed with Matrics Consensus Cognitive Battery (MCCB), measuring processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving and social cognition. The MCCB results were compared to healthy age, gender and education-matched controls. Results Mild, moderate, and severe TBE was diagnosed in 53.1%, 38.8%, and 8.2% of cases, respectively. At discharge, 25.5% of the patients had major or moderate impairments (GOS) and various levels of disability in 34.7% (RS). Up to 18 months from the onset of TBE, over 20% remained with slight to moderate disability (MRS). GOS, RS and MRS scores correlated with disease severity. At 6 months after the onset, TBE patients scored significantly lower than controls in processing speed, verbal, and visual learning. Two latter domains were significantly more impaired in patients with mild TBE. Patients aged 18-39 performed significantly worse in attention/vigilance and working memory, whereas aged 60+ in verbal learning. A year later, significant improvement was observed in six of seven cognitive domains. Conclusions Long-term neurological sequelae persist in a substantial proportion of TBE patients with significant impairment in several cognitive domains, especially in younger patients and even after mild TBE.

Severe Tick-Borne Encephalitis (TBE) in a Patient with X-Linked Agammaglobulinemia; Treatment with TBE Virus IgG Positive Plasma, Clinical Outcome and T Cell Responses

PurposeA patient with X-linked agammaglobulinemia (XLA) and severe tick-borne encephalitis (TBE) was treated with TBE virus (TBEV) IgG positive plasma. The patient’s clinical response, humoral and cellular immune responses were characterized pre- and post-infection.MethodsELISA and neutralisation assays were performed on sera and TBEV PCR assay on sera and cerebrospinal fluid. T cell assays were conducted on peripheral blood the patient and five healthy vaccinated controls.ResultsThe patient was admitted to the hospital with headache and fever. He was not vaccinated against TBE but receiving subcutaneous IgG-replacement therapy (IGRT). TBEV IgG antibodies were low-level positive (due to scIGRT), but the TBEV IgM and TBEV neutralisation tests were negative. During hospitalisation his clinical condition deteriorated (Glasgow coma scale 3/15) and he was treated in the ICU with corticosteroids and external ventricular drainage. He was then treated with plasma containing TBEV IgG without apparent side effects. His symptoms improved within a few days and the TBEV neutralisation test converted to positive. Robust CD8+ T cell responses were observed at three and 18-months post-infection, in the absence of B cells. This was confirmed by tetramers specific for TBEV.ConclusionTBEV IgG-positive plasma given to an XLA patient with TBE without evident adverse reactions may have contributed to a positive clinical outcome. Similar approaches could offer a promising foundation for researching therapeutic options for patients with humoral immunodeficiencies. Importantly, a robust CD8+ T cell response was observed after infection despite the lack of B cells and indicates that these patients can clear acute viral infections and could benefit from future vaccination programs.

Serum and CSF brain damage markers NFL and GFAP correlate with tick-borne encephalitis disease severity - a multicenter study on Lithuanian and Swedish patients.

Our aim was to examine the correlation between biomarkers of neuronal and glial cell damage and severity of disease in patients with tick-borne encephalitis. One hundred and fifteen patients with tick-borne encephalitis diagnosed in Lithuania and Sweden were prospectively included, and CSF and serum samples obtained shortly after hospitalization. Using pre-defined criteria, cases were classified as mild, moderate, or severe TBE. Additionally, the presence of spinal nerve paralysis (myelitis) and/or cranial nerve affection were noted. Concentrations of brain cell biomarkers glial fibrillary acidic protein (GFAP), YKL40, S-100B, neurogranin, neurofilament light (NFL), and tau were analyzed in CSF, and in addition, NFL, GFAP and S-100B levels were measured in serum. The Jonckheere Terpstra test was used for group comparisons of continuous variables and Spearman's partial correlation test to adjust for age. CSF and serum concentrations of GFAP and NFL correlated with disease severity, independent of age, and with presence of nerve paralysis. The markers neurogranin, YKL40, tau and S-100B in CSF and S-100B in serum were detected, but their concentrations did not correlate with disease severity. Neuronal cell damage and astroglial cell activation with increased NFL and GFAP in CSF and serum were associated with a more severe disease, independent of age. Increased GFAP and NFL concentrations in CSF and NFL in serum were also indicative of spinal and/or cranial nerve damage. NFL and GFAP are promising prognostic biomarkers in TBE, and future studies should focus on determining the association between these biomarkers and long-term sequelae.

Recovery and sequelae in 523 adults and children with tick-borne encephalitis in Germany

PurposeDespite being vaccine-preventable, tick-borne encephalitis (TBE) continues to cause considerable morbidity in Germany. Limited insight into potentially debilitating consequences of TBE may partially underly low (~ 20%) TBE vaccine uptake. We aimed to systematically assess TBE sequelae and other consequences.MethodsRoutinely notified TBE patients from 2018 to 2020 from Southern Germany were invited to telephone interviews acutely and again after 18 months. Duration of acute symptoms was prospectively assessed. Recovery was defined as score 0 on the modified RANKIN scale. Determinants of time to recovery were analysed with cox regression, adjusted for covariates identified using directed acyclic graphs, yielding hazard ratios (HR) and 95% confidence intervals (CI).ResultsOf 558 cases, 523 (93.7%) completed follow-up. Full recovery was reported by 67.3% (children: 94.9%, adults: 63.8%). Sequelae included fatigue (17.0%), weakness (13.4%), concentration deficit (13.0%), and impaired balance (12.0%). Compared with 18–39-year-olds, recovery rates were 44% lower in ≥ 50-year-olds (HR: 0.56, 95%CI 0.42–0.75) and 79% higher in children (HR: 1.79, 95%CI 1.25–2.56). The recovery rate was 64% lower after severe TBE (compared to mild; HR: 0.36, 95%CI 0.25–0.52) and 22% lower with comorbidities (HR: 0.78, 95%CI 0.62–0.99). Substantial health-care use was reported (90.1% hospitalisation, 39.8% rehabilitation). Of employed cases, 88.4% required sick leave; 10.3% planned/reported premature retirement due to sequelae.ConclusionHalf the adult and 5% of paediatric patients reported persisting sequelae after 18 months. Improved prevention could alleviate both individual (morbidity) and societal TBE burden (health-care costs, productivity losses). Insights into sequelae can help guide at-risk populations towards tick-avoidant strategies and encourage TBE vaccination.

High neutralizing antibody mismatch as a possible reason for vaccine failure in two children with severe tick-borne encephalitis

We describe two adolescents (13 and 16 years old) with severe tick-borne encephalitis (TBE) and vaccination breakthrough (VBT). Both suffer from severe persistent neurologic sequelae. Both patients had high TBE-IgG-titers after vaccination at the beginning of the infection and a low or missing TBE-IgM response (Type 2 vaccine failure). Neutralization tests show low titers against the respective infecting TBE virus strain and higher titers against the vaccine strain at the beginning of the infection implying an individual weak or impaired immune response to the respective virus as possible cause of TBE vaccine failure.We do not know of any similar observation or explanation for the phenomenon and at the moment can only speculate of a severe course correlated to highly mismatched IgG. This constellation of high TBE IgGs, the lack of immune response and a severe course strongly resembles the severe TBE courses that occurred in the past after TBE immunoglobulin administration.To our knowledge differentiation between structural and functional antibodies by neutralization tests with a) the affecting TBE virus strain and b) the vaccine virus strain in TBE vaccine failures has never been described before. We conclude (1) to consider a TBE virus infection also in vaccinated children presenting with meningoencephalitis, (2) to perform a broad immunological work-up in severe TBE especially after VBT, (3) to further study if high mismatch IgG's are a possible reason for vaccine failure.

Development of score models for severe course risk assessment of febrile form of tick-borne encephalitis

Background. There is no current generally accepted classification and clinical approaches to assess the clinical course severity of tick-borne encephalitis. The aim is to develop models for the quantitative severity scores of the febrile form of tick-borne encephalitis using the most informative predictors. Materials and methods. In accordance with clinical criteria of the height and duration of fever, two groups of 9 and 30 patients (52.2 ± 4.3 and 49.5 ± 3.9 years old) with severe and non-severe febrile form of tick-borne encephalitis were formed. The study design was a retrospective case-control study. Statistical significance assessment of variables was carried out using the chi-square test. The odds ratios were also calculated. The development of logistic regression models was carried out using Statistica 12.0 modules. Results. A questionnaire of febrile form of tick-borne encephalitis severity score was developed using the height of fever and 11 most informative clinical predictors including arthralgia, chills, sleep disturbance, dizziness, orbital pain, nausea, photophobia, myalgia, severe headache, vomiting and meningism. To predict the severe clinical course of febrile form of tick-borne encephalitis, two logistic regression models were developed with or without severity score assessment of fever syndrome (coefficients α and β were –12.13 and 0.94 and –5.78 and 0.75 for models 1 and 2, respectively). Models 1 and 2 demonstrated a high predicted probability for cut-off values equal to 14 and 9 points and excellent quality of prediction test (AUC are equal to 0.99 and 0.98, respectively). Conclusions. The models of severity score demonstrated high predicted probabilities to predict severe clinical course of febrile form of tick-borne encephalitis, which can be used in clinical practice and for scientific purposes.

The comparative genomic analysis provides insights into the phylogeny and virulence of tick-borne encephalitis virus vaccine strain Senzhang.

Tick-borne encephalitis virus (TBEV) is one of the most dangerous tick-borne viral pathogens for humans. It can cause severe tick-borne encephalitis (TBE), multiple neurological complications, and death. The European subtype (TBEV-Eu), Siberian subtype (TBEV-Sib), and Far-Eastern subtype (TBEV-FE) are three main TBEV subtypes, causing varying clinical manifestations. Though TBEV-FE is the most virulent TBEV subtype, the degree of variation in the amino acid sequence of TBEV polyprotein is not high, leaving an issue without proper explanation. We performed phylogenic analysis on 243 TBEV strains and then took Senzhang strain as a query strain and representative strains of three major TBEV subtypes as reference strains to perform the comparative genomic analysis, including synteny analysis, SNP analysis, InDel analysis, and multiple sequence alignment of their envelope (E) proteins. The results demonstrated that insertions or deletions of large fragments occurred at the 3’ end but not at the 5’ end or in the CDS region of TBEV Senzhang strain. In addition, SNP sites are mainly located in the CDS region, with few SNP sites in the non-coding region. Our data highlighted the insertions or deletions of large fragments at the 3’ end and SNP sites in the CDS region as genomic properties of the TBEV Senzhang strain compared to representative strains with the main subtypes. These features are probably related to the virulence of the TBEV Senzhang strain and could be considered in future vaccine development and drug target screening for TBEV.

Severe tick-borne encephalitis in a patient recovered from COVID 19

North-eastern Poland is an endemic region for tick-borne encephalitis (TBE). The COVID-19 pandemic overlapped with the activity period of ticks that are the main vectors for TBE. As we know from short observation worldwide, SARS-CoV-2 virus affects significantly the immune system and can lead to serious complications of other infections even in previously healthy patients.A 24-year-old female patient, who lived close to the forest, was admitted to the Department of Neurology at Medical University of Bialystok with fever, dizziness, and progressive left-sided hemiparesis for three days. She had no medical history of chronic disease and was not vaccinated against TBE. The patient had SARS-CoV-2 infection three weeks prior to admission to the hospital (positive IgG against SARS-CoV-2). During COVID-19 infection she had fever, myalgia, a mild dyspnoea without indications for oxygen therapy and recovered after one week. During hospitalisation in the Department of Neurology the patient presented neck stiffness, progressing tetraparesis, dysarthria and weakness of the neck muscles. The magnetic resonance of the head revealed numerous lesions, mainly in both thalamus, longitudinal lesion was found in the cervical spinal cord. The cerebrospinal fluid analysis indicated lymphocytic inflammation. A high level of TBE antibodies in both serum and CSF was found. After immunoglobulin and symptomatic treatment her condition gradually improved. The recovery after SARS-CoV-2 infection overlapping with TBE might have influenced the course of tick-borne disease in a bad manner. The correct diagnosis can be a challenge as COVID-19 can lead to further complications, also neurological. The co-incidence we observed is very rare, however during the pandemic it is pivotal to remember about possible occurrence of other infections and their atypical course.

The Lack of the Association of the CCR5 Genotype with the Clinical Presentation and Frequency of Tick-Borne Encephalitis in the Polish Population.

Background: The host factors influencing the susceptibility to and the severity of tick-borne encephalitis (TBE) are poorly defined. The loss-of-function Δ32 mutation in the chemokine receptor gene CCR5 was identified as a risk factor for West Nile encephalitis and possibly for TBE, suggesting a protective role of CCR5 in Flavivirus encephalitis. Methods: We studied the CCR5 genotype in 205 TBE patients stratified by a clinical presentation and 257 controls from the same endemic area (Podlasie, Poland). The genotype distribution between the groups and differences between TBE patients with different genotypes were analyzed. Results: There were 36 (17.6%) CCR5Δ32 heterozygotes and 3 (1.5%) homozygotes in the TBE group, with no statistically significant difference in comparison with the controls. The CCR5Δ32 allele did not associate with the clinical presentation or the severity of TBE. The cerebrospinal fluid (CSF) inflammatory parameters did not differ between the wild-type (wt/wt) and wt/Δ32 genotype patients. The TBE clinical presentation and CSF parameters in three Δ32/Δ32 homozygotes were unremarkable. Conclusions: The lack of association of CCR5Δ32 with the risk and clinical presentation of TBE challenges the suspected CCR5 protective role. CCR5 is not indispensable for the effective immune response against the TBE virus.

Tick-Borne Encephalitis in Vaccinated Patients: A Retrospective Case-Control Study and Analysis of Vaccination Field Effectiveness in Austria From 2000 to 2018.

There are discrepant observations on the severity of tick-borne encephalitis (TBE) in vaccinated persons. We, therefore, analyzed the occurrence of severe and mild disease in hospitalized vaccinated and nonvaccinated patients with TBE and determined the field effectiveness (FE) of vaccination against these forms of disease. The study covered all patients hospitalized with TBE in Austria from 2000 to 2018. Clinical diagnoses in vaccinated and age- and sex-matched nonvaccinated patients were compared in a nested case-control study. FE was calculated based on vaccination coverage and incidences in the nonvaccinated and vaccinated population. Of 1545 patients hospitalized with TBE, 206 were vaccinated. In those, a higher proportion of severe TBE was observed, especially in children. FE was high in all age groups and against all forms of disease. The higher proportion of severe TBE can be explained by a lower FE against severe than against mild disease, a difference especially pronounced in children (FE, 82.7% for severe vs 94.7% for mild disease). The FE of TBE vaccination is excellent. The observed higher proportion of severe disease in vaccinated persons with TBE does not reflect a higher risk associated with vaccination but is rather due to a somewhat lower FE against severe TBE. Because this effect was more pronounced in children, we recommend adapting the immunization schedule.

The epidemiology, clinical presentation, and predictors of severe Tick-borne encephalitis in Lithuania, a highly endemic country: A retrospective study of 1040 patients.

IntroductionIn recent decades, the incidence of Tick-borne encephalitis (TBE) has been increasing and posing a growing health problem because of the high costs to the healthcare system and society. The clinical manifestations are well studied but there is a lack of research analyzing the severity of the disease.ObjectiveThe aim of this study was to analyze the epidemiology and clinical presentation of severe TBE, to identify the predictors for a severe disease course, and also predictors for meningoencephalomyelitic and severe meningoencephalitic/encephalitic forms.MethodsA retrospective study was conducted in the Center of Infectious Diseases and the Center of Neurology at Vilnius University Hospital Santaros Klinikos in the years 2005–2017 to describe the clinical and epidemiological features of TBE in adults.Results1040 patients were included in the study. A total of 152/1040 (14.6%) patients had a severe course. The highest proportion of severe cases, reaching 41.2%, was reported in the 70–79 year-old age group. A total of 36/152 (23.7%) severe patients presented meningoencephalomyelitis. Myelitic patients were older, were frequently infected in their living areas, and usually reported a monophasic disease course compared with severe meningoencephalitic/encephalitic patients. Severe meningoencephalitic/encephalitic patients, compared with non-severe meningoencephalitic/encephalitic, were older, less often noticed the tick bite, and often had a monophasic course. The sequelae on discharge were observed in 810/1000 (81%) of patients.ConclusionsThe prognostic factors associated with a severe disease course and severe meningoencephalitic form are: older age, comorbidities, a monophasic course, a fever of 40˚C and above, CRP more than 30 mg/l, CSF protein more than 1 g/l, delayed immune response of TBEV IgG, pathological findings in CT. Age above 60 years, presence of CNS disease, bulbar syndrome, pleocytosis 500x106/l and above, and delayed immune response of TBEV IgG are predictors of the most severe myelitic form.

Unexpected complete recovery of a patient with severe tick-borne encephalitis treated with favipiravir

We report a case of tick-borne encephalitis (TBE) in a 22-year-old man, who was admitted to the Medical University of Vienna hospital with severe meningoencephalitis, unresponsive and dependent on a respirator. He had given a history of a recent tick bite, but because he had previously received a full course of vaccination against TBE, West Nile virus infection was suspected. Because the antiviral drug favipiravir has been reported to be active against WNV, therapy was initiated, and continued even after a diagnosis of TBE was confirmed, due to significant improvement of symptoms. Within days, the patient's symptoms resolved, and he was discharged after complete recovery at 15 days after onset. Although this single case does not permit any conclusion as to the role of favipiravir in the favorable outcome, it suggests that the drug should be further evaluated in laboratory animal models and in appropriate clinical settings.

Tick-borne encephalitis in domestic animals.

Tick-borne encephalitis (TBE), a disease caused by tick-borne encephalitis virus (TBEV), represents a serious neural infection of humans in Europe and Asia. The main reservoir hosts of TBEV are ticks, rodents and insectivores, but domestic animals may also be infected with the virus. This review summarizes what is known about TBE in domestic species (e.g., dogs, horses), in which infection may manifest with clinical signs similar to those seen in severe human cases. We also focus on TBE in ruminants where TBE infections are typically asymptomatic and do not cause health problems in the infected hosts. However, the risk to human health is the main problem of asymptomatic infection, because the presence of TBEV in the milk of infected ruminants can serve as a source of TBE infection via the alimentary route. An experimental veterinary vaccine was developed recently, and future vaccination of selected domestic animals is proposed to avoid the development of severe TBE symptoms in sensitive animals (e.g., dogs, horses) or to decrease the risk of alimentary infection in humans (e.g., goats and sheep). Keywords: tick-borne encephalitis; dog; goat; sheep; cow; horse.

Treatment of severe tick-borne encephalitis with intravenous immunoglobulin

Treatment of severe tick-borne encephalitis with intravenous immunoglobulin

Exome-wide search and functional annotation of genes associated in patients with severe tick-borne encephalitis in a Russian population

BackgroundTick-borne encephalitis (TBE) is a viral infectious disease caused by tick-borne encephalitis virus (TBEV). TBEV infection is responsible for a variety of clinical manifestations ranging from mild fever to severe neurological illness. Genetic factors involved in the host response to TBEV that may potentially play a role in the severity of the disease are still poorly understood. In this study, using whole-exome sequencing, we aimed to identify genetic variants and genes associated with severe forms of TBE as well as biological pathways through which the identified variants may influence the severity of the disease.ResultsWhole-exome sequencing data analysis was performed on 22 Russian patients with severe forms of TBE and 17 Russian individuals from the control group. We identified 2407 candidate genes harboring rare, potentially pathogenic variants in exomes of patients with TBE and not containing any rare, potentially pathogenic variants in exomes of individuals from the control group. According to DAVID tool, this set of 2407 genes was enriched with genes involved in extracellular matrix proteoglycans pathway and genes encoding proteins located at the cell periphery. A total of 154 genes/proteins from these functional groups have been shown to be involved in protein-protein interactions (PPIs) with the known candidate genes/proteins extracted from TBEVHostDB database. By ranking these genes according to the number of rare harmful minor alleles, we identified two genes (MSR1 and LMO7), harboring five minor alleles, and three genes (FLNA, PALLD, PKD1) harboring four minor alleles.When considering genes harboring genetic variants associated with severe forms of TBE at the suggestive P-value < 0.01, 46 genes containing harmful variants were identified. Out of these 46 genes, eight (MAP4, WDFY4, ACTRT2, KLHL25, MAP2K3, MBD1, OR10J1, and OR2T34) were additionally found among genes containing rare pathogenic variants identified in patients with TBE; and five genes (WDFY4,ALK, MAP4, BNIPL, EPPK1) were found to encode proteins that are involved in PPIs with proteins encoded by genes from TBEVHostDB. Three genes out of five (MAP4, EPPK1, ALK) were found to encode proteins located at cell periphery.ConclusionsWhole-exome sequencing followed by systems biology approach enabled to identify eight candidate genes (MAP4, WDFY4, ACTRT2, KLHL25, MAP2K3, MBD1, OR10J1, and OR2T34) that can potentially determine predisposition to severe forms of TBE. Analyses of the genetic risk factors for severe forms of TBE revealed a significant enrichment with genes controlling extracellular matrix proteoglycans pathway as well as genes encoding components of cell periphery.

Association of ABCB9 and COL22A1 Gene Polymorphism with Human Predisposition to Severe Forms of Tick-Borne Encephalitis

Tick-borne encephalitis (TBE) is caused by a neurotropic RNA virus from the Flavivirus genus. TBE is characterized by a significant variability of clinical manifestations from nonparalytic forms (fever, meningitis) to severe paralytic (focal) forms (meningoencephalitis, poliomyelitis, polioencephalomyelitis). The result of interaction between a virus and a host (and, consequently, the viral disease course and outcome) largely depends on genetically determined ability of the host (particularly, human) organism immune system to suppress the development of viral infection. However, hereditary predisposition to TBE has been rather poorly studied in human populations. In this study, the results of whole exome sequencing of DNA samples from 22 Russian non-immunized TBE patients with severe TBE forms and 17 control individuals from the same populations are presented. Sixteen single nucleotide polymorphisms (SNPs) associated with predisposition to severe forms of TBE were identified. The genotype and allele frequencies for three of these SNPs localized in the ABCB9 (rs4148866, G/A, intron), COL22A1 (rs4909444, G/T, Ala938Asp), and ITGAL (rs1557672, G/A, intron) genes were then studied in larger samples of patients with different forms of TBE (n = 177) and in the control population (n = 215). As a result, the association of the ABCB9 and COL22A1 gene SNPs with the development of severe forms of TBE was for the first time demonstrated in the Russian population. The hypothesis regarding a possible mechanism of the effect of the ABCB9 gene intronic SNP on the process of human infection with TBE virus is considered.

Factors associated with severity of tick-borne encephalitis: A prospective observational study

Information on parameters associated with the severity of tick-borne encephalitis (TBE) is limited. The association between 15 pre-defined parameters and the severity of TBE was evaluated in 717 consecutive adult patients diagnosed in Slovenia 2007-2012. Multivariable logistic regression showed that patient age (odds ratio, OR 1.26, 95% CI 1.11-1.44; P = 0.001), previous vaccination against TBE (OR 14.23, 95% CI 1.72-117.87; P = 0.014), blood leukocyte count (OR 1.45, 95% CI 1.13-1.85; P = 0.004), and level of specific TBE virus serum IgG antibodies (OR 0.85, 95% CI 0.75-0.96; P = 0.009) were associated with severe acute illness based on the clinical diagnosis. When severity of TBE was based on the severity score and linear regression was used, corresponding association was found for age (estimated coefficient, EC 1.70, 95% CI 1.06-2.33; P<0.001), previous vaccination against TBE (EC 11.16, 95% CI 5.05-17.27; P < 0.001), serum C-reactive protein level (EC 1.20, 95% CI 0.48-1.91; P = 0.001), and level of specific TBE virus serum IgG antibodies (EC -0.74, 95% CI -1.27-0.20; P = 0.007). Previous vaccination against TBE, low levels of TBE virus serum IgG antibodies, older age, higher blood leukocyte count, and higher serum C-reactive protein levels are associated with more severe TBE.

Magnetic resonance imaging and clinical findings in adults with tick-borne encephalitis

BackgroundMagnetic resonance imaging (MRI) in tick-borne encephalitis (TBE) is often performed for differential diagnosis, but only a few reports on the morphologic changes in TBE patients and their relation to the disease severity exist. MethodsWe retrospectively searched for all TBE patients who were admitted to the Departments of Neurology of the Medical University of Graz (Austria) and the Paracelsus Medical University of Salzburg (Austria) between 2003 and 2014. We recorded the clinical and demographic variables and rated overall disease severity as mild, moderate, severe or leading to death due to TBE. MRI scans were screened for morphologic abnormalities. ResultsOf an initial cohort of 88 patients with TBE, 45 patients with an available MRI of the brain were included in this study (median age 58.0years, range: 18–80; men n=28). Their median time spent in the hospital was 18days (range: 4–174days). 16 patients had a mild, 18 a moderate and 10 a severe disease course. One patient died due to TBE.TBE related brain abnormalities could be identified in 4 cases. They consisted of diffuse areas of T2–signal hyperintensity, which were located in the crura cerebri in three patients and in the right centrum semiovale in one patient. No contrast enhancement was observed in any of the lesions and their presence was not related to specific clinical findings or the severity of TBE. ConclusionMRI brain lesions in TBE are rare and do not correlate with the course of the disease. Diffuse areas of signal hyperintensity in the crura cerebri appear suggestive of TBE.