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Tick-borne encephalitis : clinical and pathogenetic aspects

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posted on 2024-09-02, 18:32 authored by Auksé Mickiené

The aims of this study were to investigate the morbidity associated with tick-borne encephalitis (TBE) in the acute stage and at long-term follow-up, to identify the possible host risk factors for development of clinical TBE with special reference to the role of the genetic polymorphism, and to investigate neurochemical changes in the brain induced by TBE virus (TBEV) and their possible role on severity of TBE with special reference to endogenous kynurenic acid (KYNA).

Paper I: Of 250 consecutively admitted patients with central nervous system (CNS) infections treated during a 1-year period, all 133 patients with TBE participated in the prospective follow-up study. TBE presented as mild (meningeal), moderate or severe (encephalitic) forms in 43.6%, 43.6% and 12.8%, respectively. Paralytic disease was observed in 3.8%, and cranial nerve injury in 5.3% of the TBE patients. Permanent CNS dysfunction after 1 year was found in 30.8% of patients; in 8.5% of all TBE cases, severe disabilities required adjustment of daily activities. Cognitive CNS dysfunction was the dominant symptom in patients with more pronounced sequelae. A higher risk for incomplete recovery was seen for the encephalitic form of TBE (odds ratio (OR), 4.066; 95% confidence interval (CI), 1.848–8.947).

Papers II and III: A prospectively collected material from patients with TBE (n=129), aseptic meningoencephalitis of non-TBEV aetiology (n=79) and healthy TBEV-naive Lithuanians (n=135) were used in studies on chemokine receptor 5 (CCR5) and Toll-like receptor 3 (TLR3) rs3775291 gene polymorphisms. In addition, children TBE cohort (n=117) and a cohort of adults with severe TBE (n=103) were recruited in Paper III. The prevalence of CCR5Δ32 homozygotes was higher among the adults with TBE (2.3%), among children with TBE (2.5%), among adults with severe TBE (1.9%), and in the overall cohort of TBE patients (2.3%) than in controls (0%) (p<0.05). Hence, the CCR5 polymorphism was identified as a significant risk factor for clinical TBE. The CCR5Δ32 allele prevalence was higher in the combined children and adult TBE cohort compared with TBEV-naive individuals, and suggested CCR5Δ32 allele being a risk factor for clinical TBEV infection (OR 1.672; 95% CI 1.005–2.782). The nonfunctional homozygous TLR3 genotype was less prevalent among the combined TBE cohort (11.5%) than among controls (19.9%) (p = 0.025), but did not differ between children TBE and controls. The genotype and allele prevalence of CCR5 and TLR3 did not differ in children nor adult TBE cohorts stratified by disease severity. In adults with severe TBE, homozygous functional TLR3 genotype and wt allele were less prevalent than in adults with the whole disease severity spectrum (44.4% vs 59.8% p = 0.022 and 65.2% vs 76.4% p = 0.009; respectively).

Paper IV has shown that cerebrospinal fluid (CSF) KYNA levels were considerably higher in patients with TBE recruited from Paper I (5.3 nmol L-1) than in control subjects (0.99 nmol L-1) and increased (p<0.05) with severity of TBE.

Conclusion: TBE is the main CNS infection in adults in Lithuania, causing a considerable morbidity with long-lasting sequelae in one-third of patients. Cognitive CNS dysfunction dominates and is the major cause of long-lasting impairment of the quality of life. High levels of KYNA in CSF of TBE patients serve as a marker of severity of TBE. Host genetic polymorphism plays a role in the development of clinical TBE and may even be linked to the disease severity.

List of scientific papers

I. Mickienė A, Laiškonis A, Günther G, Vene S, Lundkvist Ă, Lindquist L. Tickborne Encephalitis in an Area of High Endemicity in Lithuania: Disease Severity and Long-Term Prognosis. Clinical Infectious Diseases 2002; 35(6):650-658.
https://doi.org/10.1086/342059

II. Kindberg E, Mickienė A, Ax C, Åkerlind B, Vene S, Lindquist L, Lundkvist Å, Svensson L. A Deletion in the Chemokine Receptor 5 (CCR5) Gene Is Associated with Tickborne Encephalitis. The Journal of Infectious Diseases 2008; 197(2):266-269.
https://doi.org/10.1086/524709

III. Mickienė A, Pakalnienė J, Nordgren J, Carlsson B, Hagbom M, Svensson L, Lindquist L. Polymorphisms in Chemokine Receptor 5 and Toll-Like Receptor 3 genes Are Risk Factors for Clinical Tick-Borne Encephalitis in the Lithuanian Population. PLoS ONE 2014; 9(9): e106798.
https://doi.org/10.1371/journal.pone.0106798

IV.Holtze M, Mickienė A, Atlas A, Lindquist L, Schwieler L. Elevated cerebrospinal fluid kynurenic acid levels in patients with tick-borne encephalitis. Journal of Internal Medicine 2012; 272(4):394–401.
https://doi.org/10.1111/j.1365-2796.2012.02539.x

History

Defence date

2015-12-18

Department

  • Department of Medicine, Huddinge

Main supervisor

Lindquist, Lars

Publication year

2015

Thesis type

  • Doctoral thesis

ISBN

978-91-7676-093-2

Number of supporting papers

4

Language

  • eng

Original publication date

2015-11-25

Author name in thesis

Mickienė, Auksė

Original department name

Department of Medicine, Huddinge

Place of publication

Stockholm

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