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Cited by 90Long-Term Effects of COVID-19COVID-19 Clinical Research StudiesInfectious Encephalopathies and Encephalitis

Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses

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Needham, Edward J, Ren, Alexander L, Digby, Richard J, Norton, Emma J, Ebrahimi, Soraya, Outtrim, Joanne G, Chatfield, Doris A, Manktelow, Anne E +251 more·2022·Brain
DOI 10.1093/brain/awac321PMC PMC9494359

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Abstract

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

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  • COVID-19 is very rarely neuroinvasive, but its impact on the brain might be immune-mediated and cause glial neuroinflammation.

    “Indeed, while COVID-19 is very rarely neuroinvasive [127], its impact on the brain might be immune-mediated [126] and cause glial neuroinflammation [128,129,130].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [129]

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Authors
Needham, E. J., Ren, A. L., Digby, R. J., Norton, E. J., Ebrahimi, S., Outtrim, J. G., Chatfield, D. A., Manktelow, A. E., Leibowitz, M. M., Newcombe, V. F. J., Doffinger, R., Barcenas-Morales, G., Fonseca, C., Taussig, M. J., Burnstein, R. M., Samanta, R. J., Dunai, C., Sithole, N., Ashton, N. J., Zetterberg, H., Gisslén, M., Edén, A., Marklund, E., Openshaw, P. J. M., Dunning, J., Griffiths, M. J., Cavanagh, J., Breen, G., Irani, S. R., Elmer, A., Kingston, N., Summers, C., Bradley, J. R., Taams, L. S., Michael, B. D., Bullmore, E. T., Smith, K. G. C., Lyons, P. A., Coles, A. J., Menon, D. K., Cambridge NeuroCOVID Group, Anwar, F., Allinson, K., Bhatti, J., Bullmore, E. T., Chatfield, D. A., Christmas, D., Coles, A. J., Coles, J. P., Correia, M., Das, T., Fletcher, P. C., Jubb, A. W., Lupson, V. C., Manktelow, A. E., Menon, D. K., Michell, A., Needham, E. J., Newcombe, V. F. J., Outtrim, J. G., Pointon, L., Rodgers, C. T., Rowe, J. B., Rua, C., Sithole, N., Spindler, L. R. B., Stamatakis, E. A., Taylor, J., Valerio, F., Widmer, B., Williams, G. B., Chinnery, P. F., CITIID-NIHR COVID-19 BioResource Collaboration, Allison, J., Alvio, G., Ansaripour, A., Baker, S., Baker, S., Bergamaschi, L., Bermperi, A., Betancourt, A., Biggs, H., Bong, S.-H., Bower, G., Bradley, J. R., Brookes, K., Bucke, A., Bullman, B., Bunclark, K., Butcher, H., Caddy, S., Calder, J., Caller, L., Canna, L., Caputo, D., Chandler, M., Chaudhry, Y., Chinnery, P., Clapham-Riley, D., Cooper, D., Cossetti, C., Crucusio, C., Cruz, I., Curran, M., Coudert, J. D., Bie, E. M. D. D. D., Jesus, R. D., Sa, A. D., Dean, A.-M., Dempsey, K., Dewhurst, E., Stefano, G. D., Domingo, J., Dougan, G., Dunmore, B. J., Elmer, A., Epping, M., Fahey, C., Fawke, S., Feltwell, T., Fernandez, C., Fuller, S., Furlong, A., Georgana, I., George, A., Gleadall, N., Goodfellow, I. G., Gräf, S., Graves, B., Gray, J., Grenfell, R., Gupta, R. K., Hall, G., Hamilton, W., Harris, J., Hein, S., Hess, C., Hewitt, S., Hinch, A., Hodgson, J., Hosmillo, M., Holmes, E., Houldcroft, C., Huang, C., Huhn, O., Hunter, K., Ivers, T., Jahun, A., Jackson, S., Jarvis, I., Jones, E., Jones, H., Jose, S., Josipović, M., Kasanicki, M., Kennet, J., Khokhar, F., King, Y., Kingston, N., Kourampa, J., Gresley, E. L., Laurenti, E., Legchenko, E., Lehner, P. J., Lewis, D., Li, E., Linger, R., Lyons, P. A., Mackay, M., Marioni, J. C., Marsden, J., Martin, J., Matara, C., Matheson, N. J., McMahon, C., Meadows, A., Meloy, S., Mendoza, V., Meredith, L., Mende, N., Mescia, F., Michael, A., Moulton, A., Michel, R., Mwaura, L., Muldoon, F., Nice, F., O’Brien, C., Ocaya, C., O’Donnell, C., Okecha, G., Omarjee, O., Ovington, N., Owehand, W. H., Papadia, S., Paraschiv, R., Parmar, S., Pascuale, C., Patterson, C., Penkett, C., Perales, M., Perera, M., Phelan, I., Pinckert, M., Pointon, L., Polgarova, P., Polwarth, G., Pond, N., Price, J., Ranganath, V., Publico, C., Rastall, R., Ribeiro, C., Richoz, N., Romashova, V., Rossi, S., Rowlands, J., Ruffolo, V., Sambrook, J., Saunders, C., Yarkoni, N. S., Schon, K., Selvan, M., Sharma, R., Shih, J., Smith, K. G. C., Spencer, S., Stefanucci, L., Stark, H., Stephens, J., Stirrups, K. E., Strezlecki, M., Summers, C., Sutcliffe, R., Thaventhiran, J. E. D., Tilly, T., Tong, Z., Tordesillas, H., Treacy, C., Toshner, M., Townsend, P., Treacy, C., Turner, L., Vargas, P., Vergese, B., Ziegenweidt, J. V., Walker, N., Watson, L., Webster, J., Weekes, M. P., Wilson, N. K., Wood, J., Worsley, J., Wylot, M., Yakovleva, A., Zerrudo, C. Y. A. J.-A., Facility, C. N. C. R., Saunders, C., & Elmer, A.
Affiliations
  • University of Cambridge (GB)
  • Department of Clinical Biochemistry and Immunology, Addenbrooke’s Hospital , Cambridge , UK
  • Cambridge Protein Arrays Ltd, Babraham Research Campus , Cambridge , UK
  • Clinical Infection Microbiology and Neuroimmunology, Institute of Infection, Veterinary and Ecological Science , Liverpool , UK
  • University of Gothenburg (SE)
  • Sahlgrenska University Hospital (SE)
  • Imperial College London (GB)
  • University of Oxford (GB)
  • University of Liverpool (GB)
  • University of Glasgow (GB)
  • King's College London (GB)
  • National Institute for Health and Care Research (GB)
  • Cambridge University Hospitals NHS Foundation Trust (GB)
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2022-09-06
Volume
145
Issue
11
Pages
4097-4107
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awac321
PMC
PMC9494359
OpenAlex
W4297463106
Cited by
90
References
0
Citations by year
2026: 9 · 2025: 16 · 2024: 31 · 2023: 27 · 2022: 7
FWCI
10.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • ePrints Soton (University of Southampton) (acceptedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
NIHR Cambridge Biomedical Centre
Topics
  • Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
Keywords
COVID-19 pandemic, brain injury, neuroinflammation, neurofilament light chain, glial fibrillary acidic protein, total tau, autoantibodies, inflammatory cytokines, innate immune response, adaptive immune response, influenza, post-viral syndromes, myelin-associated glycoprotein, lung surfactant proteins, neurological complications
MeSH terms
COVID-19, Autoantibodies, Brain Injuries, Humans, Immunity, Influenza, Human, Biomarkers, Neurofilament Proteins

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