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

Needham, Edward; Ren, Alexander; Digby, Richard; Norton, Emma; Ebrahimi, Soraya; Outtrim, Joanne; Chatfield, Doris A.; Manktelow, Anne; Leibowitz, Maya M.; Newcombe, Virginia; Döffinger, Rainer; Barcenas-Morales, Gabriela; Fonseca, Claudia; Taussig, Michael J.; Burnstein, Rowan; Samanta, Romit; Dunai, Cordelia; Sithole, Nyaradzai; Ashton, Nicholas J.; Zetterberg, Henrik; Gisslén, Magnus; Edén, Arden; Marklund, Emelie; Openshaw, Peter; Dunning, Jake; Griffiths, Michael J.; Cavanagh, Jonathan; Breen, Gerome; Irani, Sarosh R.; Elmer, Anne; Kingston, Nathalie; Summers, Charlotte; Bradley, John R.; Taams, Leonie S.; Michael, Benedict; Bullmore, Edward T.; Smith, Kenneth; Lyons, Paul; Coles, Alasdair; Menon, David K.

doi:10.1093/brain/awac321

Cited by 59 publications

(58 citation statements)

References 54 publications

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“…Acute elevations in NfL and GFAP are associated with raised pro-inflammatory cytokines, and the presence of autoantibodies to lung surfactant protein and myelin-associated glycoprotein. A similar pattern was found in patients after influenza and so may represent a feature of severe viral infection rather than a specific COVID-19 response [33 ▪▪ ]. Months after infection, serum total tau is elevated with resolution of GFAP and NFL elevations towards normal.…”

Section: Biomarkers Of Brain Injurysupporting

confidence: 58%

Neurological complications of critically ill COVID-19 patients

Sonneville

Dangayach

Newcombe

2023

Current Opinion in Critical Care

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Purpose of review COVID-19 and systemic critical illness are both associated with neurological complications. We provide an update on the diagnosis and critical care management of adult patients with neurological complications of COVID-19. Recent findingsLarge prospective multicentre studies conducted in the adult population over the last 18 months improved current knowledge on severe neurological complications of COVID-19. In COVID-19 patients presenting with neurological symptoms, a multimodal diagnostic workup (including CSF analysis, brain MRI, and EEG) may identify different syndromes associated with distinct trajectories and outcomes. Acute encephalopathy, which represents the most common neurological presentation of COVID-19, is associated with hypoxemia, toxic/metabolic derangements, and systemic inflammation. Other less frequent complications include cerebrovascular events, acute inflammatory syndromes, and seizures, which may be linked to more complex pathophysiological processes. Neuroimaging findings include infarction, haemorrhagic stroke, encephalitis, microhaemorrhages and leukoencephalopathy. In the absence of structural brain injury, prolonged unconsciousness is usually fully reversible, warranting a cautious approach for prognostication. Advanced quantitative MRI may provide useful insights into the extent and pathophysiology of the consequences of COVID-19 infection including atrophy and functional imaging changes in the chronic phase. SummaryOur review highlights the importance of a multimodal approach for the accurate diagnosis and management of complications of COVID-19, both at the acute phase and in the long-term.

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Section: Biomarkers Of Brain Injurysupporting

confidence: 58%

Neurological complications of critically ill COVID-19 patients

Sonneville

Dangayach

Newcombe

2023

Current Opinion in Critical Care

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“…Astrocytic end-feet containing glial fibrillary acidic protein (GFAP) are an essential component of the BBB. High blood GFAP is a marker of structural damage in the acute phase of brain injury and a severity-dependent increase has been detected in COVID-19 patients ( 11 , 25 ). These data highlight PPIA, MMP-9, and GFAP as key disease biomarkers, so their measurement in association with NFL, an established marker of brain injury, may help identify a blood signature for disease severity and neurological complications in COVID-19 patients (NeuroCovid).…”

Section: Introductionmentioning

confidence: 99%

“…There is neurochemical evidence of neuronal injury in patients with COVID-19 ( 9 , 10 ), with reports of a severity-dependent increase of neurofilament light chain (NFL) at 4-month follow-up, further supporting ongoing brain injury even weeks and months after acute infection ( 11 ). Not surprisingly, the neurological complications are associated with worse functional outcome, particularly in older subjects and those with comorbidities ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations

et al. 2022

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BackgroundCoronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with disorders affecting the peripheral and the central nervous system. A high number of patients develop post-COVID-19 syndrome with the persistence of a large spectrum of symptoms, including neurological, beyond 4 weeks after infection. Several potential mechanisms in the acute phase have been hypothesized, including damage of the blood-brain-barrier (BBB). We tested weather markers of BBB damage in association with markers of brain injury and systemic inflammation may help in identifying a blood signature for disease severity and neurological complications.MethodsBlood biomarkers of BBB disruption (MMP-9, GFAP), neuronal damage (NFL) and systemic inflammation (PPIA, IL-10, TNFα) were measured in two COVID-19 patient cohorts with high disease severity (ICUCovid; n=79) and with neurological complications (NeuroCovid; n=78), and in two control groups free from COVID-19 history, healthy subjects (n=20) and patients with amyotrophic lateral sclerosis (ALS; n=51). Samples from COVID-19 patients were collected during the first and the second wave of COVID-19 pandemic in Lombardy, Italy. Evaluations were done at acute and chronic phases of the COVID-19 infection.ResultsBlood biomarkers of BBB disruption and neuronal damage are high in COVID-19 patients with levels similar to or higher than ALS. NeuroCovid patients display lower levels of the cytokine storm inducer PPIA but higher levels of MMP-9 than ICUCovid patients. There was evidence of different temporal dynamics in ICUCovid compared to NeuroCovid patients with PPIA and IL-10 showing the highest levels in ICUCovid patients at acute phase. On the contrary, MMP-9 was higher at acute phase in NeuroCovid patients, with a severity dependency in the long-term. We also found a clear severity dependency of NFL and GFAP levels, with deceased patients showing the highest levels.DiscussionThe overall picture points to an increased risk for neurological complications in association with high levels of biomarkers of BBB disruption. Our observations may provide hints for therapeutic approaches mitigating BBB disruption to reduce the neurological damage in the acute phase and potential dysfunction in the long-term.

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“…Thus, it seems more likely that the virus affects the brain indirectly. This could be through peripherally generated inflammatory mediators, immune cells, autoantibodies and/or blood brain barrier changes associated with endothelial damage 12,13 . Immune infiltrates have been found in autopsy studies, including neutrophils and T cells, although agonal effects could not be excluded 14 .…”

Section: Introductionmentioning

confidence: 99%

“…The brain injury markers NfL and GFAP, and inflammatory cytokines are elevated in COVID-19 and scale with severity, but their relationship to neuropathology has not been reported [18][19][20][21] . Finally, specific neuronal autoantibodies have been reported in some neurological patients raising the possibility of para-or post-infectious autoimmunity 12,22 .…”

Section: Introductionmentioning

confidence: 99%

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

Michael

Dunai

Tharmaratnam

et al. 2023

Preprint

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We measured brain injury markers, inflammatory mediators, and autoantibodies in 203 participants with COVID-19; 111 provided acute sera (1-11 days post admission) and 56 with COVID-19-associated neurological diagnoses provided subacute/convalescent sera (6-76 weeks post-admission). Compared to 60 controls, brain injury biomarkers (Tau, GFAP, NfL, UCH-L1) were increased in acute sera, significantly more so for NfL and UCH-L1, in patients with altered consciousness. Tau and NfL remained elevated in convalescent sera, particularly following cerebrovascular and neuroinflammatory disorders. Acutely, inflammatory mediators (including IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) were higher in participants with altered consciousness, and correlated with brain injury biomarker levels. Inflammatory mediators were lower than acute levels in convalescent sera, but levels of CCL2, CCL7, IL-1RA, IL-2Rα, M-CSF, SCF, IL-16 and IL-18 in individual participants correlated with Tau levels even at this late time point. When compared to acute COVID-19 patients with a normal GCS, network analysis showed significantly altered immune responses in patients with acute alteration of consciousness, and in convalescent patients who had suffered an acute neurological complication. The frequency and range of autoantibodies did not associate with neurological disorders. However, autoantibodies against specific antigens were more frequent in patients with altered consciousness in the acute phase (including MYL7, UCH-L1, GRIN3B, and DDR2), and in patients with neurological complications in the convalescent phase (including MYL7, GNRHR, and HLA antigens). In a novel low-inoculum mouse model of SARS-CoV-2, while viral replication was only consistently seen in mouse lungs, inflammatory responses were seen in both brain and lungs, with significant increases in CCL4, IFNγ, IL-17A, and microglial reactivity in the brain. Neurological injury is common in the acute phase and persists late after COVID-19, and may be driven by a para-infectious process involving a dysregulated host response.

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

Cited by 59 publications

References 54 publications

Neurological complications of critically ill COVID-19 patients

Neurological complications of critically ill COVID-19 patients

Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations

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

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