Skip to main content

Advertisement

SpringerLink
Log in

COVID-19-associated serum and cerebrospinal fluid cytokines in post- versus para-infectious SARS-CoV-2-related Guillain–Barré syndrome

  • COVID-19
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Introduction

Guillain–Barré syndrome associated with Coronavirus-2-related severe acute respiratory syndrome (COV-GBS) occurs as para- or post-infectious forms, depending on the timing of disease onset. In these two forms, we aimed to compare the cerebrospinal fluid (CSF) and serum proinflammatory cytokine profiles to evaluate differences that could possibly have co-pathogenic relevance.

Materials and methods

We studied a retrospective cohort of 26 patients with either post-COV-GBS (n = 15), with disease onset occurring > 7 days after SARS-CoV-2 infection, or para-COV-GBS (n = 11), with disease onset 7 days or less. TNF-α, IL-6, and IL-8 were measured in the serum with SimplePlex™ Ella™ immunoassay. In addition to the para-/post-COV-GBS patients, serum levels of these cytokines were determined in those with non-COVID-associated-GBS (NC-GBS; n = 43), paucisymptomatic SARS-CoV-2 infection without GBS (COVID, n = 20), and in healthy volunteers (HV; n = 12). CSF cytokine levels were measured in patients with para-/post-COV-GBS, in those with NC-GBS (n = 29), or with Alzheimer’s disease (AD; n = 24).

Results

Serum/CSF cytokine levels did not differ in para- vs post-COV-GBS. We found that SARS-CoV-2 infection raises the serum levels of TNF-α, IL-6, and IL-8, as well as an increase of IL-6 (in serum and CSF) and IL-8 (in CSF) in either NC-GBS or COV-GBS than controls. CSF and serum cytokine levels resulted independent one with another.

Conclusions

The change of cytokines linked to SARS-CoV-2 in COV-GBS appears to be driven by viral infection, although it has unique characteristics in GBS as such and does not account for cases with para- or post-infectious onset.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Data are available upon reasonable request from the corresponding author.

References

  1. Van den Berg B, Walgaard C, Drenthen J et al (2014) Guillain-Barré syndrome: pathogenesis, diagnosis, treatment and prognosis. Nat Rev Neurol 10:469–482. https://doi.org/10.1038/nrneurol.2014.121

    Article  CAS  PubMed  Google Scholar 

  2. Zhao H, Shen D, Zhou H et al (2020) Guillain-Barré; syndrome associated with SARS-CoV-2 infection: causality or coincidence? Lancet Neurol 19:383–384. https://doi.org/10.1016/S1474-4422(20)30109-5

    Article  CAS  PubMed  PubMed Central  MATH  Google Scholar 

  3. Abu-Rumeileh S, Abdelhak A, Foschi M et al (2021) Guillain-Barré syndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases. J Neurol 268:1133–1170. https://doi.org/10.1007/s00415-020-10124-x

    Article  CAS  PubMed  Google Scholar 

  4. Masuccio FG, Tipa V, Invernizzi M, Solaro C (2022) Guillain-Barré syndrome related and unrelated to COVID-19: clinical follow-up in the COVID-19 era. Phys Ther pzac049. https://doi.org/10.1093/ptj/pzac049

  5. Paterson RW, Brown RL, Benjamin L et al (2020) The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain 143:3104–3120. https://doi.org/10.1093/brain/awaa240

    Article  PubMed  PubMed Central  MATH  Google Scholar 

  6. Ottaviani D, Boso F, Tranquillini E et al (2020) Early Guillain-Barré syndrome in coronavirus disease 2019 (COVID-19): a case report from an Italian COVID-hospital. Neurol Sci 41:1351–1354. https://doi.org/10.1007/s10072-020-04449-8

    Article  PubMed  PubMed Central  Google Scholar 

  7. Alberti P, Beretta S, Piatti M et al (2020) Guillain-Barré syndrome related to COVID-19 infection. Neurol Neuroimmunol Neuroinflamm 7:e741. https://doi.org/10.1212/NXI.0000000000000741

    Article  PubMed  PubMed Central  Google Scholar 

  8. Abolmaali M, Heidari M, Zeinali M et al (2021) Guillain-Barré syndrome as a parainfectious manifestation of SARS-CoV-2 infection: a case series. J Clin Neurosci 83:119–122. https://doi.org/10.1016/j.jocn.2020.11.013

    Article  CAS  PubMed  Google Scholar 

  9. Parra B, Lizarazo J, Jiménez-Arango JA et al (2016) Guillain-Barré syndrome associated with Zika virus infection in Colombia. N Engl J Med 375:1513–1523. https://doi.org/10.1056/nejmoa1605564

    Article  PubMed  Google Scholar 

  10. Uncini A, Shahrizaila N, Kuwabara S (2017) Zika virus infection and Guillain-Barré syndrome: a review focused on clinical and electrophysiological subtypes. J Neurol Neurosurg Psychiatry 88:266 LP – 271. https://doi.org/10.1136/jnnp-2016-314310

  11. Grisanti SG, Franciotta D, Garnero M et al (2021) A case series of parainfectious Guillain-Barré syndrome linked to influenza A (H1N1) virus infection. J Neuroimmunol 357:577605. https://doi.org/10.1016/J.JNEUROIM.2021.577605

    Article  CAS  PubMed  Google Scholar 

  12. Nyati KK, Prasad KN (2014) Role of cytokines and toll-like receptors in the immunopathogenesis of Guillain-Barré syndrome. Mediators Inflamm 2014:758639. https://doi.org/10.1155/2014/758639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hu B, Huang S, Yin L (2021) The cytokine storm and COVID-19. J Med Virol 93:250–256. https://doi.org/10.1002/jmv.26232

    Article  CAS  PubMed  MATH  Google Scholar 

  14. Houston H, Hakki S, Pillay TD et al (2022) Broadening symptom criteria improves early case identification in SARS-CoV-2 contacts. Eur Respir J 60:2102308. https://doi.org/10.1183/13993003.02308-2021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Asbury AK, Cornblath DR (1990) Assessment of current diagnostic criteria for Guillain-Barré syndrome. Ann Neurol 27:S21–S24. https://doi.org/10.1002/ana.410270707

    Article  PubMed  MATH  Google Scholar 

  16. Hadden RDM, Cornblath DR, Hughes RAC et al (1998) Electrophysiological classification of Guillain-Barre syndrome: clinical associations and outcome. Ann Neurol 44:780–788. https://doi.org/10.1002/ana.410440512

    Article  CAS  PubMed  MATH  Google Scholar 

  17. Uncini A, Manzoli C, Notturno F, Capasso M (2010) Pitfalls in electrodiagnosis of Guillain–Barré syndrome subtypes. J Neurol Neurosurg Psychiatry 81:1157 LP – 1163. https://doi.org/10.1136/jnnp.2010.208538

  18. Hughes RAC, Newsom-Davis JM, Perkin GD, Pierce JM (1978) Controlled trial of prednisolone in acute polyneuropathy. The Lancet 312:750–753. https://doi.org/10.1016/S0140-6736(78)92644-2

    Article  Google Scholar 

  19. Teunissen CE, Petzold A, Bennett JL et al (2009) A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology 73:1914–1922. https://doi.org/10.1212/WNL.0b013e3181c47cc2

    Article  CAS  PubMed  PubMed Central  MATH  Google Scholar 

  20. Jack CR, Bennett DA, Blennow K et al (2018) NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimer’s Dement 14:535–562. https://doi.org/10.1016/j.jalz.2018.02.018

    Article  MATH  Google Scholar 

  21. Maimone D, Annunziata P, Simone IL et al (1993) Interleukin-6 levels in the cerebrospinal fluid and serum of patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. J Neuroimmunol 47:55–61. https://doi.org/10.1016/0165-5728(93)90284-6

    Article  CAS  PubMed  Google Scholar 

  22. Tandon M, Kataria S, Patel J et al (2021) A comprehensive systematic review of CSF analysis that defines neurological manifestations of COVID-19. Int J Infect Dis 104:390–397. https://doi.org/10.1016/j.ijid.2021.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Alexopoulos H, Magira E, Bitzogli K et al (2020) Anti–SARS-CoV-2 antibodies in the CSF, blood-brain barrier dysfunction, and neurological outcome. Neurol - Neuroimmunol Neuroinflamm 7:e893. https://doi.org/10.1212/NXI.0000000000000893

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jarius S, Pache F, Körtvelyessy P et al (2022) Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients. J Neuroinflammation 19:19. https://doi.org/10.1186/s12974-021-02339-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Caso F, Costa L, Ruscitti P et al (2020) Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects? Autoimmun Rev 19:102524. https://doi.org/10.1016/j.autrev.2020.102524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM et al (2020) SARS-CoV-2 infection: the role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev 54:62–75. https://doi.org/10.1016/j.cytogfr.2020.06.001

    Article  CAS  PubMed  PubMed Central  MATH  Google Scholar 

  27. Debnath M, Nagappa M, Dutta D et al (2020) Evidence of altered Th17 pathway signatures in the cerebrospinal fluid of patients with Guillain Barré Syndrome. J Clin Neurosci 75:176–180. https://doi.org/10.1016/J.JOCN.2020.03.010

    Article  CAS  PubMed  Google Scholar 

  28. Manganotti P, Bellavita G, Tommasini V et al (2021) Cerebrospinal fluid and serum interleukins 6 and 8 during the acute and recovery phase in COVID-19 neuropathy patients. J Med Virol 93:5432. https://doi.org/10.1002/JMV.27061

    Article  CAS  PubMed  PubMed Central  MATH  Google Scholar 

  29. Breville G, Lascano AM, Roux-Lombard P et al (2021) Interleukin 8, a biomarker to differentiate Guillain-Barré syndrome from CIDP. Neurol Neuroimmunol Neuroinflamm 8:e1031. https://doi.org/10.1212/NXI.0000000000001031

    Article  PubMed  PubMed Central  MATH  Google Scholar 

  30. Hesse R, Wahler A, Gummert P et al (2016) Decreased IL-8 levels in CSF and serum of AD patients and negative correlation of MMSE and IL-1β. BMC Neurol 16:185. https://doi.org/10.1186/s12883-016-0707-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Swardfager W, Lanctôt K, Rothenburg L et al (2010) A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68:930–941. https://doi.org/10.1016/j.biopsych.2010.06.012

    Article  CAS  PubMed  Google Scholar 

  32. Lattanzi R, Maftei D, Petrella C et al (2019) Involvement of the chemokine prokineticin-2 (PROK2) in Alzheimer’s disease: from animal models to the human pathology. Cells 8. https://doi.org/10.3390/CELLS8111430

  33. Bonetto V, Pasetto L, Lisi I et al (2022) Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations. Front Immunol 13. https://doi.org/10.3389/FIMMU.2022.1070379

  34. Senel M, Abu-Rumeileh S, Michel D et al (2020) Miller-Fisher syndrome after COVID-19: neurochemical markers as an early sign of nervous system involvement. Eur J Neurol 27. https://doi.org/10.1111/ene.14473

  35. Paterson RW, Benjamin LA, Mehta PR et al (2021) Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes. Brain Commun 3. https://doi.org/10.1093/braincomms/fcab099

  36. Schirinzi T, Lattanzi R, Maftei D et al (2023) Substance P and prokineticin-2 are overexpressed in olfactory neurons and play differential roles in persons with persistent post-COVID-19 olfactory dysfunction. Brain Behav Immun 108. https://doi.org/10.1016/j.bbi.2022.12.017

  37. Abdelhak A, Barba L, Romoli M et al (2023) Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis. J Neurol 270. https://doi.org/10.1007/s00415-023-11768-1

  38. Sievert T, Didriksson I, Spångfors M et al (2023) Neurofilament light chain on intensive care admission is an independent predictor of mortality in COVID-19: a prospective multicenter study. Intensive Care Med Exp 11. https://doi.org/10.1186/s40635-023-00547-x

Download references

Acknowledgements

We would like to thank the Italian Ministry of Health for supporting our research. A.S. and L.B. are members of the ERN-NMD.

Funding

This research was supported by grants from the Italian Ministry of Health (Fondi per la Ricerca Corrente), #NEXTGENERATIONEU (NGEU), and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), and project MNESYS (PE0000006)—a multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022).

Author information

Authors and Affiliations

  1. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genova, Largo Paolo Daneo 3, 16132, Genova, Italy

    Federico Massa, Margherita Bellucci, Debora Giunti, Davide Visigalli, Giovanna Capodivento, Denise Cerne, Antonio Uccelli, Angelo Schenone & Luana Benedetti

  2. IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genova, Italy

    Federico Massa, Tiziana Vigo, Debora Giunti, Maria Mobilia Emanuela, Davide Visigalli, Giovanna Capodivento, Antonio Uccelli, Angelo Schenone & Luana Benedetti

  3. Neurology Unit, Galliera Hospital, Via Mura Delle Cappuccine 14, 1628, Genova, Italy

    Andrea Assini

  4. Department of Infectious Diseases, Galliera Hospital, Via Mura Delle Cappuccine 14, 1628, Genoa, Italy

    Silvia Boni

  5. Neurology Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genova, Italy

    Domenica Rizzi

  6. Department of Neurology, ASL3 Genovese, Corso Onofrio Scassi 1, 16149, Genova, Italy

    Eleonora Narciso

  7. Department of Neurology, Santa Corona Hospital, Viale XXV Aprile 38, 17027, Pietra Ligure, Savona, Italy

    Giuseppe Stefano Grisanti & Elena Coco

  8. IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy

    Diego Franciotta

Authors
  1. Federico Massa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tiziana Vigo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Margherita Bellucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Debora Giunti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Mobilia Emanuela
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Davide Visigalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giovanna Capodivento
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Denise Cerne
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Andrea Assini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Silvia Boni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Domenica Rizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eleonora Narciso
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Giuseppe Stefano Grisanti
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Elena Coco
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Antonio Uccelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Angelo Schenone
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Diego Franciotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Luana Benedetti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Federico Massa.

Ethics declarations

Ethical approval

 Ethical review and approval were waived for this study due to its retrospective nature. All procedures were performed in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study. All subjects consented to publish their anonymized data for research purposes according to the university hospital’s rules for using retrospective data collected during the clinical routine.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Ethical statement

The paper reflects the authors’ own research and analysis in a truthful and complete manner. It has not been previously published elsewhere, nor is being considered for publication elsewhere. All authors have been personally and actively involved in substantial work leading to the paper, and will take public responsibility for its content.

Massa Federico and Vigo Tiziana contributed equally as first authors.

Franciotta Diego and Benedetti Luana contributed equally as last authors.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 18 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Massa, F., Vigo, T., Bellucci, M. et al. COVID-19-associated serum and cerebrospinal fluid cytokines in post- versus para-infectious SARS-CoV-2-related Guillain–Barré syndrome. Neurol Sci 45, 849–859 (2024). https://doi.org/10.1007/s10072-023-07279-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-023-07279-6

Keywords

Search

Navigation