Serum Neurofilament Light Chain Levels in the Intensive Care Unit: Comparison between Severely Ill Patients with and without Coronavirus Disease 2019

Sutter, Raoul; Hert, Lisa; Marchis, Gian Marco De; Twerenbold, Raphael; Kappos, Ludwig; Naegelin, Yvonne; Kuster, Gabriela M.; Benkert, Pascal; Jost, Jasmine; Maceski, Aleksandra; Rüegg, Stephan; Siegemund, Martin; Leppert, David; Tschudin‐Sutter, Sarah; Kühle, Jens

doi:10.1002/ana.26004

Cited by 73 publications

(82 citation statements)

References 20 publications

(25 reference statements)

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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

120

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

120

116

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“…Levels of serum Nfl have been found to be elevated in subjects with a number of neurological degenerative diseases (12), (13), (14), (15), as well as those with acute conditions such as hypoxic brain injury (16), cardiac and related surgeries (17), (18), and traumatic brain injury (19). Recent studies have found increased levels of Nfl in COVID-19 patients (20), (21),(22) but the effects of concomitant systemic inflammatory disease such as cardiac disease or diabetes on neuronal injury as measured by NfL in COVID-19 patients has not been previously reported. In the present study we examined the relationship between levels of serum Nfl in COVID-19 positive ICU patients and the presence of cardiovascular disease, diabetes, and acute neurological complications.…”

Section: Introductionmentioning

confidence: 99%

Serum Neurofilament Light is Elevated in COVID-19 Positive Adults in the ICU and is Associated with Co-Morbid Cardiovascular Disease, Neurological Complications, and Acuity of Illness

Hay

Ryan

Huentelman

et al. 2021

Preprint

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In critically ill COVID-19 patients, the risk of long-term neurological consequences is just beginning to be appreciated. While recent studies have identified that there is an increase in structural injury to the nervous system in critically ill COVID-19 patients, there is little known about the relationship of COVID-19 neurological damage to the systemic inflammatory diseases also observed in COVID-19 patients. The purpose of this pilot observational study was to examine the relationships between serum neurofilament light protein (NfL, a measure of neuronal injury) and co-morbid cardiovascular disease (CVD) and neurological complications in COVID-19 positive patients admitted to the intensive care unit (ICU). In this observational study of one-hundred patients who were admitted to the ICU in Tucson, Arizona between April and August 2020, 89 were positive for COVID-19 (COVID-pos) and 11 were COVID-negative (COVID-neg). A healthy control group (n=8) was examined for comparison. The primary outcomes and measures were subject demographics, serum NfL, presence and extent of CVD, diabetes, sequential organ failure assessment score (SOFA), presence of neurological complications, and blood chemistry panel data. COVID-pos patients in the ICU had significantly higher mean levels of Nfl (229.6±163 pg/ml) compared to COVID-neg ICU patients (19.3±5.6 pg/ml), Welch’s t-test, p =.01 and healthy controls (12.3±3.1 pg/ml), Welch’s t-test p =.005. Levels of Nfl in COVID-pos ICU patients were significantly higher in patients with concomitant CVD and diabetes (n=35, log Nfl 1.6±.09), and correlated with higher SOFA scores (r=.5, p =.001). These findings suggest that in severe COVID-19 disease, the central neuronal and axonal damage in these patients may be driven, in part, by the level of systemic cardiovascular disease and peripheral inflammation. Understanding the contributions of systemic inflammatory disease to central neurological degeneration in these COVID-19 survivors will be important to the design of interventional therapies to prevent long-term neurological and cognitive dysfunction.

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“…Biomarkers re ecting nervous system damage in COVID-19 patients A prospective study showed that total Tau, GFAP, and NFL protein levels in cerebrospinal uid were elevated in 63%, 37%, and 16% of patients, respectively, and NFL protein was associated with disease severity, duration of intensive care and level of consciousness [110] .Multiple studies on COVID-19 patients with ischemic stroke have shown that the neutrophil-lymphocyte ratio (NLR) is increased in 90% of the patients [111] , CRP is increased in over 90% of the patients [112] , and serum ferritin is also increased [113] , in which serum ferritin can also predict the degree of nerve injury in patients with acute ischemic stroke [114] .There was a signi cant correlation between the decrease of interleukin-6 level and the improvement of olfaction and taste function in COVID-19 patients [115] .Elevated serum nerve lament light chain (SNFL) levels in critically ill patients with COVID-19 are closely associated with poor prognosis [116] .…”

Section: Evidence Of Neurological Damage In Covid-19 Patientsmentioning

confidence: 99%

What can the neurological manifestations of COVID-19 tell us : a meta-analysis

Bai

Zhu

et al. 2021

Preprint

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Background Covid-19 became a global pandemic in 2019. Studies have shown that coronavirus can cause neurological symptoms, but clinical studies on its neurological symptoms are limited. In this meta-analysis, we aim to gather and discuss COVID-19 various neurological symptoms of infection, and to assess the prevalence of each of the nervous system symptoms, and characterized by neurological in-depth discussions of nervous system damage mechanism, biomarkers and inspection methods, recovery and prognosis, and provide the research behind the potential target and direction. Methods We systematically searched all published English literature related to the neurological manifestations of COVID-19 from January 1, 2020 to November 20, 2020 in Pubmed, Embase, and Cochrane library.The keywords used were COVID-19 and terminology related to nervous system performance.All included studies were selected by two independent reviewers using EndNote and NoteExpress software, any disagreement was resolved by consensus or by a third reviewer, and the selected data was then collected for meta-analysis using a random-effects model. Results A total of 62 articles (n =32729) were included in the study, and the meta-analysis showed that the most common neurological manifestations of COVID-19 were altered mental status (39% ; 95% CI 0.17-0.64 ; I 2 98.59%), encephalopathy (37% ; 95% CI 0.17-0.60 ; I 2 97.36%), myalgia(31% ; 95% CI 0.25-0.38; I 2 98.79%), headache(30% ; 95% CI 0.22-0.37; I 2 99.28%), smell impairment(28% ; 95% CI 99.57% ; I 2 0.17-0.39), taste dysfunction (27% ; 95% CI 0.18 -0.38 ; I 2 99.35%), acute ischemic stroke (23% ; 95% CI 0.06-0.47 ; I 2 99.30%), alteration of consciousness(17% ; 95% CI 0.06-0.31 ; I 2 96.78%), dizziness (10% ; 95% CI 0.06-0.15; I 2 95.30%), intracerebral haemorrhage (7% ; 95% CI 0.02-0.14 ; I 2 93.64%), vision impairment(5% ; 95% CI 0.02-0.10 ; I 2 92.73%), seizure(2% ; 95% CI 0.01-0.04 ; I 2 84.67%). Conclusions Neurological symptoms are common and varied in Covid-19 infections, and a growing number of reports suggest that the prevalence of neurological symptoms may be increasing. In the future, the role of COVID-19 neurological symptoms in the progression of COVID-19 should be further studied, and its pathogenesis and assessment methods should be explored, so as to detect and treat early neurological complications of COVID-19 and reduce mortality.

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Serum Neurofilament Light Chain Levels in the Intensive Care Unit: Comparison between Severely Ill Patients with and without Coronavirus Disease 2019

Cited by 73 publications

References 20 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

Serum Neurofilament Light is Elevated in COVID-19 Positive Adults in the ICU and is Associated with Co-Morbid Cardiovascular Disease, Neurological Complications, and Acuity of Illness

What can the neurological manifestations of COVID-19 tell us : a meta-analysis

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