Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

Benedict D. Michael; Cordelia Dunai; Edward J. Needham; Kukatharmini Tharmaratnam; Robyn Williams; Yun Huang; Sarah A. Boardman; Jordan J. Clark; Parul Sharma; Krishanthi Subramaniam; Greta K. Wood; Ceryce Collie; Richard Digby; Alexander Ren; Emma Norton; Maya Leibowitz; Soraya Ebrahimi; Andrew Fower; Hannah Fox; Esteban Tato; Mark A. Ellul; Geraint Sunderland; Marie Held; Claire Hetherington; Franklyn N. Egbe; Alish Palmos; Kathy Stirrups; Alexander Grundmann; Anne-Cecile Chiollaz; Jean-Charles Sanchez; James P. Stewart; Michael Griffiths; Tom Solomon; Gerome Breen; Alasdair J. Coles; Nathalie Kingston; John R. Bradley; Patrick F. Chinnery; Jonathan Cavanagh; Sarosh R. Irani; Angela Vincent; J. Kenneth Baillie; Peter J. Openshaw; Malcolm G. Semple; ISARIC4C Investigators; Tassos Grammatikopoulos; Marlies Ostermann; COVID-CNS Consortium; Alex Dregan; Alish Palmos; Ammar Al-Chalabi; Anthony S. David; Fernando Zelaya; Henry C. Rogers; Matthew Hotopf; Michael P. Lunn; Monika Hartmann; Silvia Rota; Simon Keller; Leonie S. Taams; David K. Menon

doi:10.1038/s41467-023-42320-4

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

Benedict D. Michael^*, Cordelia Dunai, Edward J. Needham, Kukatharmini Tharmaratnam, Robyn Williams, Yun Huang, Sarah A. Boardman, Jordan J. Clark, Parul Sharma, Krishanthi Subramaniam, Greta K. Wood, Ceryce Collie, Richard Digby, Alexander Ren, Emma Norton, Maya Leibowitz, Soraya Ebrahimi, Andrew Fower, Hannah Fox, Esteban TatoMark A. Ellul, Geraint Sunderland, Marie Held, Claire Hetherington, Franklyn N. Egbe, Alish Palmos, Kathy Stirrups, Alexander Grundmann, Anne-Cecile Chiollaz, Jean-Charles Sanchez, James P. Stewart, Michael Griffiths, Tom Solomon, Gerome Breen, Alasdair J. Coles, Nathalie Kingston, John R. Bradley, Patrick F. Chinnery, Jonathan Cavanagh, Sarosh R. Irani, Angela Vincent, J. Kenneth Baillie, Peter J. Openshaw, Malcolm G. Semple, ISARIC4C Investigators, Tassos Grammatikopoulos, Marlies Ostermann, COVID-CNS Consortium, Alex Dregan, Alish Palmos, Ammar Al-Chalabi, Anthony S. David, Fernando Zelaya, Henry C. Rogers, Matthew Hotopf, Michael P. Lunn, Monika Hartmann, Silvia Rota, Simon Keller, Leonie S. Taams, David K. Menon

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.

Original language	English
Article number	8487
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-42320-4
Publication status	Published - 22 Dec 2023

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Michael, B. D., Dunai, C., Needham, E. J., Tharmaratnam, K., Williams, R., Huang, Y., Boardman, S. A., Clark, J. J., Sharma, P., Subramaniam, K., Wood, G. K., Collie, C., Digby, R., Ren, A., Norton, E., Leibowitz, M., Ebrahimi, S., Fower, A., Fox, H., ... Menon, D. K. (2023). Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses. Nature Communications, 14(1), Article 8487. https://doi.org/10.1038/s41467-023-42320-4

@article{b2590a16f1184dd3bd887e44f12c9d97,

title = "Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses",

abstract = "To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.",

author = "Michael, {Benedict D.} and Cordelia Dunai and Needham, {Edward J.} and Kukatharmini Tharmaratnam and Robyn Williams and Yun Huang and Boardman, {Sarah A.} and Clark, {Jordan J.} and Parul Sharma and Krishanthi Subramaniam and Wood, {Greta K.} and Ceryce Collie and Richard Digby and Alexander Ren and Emma Norton and Maya Leibowitz and Soraya Ebrahimi and Andrew Fower and Hannah Fox and Esteban Tato and Ellul, {Mark A.} and Geraint Sunderland and Marie Held and Claire Hetherington and Egbe, {Franklyn N.} and Alish Palmos and Kathy Stirrups and Alexander Grundmann and Anne-Cecile Chiollaz and Jean-Charles Sanchez and Stewart, {James P.} and Michael Griffiths and Tom Solomon and Gerome Breen and Coles, {Alasdair J.} and Nathalie Kingston and Bradley, {John R.} and Chinnery, {Patrick F.} and Jonathan Cavanagh and Irani, {Sarosh R.} and Angela Vincent and Baillie, {J. Kenneth} and Openshaw, {Peter J.} and Semple, {Malcolm G.} and {ISARIC4C Investigators} and Tassos Grammatikopoulos and Marlies Ostermann and {COVID-CNS Consortium} and Alex Dregan and Alish Palmos and Ammar Al-Chalabi and David, {Anthony S.} and Fernando Zelaya and Rogers, {Henry C.} and Matthew Hotopf and Lunn, {Michael P.} and Monika Hartmann and Silvia Rota and Simon Keller and Taams, {Leonie S.} and Menon, {David K.}",

note = "Funding Information: We thank the patients and their loved ones who volunteered to contribute to these studies at one of the most difficult times in their lives, and the research staff in every hospital who recruited patients at personal risk under challenging conditions. This research was funded by the National Institute for Health and Care Research (NIHR) (CO-CIN-01) and jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). B.D.M. is supported by the UKRI/MRC (MR/V03605X/1), the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). C.D. is supported by MRC (MC_PC_19044). We would like to thank the University of Liverpool GCP laboratory facility team for Luminex assistance and the Liverpool University Biobank team for all their help, especially Dr. Victoria Shaw, Lara Lavelle-Langham, and Sue Holden. We would like to acknowledge the Liverpool Experimental Cancer Medicine Centre for providing infrastructure support for this research (Grant Reference: C18616/A25153). We acknowledge the Liverpool Centre for Cell Imaging (CCI) for provision of imaging equipment (Dragonfly confocal microscope) and excellent technical assistance (BBSRC grant number BB/R01390X/1). Tom Solomon is supported by The Pandemic Institute and the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool. D.K.M. and E.N. are supported by the NIHR Cambridge Biomedical Centre and by NIHR funding to the NIHR BioResource (RG94028 and RG85445), and by funding from Brain Research UK 201819-20. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health and Care Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. The authors would like to acknowledge the eDRIS team (Public Health Scotland) for their support in obtaining approvals, the provisioning and linking of data and facilitating access to the National Safe Haven. The views expressed are those of the author(s) and not necessarily those of the UKRI, NHS, the NIHR or the Department of Health and Social Care. T.S. is the Director of The Pandemic Institute which has received funding from Innova and CSL Seqirus and Aviva and DAM Health. T.S. was an advisor to the GSK Ebola Vaccine programme and the Siemens Diagnostic Programme. T.S. Chaired the Siemens Healthineers Clinical Advisory Board. T.S. Co-Chaired the WHO Neuro-COVID task force and sat on the UK Government Advisory Committee on Dangerous Pathogens, and the Medicines and Healthcare Products Regulatory Agency (MHRA) Expert Working Group on Covid-19 vaccines. T.S. Advised to the UK COVID-19 Therapeutics Advisory Panel (UK-TAP). T.S. was a Member of COVID-19 Vaccines Benefit Risk Expert Working Group for the Commission on Human Medicines (CHM) committee of the Medicines and Healthcare products Regulatory Agency (MHRA). T.S. has been a member of the Encephalitis Society since 1998 and President of the Encephalitis Society since 2019. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

day = "22",

doi = "10.1038/s41467-023-42320-4",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Michael, BD, Dunai, C, Needham, EJ, Tharmaratnam, K, Williams, R, Huang, Y, Boardman, SA, Clark, JJ, Sharma, P, Subramaniam, K, Wood, GK, Collie, C, Digby, R, Ren, A, Norton, E, Leibowitz, M, Ebrahimi, S, Fower, A, Fox, H, Tato, E, Ellul, MA, Sunderland, G, Held, M, Hetherington, C, Egbe, FN, Palmos, A, Stirrups, K, Grundmann, A, Chiollaz, A-C, Sanchez, J-C, Stewart, JP, Griffiths, M, Solomon, T, Breen, G, Coles, AJ, Kingston, N, Bradley, JR, Chinnery, PF, Cavanagh, J, Irani, SR, Vincent, A, Baillie, JK, Openshaw, PJ, Semple, MG, ISARIC4C Investigators, Grammatikopoulos, T , Ostermann, M, COVID-CNS Consortium, Dregan, A , Palmos, A , Al-Chalabi, A , David, AS , Zelaya, F , Rogers, HC , Hotopf, M , Lunn, MP , Hartmann, M , Rota, S , Keller, S , Taams, LS & Menon, DK 2023, 'Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses', Nature Communications, vol. 14, no. 1, 8487. https://doi.org/10.1038/s41467-023-42320-4

TY - JOUR

T1 - Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

AU - Michael, Benedict D.

AU - Dunai, Cordelia

AU - Needham, Edward J.

AU - Tharmaratnam, Kukatharmini

AU - Williams, Robyn

AU - Huang, Yun

AU - Boardman, Sarah A.

AU - Clark, Jordan J.

AU - Sharma, Parul

AU - Subramaniam, Krishanthi

AU - Wood, Greta K.

AU - Collie, Ceryce

AU - Digby, Richard

AU - Ren, Alexander

AU - Norton, Emma

AU - Leibowitz, Maya

AU - Ebrahimi, Soraya

AU - Fower, Andrew

AU - Fox, Hannah

AU - Tato, Esteban

AU - Ellul, Mark A.

AU - Sunderland, Geraint

AU - Held, Marie

AU - Hetherington, Claire

AU - Egbe, Franklyn N.

AU - Palmos, Alish

AU - Stirrups, Kathy

AU - Grundmann, Alexander

AU - Chiollaz, Anne-Cecile

AU - Sanchez, Jean-Charles

AU - Stewart, James P.

AU - Griffiths, Michael

AU - Solomon, Tom

AU - Breen, Gerome

AU - Coles, Alasdair J.

AU - Kingston, Nathalie

AU - Bradley, John R.

AU - Chinnery, Patrick F.

AU - Cavanagh, Jonathan

AU - Irani, Sarosh R.

AU - Vincent, Angela

AU - Baillie, J. Kenneth

AU - Openshaw, Peter J.

AU - Semple, Malcolm G.

AU - ISARIC4C Investigators

AU - Grammatikopoulos, Tassos

AU - Ostermann, Marlies

AU - COVID-CNS Consortium

AU - Dregan, Alex

AU - Palmos, Alish

AU - Al-Chalabi, Ammar

AU - David, Anthony S.

AU - Zelaya, Fernando

AU - Rogers, Henry C.

AU - Hotopf, Matthew

AU - Lunn, Michael P.

AU - Hartmann, Monika

AU - Rota, Silvia

AU - Keller, Simon

AU - Taams, Leonie S.

AU - Menon, David K.

N1 - Funding Information: We thank the patients and their loved ones who volunteered to contribute to these studies at one of the most difficult times in their lives, and the research staff in every hospital who recruited patients at personal risk under challenging conditions. This research was funded by the National Institute for Health and Care Research (NIHR) (CO-CIN-01) and jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). B.D.M. is supported by the UKRI/MRC (MR/V03605X/1), the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). C.D. is supported by MRC (MC_PC_19044). We would like to thank the University of Liverpool GCP laboratory facility team for Luminex assistance and the Liverpool University Biobank team for all their help, especially Dr. Victoria Shaw, Lara Lavelle-Langham, and Sue Holden. We would like to acknowledge the Liverpool Experimental Cancer Medicine Centre for providing infrastructure support for this research (Grant Reference: C18616/A25153). We acknowledge the Liverpool Centre for Cell Imaging (CCI) for provision of imaging equipment (Dragonfly confocal microscope) and excellent technical assistance (BBSRC grant number BB/R01390X/1). Tom Solomon is supported by The Pandemic Institute and the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool. D.K.M. and E.N. are supported by the NIHR Cambridge Biomedical Centre and by NIHR funding to the NIHR BioResource (RG94028 and RG85445), and by funding from Brain Research UK 201819-20. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health and Care Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. The authors would like to acknowledge the eDRIS team (Public Health Scotland) for their support in obtaining approvals, the provisioning and linking of data and facilitating access to the National Safe Haven. The views expressed are those of the author(s) and not necessarily those of the UKRI, NHS, the NIHR or the Department of Health and Social Care. T.S. is the Director of The Pandemic Institute which has received funding from Innova and CSL Seqirus and Aviva and DAM Health. T.S. was an advisor to the GSK Ebola Vaccine programme and the Siemens Diagnostic Programme. T.S. Chaired the Siemens Healthineers Clinical Advisory Board. T.S. Co-Chaired the WHO Neuro-COVID task force and sat on the UK Government Advisory Committee on Dangerous Pathogens, and the Medicines and Healthcare Products Regulatory Agency (MHRA) Expert Working Group on Covid-19 vaccines. T.S. Advised to the UK COVID-19 Therapeutics Advisory Panel (UK-TAP). T.S. was a Member of COVID-19 Vaccines Benefit Risk Expert Working Group for the Commission on Human Medicines (CHM) committee of the Medicines and Healthcare products Regulatory Agency (MHRA). T.S. has been a member of the Encephalitis Society since 1998 and President of the Encephalitis Society since 2019. Publisher Copyright: © 2023, The Author(s).

PY - 2023/12/22

Y1 - 2023/12/22

N2 - To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.

AB - To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.

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U2 - 10.1038/s41467-023-42320-4

DO - 10.1038/s41467-023-42320-4

M3 - Article

C2 - 38135686

AN - SCOPUS:85181178155

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 8487

ER -

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

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