1887

Journal of General Virology header logo

Volume 103, Issue 5

Serum and cerebrospinal fluid phosphorylated neurofilament heavy subunit as a marker of neuroaxonal damage in tick-borne encephalitis No Access

Abstract

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 (<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 (<0.0001) than in controls. TBE patients with the highest peak values of serum pNF-H, exceeding 10 000 pg ml, 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 (<0.01). Elevated serum pNF-H values were also observed in patients with incomplete recovery (<0.05). Peak serum pNF-H levels correlated positively with the duration of hospitalization (=0.005). Measurement of pNF-H levels in TBE patients might be useful for assessing disease severity and determining prognosis.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): biomarker , brain injury , flavivirus , neurofilament and tick-borne encephalitis
Funding
This study was supported by the:
  • Grantová Agentura České Republiky (Award 20-30500S)
    • Principle Award Recipient: PalusMartin
  • Grantová Agentura České Republiky (Award 20-14325S)
    • Principle Award Recipient: RuzekDaniel
  • Ministerstvo Zdravotnictví Ceské Republiky (Award NV19-05-00457)
    • Principle Award Recipient: DanielRuzek
© 2022 The Authors
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001743
2022-05-04
2024-04-23
Loading full text...

Full text loading...

References

  1. Ruzek D, Avšič Županc T, Borde J, Chrdle A, Eyer L et al. Tick-borne encephalitis in Europe and Russia: Review of pathogenesis, clinical features, therapy, and vaccines. Antiviral Res 2019; 164:23–51 [View Article] [PubMed]
     [Google Scholar]
  2. Bogovic P, Strle F. Tick-borne encephalitis: A review of epidemiology, clinical characteristics, and management. World J Clin Cases 2015; 3:430–441 [View Article] [PubMed]
     [Google Scholar]
  3. Kríz B, Benes C, Daniel M. Alimentary transmission of tick-borne encephalitis in the Czech Republic (1997-2008). Epidemiol Mikrobiol Imunol 2009; 58:98–103 [PubMed]
     [Google Scholar]
  4. Kohlmaier B, Schweintzger NA, Sagmeister MG, Švendová V, Kohlfürst DS et al. Clinical characteristics of patients with tick-borne encephalitis (TBE): A European multicentre study from 2010 to 2017. Microorganisms 2021; 9:1420 [View Article] [PubMed]
     [Google Scholar]
  5. Taba P, Schmutzhard E, Forsberg P, Lutsar I, Ljøstad U et al. EAN consensus review on prevention, diagnosis and management of tick-borne encephalitis. Eur J Neurol 2017; 24:1214–e61 [View Article] [PubMed]
     [Google Scholar]
  6. Saksida A, Duh D, Lotric-Furlan S, Strle F, Petrovec M et al. The importance of tick-borne encephalitis virus RNA detection for early differential diagnosis of tick-borne encephalitis. J Clin Virol 2005; 33:331–335 [View Article] [PubMed]
     [Google Scholar]
  7. Veje M, Studahl M, Norberg P, Roth A, Möbius U et al. Detection of tick-borne encephalitis virus RNA in urine. J Clin Microbiol 2014; 52:4111–4112 [View Article] [PubMed]
     [Google Scholar]
  8. Nagy A, Nagy O, Tarcsai K, Farkas Á, Takács M. First detection of tick-borne encephalitis virus RNA in clinical specimens of acutely ill patients in Hungary. Ticks Tick Borne Dis 2018; 9:485–489 [View Article] [PubMed]
     [Google Scholar]
  9. Caracciolo I, Bassetti M, Paladini G, Luzzati R, Santon D et al. Persistent viremia and urine shedding of tick-borne encephalitis virus in an infected immunosuppressed patient from a new epidemic cluster in North-Eastern Italy. J Clin Virol 2015; 69:48–51 [View Article] [PubMed]
     [Google Scholar]
  10. Lotric-Furlan S, Strle F. Thrombocytopenia--a common finding in the initial phase of tick-borne encephalitis. Infection 1995; 23:203–206 [View Article] [PubMed]
     [Google Scholar]
  11. Kaiser R. Tick-borne encephalitis in southwestern Germany. Infection 1996; 24:398–399 [View Article] [PubMed]
     [Google Scholar]
  12. Barp N, Trentini A, Di Nuzzo M, Mondardini V, Francavilla E et al. Clinical and laboratory findings in tick-borne encephalitis virus infection. Parasite Epidemiol Control 2020; 10:e00160 [View Article] [PubMed]
     [Google Scholar]
  13. Kaiser R. The clinical and epidemiological profile of tick-borne encephalitis in southern Germany 1994-98: a prospective study of 656 patients. Brain 1999; 122 (Pt 11):2067–2078 [View Article] [PubMed]
     [Google Scholar]
  14. Mickiene A, Laiskonis A, Günther G, Vene S, Lundkvist A et al. Tickborne encephalitis in an area of high endemicity in lithuania: disease severity and long-term prognosis. Clin Infect Dis 2002; 35:650–658 [View Article] [PubMed]
     [Google Scholar]
  15. Gudowska-Sawczuk M, Mroczko B. Selected biomarkers of tick-borne encephalitis: a review. Int J Mol Sci 2021; 22:19 [View Article] [PubMed]
     [Google Scholar]
  16. Toczylowski K, Grygorczuk S, Osada J, Wojtkowska M, Bojkiewicz E et al. Evaluation of cerebrospinal fluid CXCL13 concentrations and lymphocyte subsets in tick-borne encephalitis. Int J Infect Dis 2020; 93:40–47 [View Article] [PubMed]
     [Google Scholar]
  17. Pilz G, Wipfler P, Otto F, Hitzl W, Afazel S et al. Cerebrospinal fluid CXLC13 indicates disease course in neuroinfection: an observational study. J Neuroinflammation 2019; 16:13 [View Article] [PubMed]
     [Google Scholar]
  18. Gudowska-Sawczuk M, Czupryna P, Moniuszko-Malinowska A, Pancewicz S, Mroczko B. Free immunoglobulin light chains in patients with tick-borne encephalitis: before and after treatment. J Clin Med 2021; 10:13 [View Article] [PubMed]
     [Google Scholar]
  19. Palus M, Zampachová E, Elsterová J, Růžek D. Serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels in patients with tick-borne encephalitis. J Infect 2014; 68:165–169 [View Article] [PubMed]
     [Google Scholar]
  20. Palus M, Formanová P, Salát J, Žampachová E, Elsterová J et al. 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. J Med Virol 2015; 87:885–892 [View Article] [PubMed]
     [Google Scholar]
  21. Grygorczuk S, Czupryna P, Pancewicz S, Świerzbińska R, Kondrusik M et al. Intrathecal expression of IL-5 and humoral response in patients with tick-borne encephalitis. Ticks Tick Borne Dis 2018; 9:896–911 [View Article] [PubMed]
     [Google Scholar]
  22. Grygorczuk S, Świerzbińska R, Kondrusik M, Dunaj J, Czupryna P et al. The intrathecal expression and pathogenetic role of Th17 cytokines and CXCR2-binding chemokines in tick-borne encephalitis. J Neuroinflammation 2018; 15:115 [View Article] [PubMed]
     [Google Scholar]
  23. Grygorczuk S, Czupryna P, Pancewicz S, Świerzbińska R, Dunaj J et al. The increased intrathecal expression of the monocyte-attracting chemokines CCL7 and CXCL12 in tick-borne encephalitis. J Neurovirol 2021; 27:452–462 [View Article] [PubMed]
     [Google Scholar]
  24. Koper OM, Kamińska J, Grygorczuk S, Zajkowska J, Kemona H. CXCL9 concentrations in cerebrospinal fluid and serum of patients with tick-borne encephalitis. Arch Med Sci 2018; 14:313–320 [View Article] [PubMed]
     [Google Scholar]
  25. Zajkowska J, Moniuszko-Malinowska A, Pancewicz SA, Muszyńska-Mazur A, Kondrusik M et al. Evaluation of CXCL10, CXCL11, CXCL12 and CXCL13 chemokines in serum and cerebrospinal fluid in patients with tick borne encephalitis (TBE). Adv Med Sci 2011; 56:311–317 [View Article] [PubMed]
     [Google Scholar]
  26. Lepej SZ, Misić-Majerus L, Jeren T, Rode OD, Remenar A et al. Chemokines CXCL10 and CXCL11 in the cerebrospinal fluid of patients with tick-borne encephalitis. Acta Neurol Scand 2007; 115:109–114 [View Article] [PubMed]
     [Google Scholar]
  27. Moniuszko-Malinowska A, Penza P, Czupryna P, Zajkowska O, Pancewicz S et al. Assessment of HMGB-1 concentration in tick-borne encephalitis and neuroborreliosis. Int J Infect Dis 2018; 70:131–136 [View Article] [PubMed]
     [Google Scholar]
  28. Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol 2018; 14:577–589 [View Article] [PubMed]
     [Google Scholar]
  29. Lee Y, Lee BH, Yip W, Chou P, Yip BS. Neurofilament proteins as prognostic biomarkers in neurological disorders. Curr Pharm Des 2020; 25:4560–4569 [View Article] [PubMed]
     [Google Scholar]
  30. Sternberger LA, Sternberger NH. Monoclonal antibodies distinguish phosphorylated and nonphosphorylated forms of neurofilaments in situ. Proc Natl Acad Sci U S A 1983; 80:6126–6130 [View Article] [PubMed]
     [Google Scholar]
  31. Hirokawa N, Glicksman MA, Willard MB. Organization of mammalian neurofilament polypeptides within the neuronal cytoskeleton. J Cell Biol 1984; 98:1523–1536 [View Article] [PubMed]
     [Google Scholar]
  32. Shaw G. The use and potential of pNF-H as a general blood biomarker of axonal loss: an immediate application for CNS injury. In Kobeissy FH. eds Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects Boca Raton (FL): CRC Press/Taylor & Francis; 2015
     [Google Scholar]
  33. Xu D-M, Cai S-N, Li R, Wu Y, Liu S-A et al. Elevation of cerebrospinal fluid light and heavy neurofilament levels in symptomatic neurosyphilis. Sex Transm Dis 2020; 47:634–638 [View Article] [PubMed]
     [Google Scholar]
  34. Bílý T, Palus M, Eyer L, Elsterová J, Vancová M et al. Electron tomography analysis of tick-borne encephalitis virus infection in human neurons. Sci Rep 2015; 5:10745 [View Article] [PubMed]
     [Google Scholar]
  35. Gelpi E, Preusser M, Garzuly F, Holzmann H, Heinz FX et al. Visualization of Central European tick-borne encephalitis infection in fatal human cases. J Neuropathol Exp Neurol 2005; 64:506–512 [View Article] [PubMed]
     [Google Scholar]
  36. Gelpi E, Preusser M, Laggner U, Garzuly F, Holzmann H et al. Inflammatory response in human tick-borne encephalitis: analysis of postmortem brain tissue. J Neurovirol 2006; 12:322–327 [View Article] [PubMed]
     [Google Scholar]
  37. Růzek D, Salát J, Palus M, Gritsun TS, Gould EA et al. CD8+ T-cells mediate immunopathology in tick-borne encephalitis. Virology 2009; 384:1–6 [View Article] [PubMed]
     [Google Scholar]
  38. Fares M, Cochet-Bernoin M, Gonzalez G, Montero-Menei CN, Blanchet O et al. Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection. J Neuroinflammation 2020; 17:76 [View Article] [PubMed]
     [Google Scholar]
  39. Czupryna P, Grygorczuk S, Pancewicz S, Świerzbińska R, Zajkowska J et al. Evaluation of NSE and S100B in patients with tick-borne encephalitis. Brain Behav 2018; 8:12 [View Article] [PubMed]
     [Google Scholar]
  40. Palus M, Bílý T, Elsterová J, Langhansová H, Salát J et al. Infection and injury of human astrocytes by tick-borne encephalitis virus. J Gen Virol 2014; 95:2411–2426 [View Article] [PubMed]
     [Google Scholar]
  41. Pokorna Formanova P, Palus M, Salat J, Hönig V, Stefanik M et al. Changes in cytokine and chemokine profiles in mouse serum and brain, and in human neural cells, upon tick-borne encephalitis virus infection. J Neuroinflammation 2019; 16:205 [View Article] [PubMed]
     [Google Scholar]
  42. Potokar M, Jorgačevski J, Zorec R. Astrocytes in Flavivirus Infections. Int J Mol Sci 2019; 20:E691 [View Article] [PubMed]
     [Google Scholar]
  43. Potokar M, Korva M, Jorgačevski J, Avšič-Županc T, Zorec R. Tick-borne encephalitis virus infects rat astrocytes but does not affect their viability. PLoS One 2014; 9:e86219 [View Article] [PubMed]
     [Google Scholar]
  44. Studahl M, Günther G, Rosengren L. Serum S-100B protein levels in patients with herpes simplex encephalitis and tick-borne encephalitis--a marker of CNS damage during the initial stage of disease. J Neurol 2009; 256:586–590 [View Article] [PubMed]
     [Google Scholar]
  45. Lewis SB, Wolper R, Chi Y-Y, Miralia L, Wang Y et al. Identification and preliminary characterization of ubiquitin C terminal hydrolase 1 (UCHL1) as a biomarker of neuronal loss in aneurysmal subarachnoid hemorrhage. J Neurosci Res 2010; 88:1475–1484 [View Article] [PubMed]
     [Google Scholar]
  46. Tyrberg T, Nilsson S, Blennow K, Zetterberg H, Grahn A. Serum and cerebrospinal fluid neurofilament light chain in patients with central nervous system infections caused by varicella-zoster virus. J Neurovirol 2020; 26:719–726 [View Article] [PubMed]
     [Google Scholar]
  47. Grahn A, Hagberg L, Nilsson S, Blennow K, Zetterberg H et al. Cerebrospinal fluid biomarkers in patients with varicella-zoster virus CNS infections. J Neurol 2013; 260:1813–1821 [View Article] [PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001743
Loading
Serum and cerebrospinal fluid phosphorylated neurofilament heavy subunit as a marker of neuroaxonal damage in tick-borne encephalitis
J. Gen. Virol. 103, 001743 (2022); https://doi.org/10.1099/jgv.0.001743
/content/journal/jgv/10.1099/jgv.0.001743
/content/journal/jgv/10.1099/jgv.0.001743
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error