Quantification of Neurological Blood-Based Biomarkers in Critically Ill Patients With Coronavirus Disease 2019

Cooper, Jennifer; Stukas, Sophie; Hoiland, Ryan L.; Fergusson, Nicholas A; Thiara, Sonny; Foster, Denise; Mitra, Anish R; Stoessl, A. Jon; Panenka, William J.; Sekhon, Mypinder S.; Wellington, Cheryl L.

doi:10.1097/cce.0000000000000238

Cited by 44 publications

(61 citation statements)

References 27 publications

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“…We concluded that changes in these CNS damage biomarkers were more pronounced in hospitalized patients compared to non-hospitalized individuals and healthy controls [8] . Results confirming this have subsequently been reported in other studies [ 9 , 10 ]. In addition, in the search for useful biomarkers to predict COVID-19 outcomes, cytokine growth differentiation factor 15 (GDF-15) was recently proposed as a biomarker of general disease severity and unfavourable outcomes [11] .…”

Section: Introductionsupporting

confidence: 92%

Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up

Kanberg¹,

Simrén²,

Edén³

et al. 2021

EBioMedicine

124

116

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Background Neurologic manifestations are well-recognized features of coronavirus disease 2019 (COVID-19). However, the longitudinal association of biomarkers reflecting CNS impact and neurological symptoms is not known. We sought to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID-19. Methods Patients with confirmed acute COVID-19 were studied prospectively. Neurological symptoms were recorded during the acute phase of the disease and at six months follow-up, and blood samples were collected longitudinally. Healthy age-matched individuals were included as controls. We analysed plasma concentrations of neurofilament light-chain (NfL), glial fibrillary acidic protein (GFAp), and growth differentiation factor 15 (GDF-15). Findings One hundred patients with mild ( n = 24), moderate ( n = 28), and severe ( n = 48) COVID-19 were followed for a median (IQR) of 225 (187–262) days. In the acute phase, patients with severe COVID-19 had higher concentrations of NfL than all other groups (all p < 0·001), and higher GFAp than controls ( p < 0·001). GFAp was also significantly increased in moderate disease ( p < 0·05) compared with controls. NfL ( r = 0·53, p < 0·001) and GFAp ( r = 0·39, p < 0·001) correlated with GDF-15 during the acute phase. After six months, NfL and GFAp concentrations had normalized, with no persisting group differences. Despite this, 50 patients reported persistent neurological symptoms, most commonly fatigue ( n = 40), “brain-fog” ( n = 29), and changes in cognition ( n = 25). We found no correlation between persistent neurological symptoms and CNS injury biomarkers in the acute phase. Interpretation The normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicates that post COVID-19 neurological sequelae are not accompanied by ongoing CNS injury. Funding The Swedish State Support for Clinical Research, SciLifeLab Sweden, and the Knut and Alice Wallenberg Foundation have provided funding for this project.

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Section: Introductionsupporting

confidence: 92%

Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up

Kanberg¹,

Simrén²,

Edén³

et al. 2021

EBioMedicine

124

116

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“…In a relatively small study including as controls ICU patients with pneumonia of other etiology, patients with COVID-19 were found to have significantly higher blood GFAP levels. Furthermore, GFAP, UCH-L1, and NfL positively correlated with Intensive Care Delirium Screening Checklist score and were increased in patients with delirium in the COVID-19 group but not in the ICU controls [ 24 ]. In another study, NfL and GFP blood levels measured at hospitalization were found to be more elevated in patients with fatal outcome [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…A small study investigating a large number of biomarkers, has found elevated total tau levels in blood extracellular vesicles in COVID-19 patients as compared to historical controls [ 26 ]. Finally, no associations were found between NfL, GFAP, UCH-L1 or tau and respiratory function or cytokines in COVID-19 patients [ 24 ]. The measures in all these studies were performed in samples not obtained early at hospital admission, but rather during disease course or even in the ICU.…”

Section: Discussionmentioning

confidence: 99%

Blood neurofilament light chain and total tau levels at admission predict death in COVID-19 patients

et al. 2021

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Background and aims Patients infected with SARS-CoV-2 range from asymptomatic, to mild, moderate or severe disease evolution including fatal outcome. Thus, early predictors of clinical outcome are highly needed. We investigated markers of neural tissue damage as a possible early sign of multisystem involvement to assess their clinical prognostic value on survival or transfer to intensive care unit (ICU). Methods We collected blood from 104 patients infected with SARS-CoV-2 the day of admission to the emergency room and measured blood neurofilament light chair (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and total tau protein levels. Results We found that NfL, GFAP, and tau were significantly increased in patients with fatal outcome, while NfL and UCH-L1 in those needing ICU transfer. ROC and Kaplan–Meier curves indicated that total tau levels at admission accurately predict mortality. Conclusions Blood neural markers may provide additional prognostic value to conventional biomarkers used to predict COVID-19 outcome. Supplementary Information The online version contains supplementary material available at 10.1007/s00415-021-10595-6.

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“…Although peripheral axonal injury can potentially contribute to increased plasma concentrations of NfL and GFAp, a strong correlation between plasma and CSF concentration was seen in patients with neurological symptoms, suggesting that plasma levels parallel CSF levels in patients with neuro‐COVID (Virhammar, Naas, et al., 2020). In critically ill patients treated in the ICU, significantly higher plasma GFAp was seen in patients with COVID‐19 than in patients with respiratory failure due to other causes (Cooper et al., 2020). Higher plasma NfL was also seen in patients with delirium.…”

Section: Csf and Serum Biomarkers Of Cns Involvement In Covid‐19mentioning

confidence: 99%

“…Higher plasma NfL was also seen in patients with delirium. However, patients with COVID‐19 were older than controls and the number of patients were small, making the evaluation of results uncertain (Cooper et al., 2020). Higher serum NfL was also seen in 29 COVID‐19 ICU patients compared to 10 general ICU patients after adjusting for neurological comorbidities and age (Sutter et al., 2020) Although these studies are limited in size, results may indicate that additional neuronal damage can potentially be associated with COVID‐19 beyond what is seen a non‐COVID‐19 ICU population.…”

Section: Csf and Serum Biomarkers Of Cns Involvement In Covid‐19mentioning

confidence: 99%

Neurochemical biomarkers to study CNS effects of COVID‐19: A narrative review and synthesis

Edén

Simrén

Price

et al. 2021

Journal of Neurochemistry

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Neurological symptoms are frequently reported in patients suffering from COVID‐19. Common CNS‐related symptoms include anosmia, caused by viral interaction with either neurons or supporting cells in nasal olfactory tissues. Diffuse encephalopathy is the most common sign of CNS dysfunction, which likely results from the CNS consequences of the systemic inflammatory syndrome associated with severe COVID‐19. Additionally, microvascular injuries and thromboembolic events likely contribute to the neurologic impact of acute COVID‐19. These observations are supported by evidence of CNS immune activation in cerebrospinal fluid (CSF) and in autopsy tissue, along with the detection of microvascular injuries in both pathological and neuroimaging studies. The frequent occurrence of thromboembolic events in patients with COVID‐19 has generated different hypotheses, among which viral interaction with perivascular cells is particularly attractive, yet unproven. A distinguishing feature of CSF findings in SARS‐CoV‐2 infection is that clinical signs characteristic of neurotropic viral infections (CSF pleocytosis and blood–brain barrier injury) are mild or absent. Moreover, virus detection in CSF is rare and often of uncertain significance. In this review, we provide an overview of the neurological impact that occurs in the acute phase of COVID‐19, and the role of CSF biomarkers in the clinical management and research to better treat and understand the disease. In addition to aiding as diagnostic and prognostic tools during acute infection, the use of comprehensive and well‐characterized CSF and blood biomarkers will be vital in understanding the potential impact on the CNS in the rapidly increasing number of individuals recovering from COVID‐19.

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Quantification of Neurological Blood-Based Biomarkers in Critically Ill Patients With Coronavirus Disease 2019

Abstract: Supplemental Digital Content is available in the text.

Cited by 44 publications

References 27 publications

Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up

Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up

Blood neurofilament light chain and total tau levels at admission predict death in COVID-19 patients

Neurochemical biomarkers to study CNS effects of COVID‐19: A narrative review and synthesis

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