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08.07.2020 | COVID-19 | Letter to the Editors Open Access

Association of neuronal injury blood marker neurofilament light chain with mild-to-moderate COVID-19

Journal of Neurology
Markus Ameres, Susanne Brandstetter, Antoaneta A. Toncheva, Michael Kabesch, David Leppert, Jens Kuhle, Sven Wellmann
Wichtige Hinweise
Jens Kuhle and Sven Wellmann these authors contributed equally to this work.
Dear Sir,
Even though the coronavirus disease 2019 (COVID-19) affects primarily the respiratory system some reports describe nervous system involvement as well [ 13]. Headache and anosmia have been frequently described as neurological symptoms of mild-to-moderate COVID-19 but a direct impact of COVID-19 on neuronal integrity has not been clarified yet [ 4]. Therefore, a neuronal biomarker would be extremely useful to elucidate neuro-axonal injury during an infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and in the post-infection follow-up period. Serum neurofilament light chain (sNfL) has recently been considered as a specific biomarker to quantitate neuro-axonal damage in several disorders of the peripheral and central nervous system [ 5]. Hence, sNfL might also serve as a sensitive screening and follow-up marker for neuronal injury in COVID-19 patients.
We conducted a prospective cohort study in 100 healthcare workers (84 females, 16 males) following a COVID-19 outbreak in a major German children's and women's hospital [ 6]. The Ethics Committee of the University of Regensburg approved the study (file-number: 20-1767-101), and written informed consent was obtained from all study participants. They were categorized according to their SARS-CoV-2 infection status, n = 28 tested positive, n = 72 negative in PCR-based viral RNA amplification from nasopharyngeal swabs (Xpert© Xpress SARS-CoV-2, Cepheid) [ 5]. To preserve anonymity of study participants, age was assessed in three categories (18–35 years n = 33, 36–50 years n = 37 and 51–65 years n = 30) [ 7]. sNfL concentrations were measured using the single molecule array (Simoa) NF-light ® kit on the HD-X Analyzer (Quanterix, Lexington, MA) [ 5]. First, descriptive statistics were calculated. Then, a multivariable linear regression model was fitted with sNfL as dependent variable and with sex, age and COVID-19 status as independent variables.
All COVID-19 patients had mild-to-moderate symptoms and recovered after 1–3 weeks and showed no or only minor neurological symptoms, including anosmia and headache. First, sNfL measurement was done in COVID-19 patients 23 days (median, IQR 21–26) after onset of disease. sNfL levels for COVID-19 patients and for controls, stratified for age group, are depicted in Fig.  1. Median and interquartile range for COVID-19 patients were 4.5 pg/ml [IQR 3.7–5.7] for the age group 18–35 years, 9.6 [6.5–11.3] for the age group 36–50 years, and 11.6 [8.4–18.3] for the age group 51–65 years, respectively. sNFL levels for controls were 4.4 [3.5–5.5] for the youngest group, 6.8 [5.6–8.8] for the group 36–50 years, and 9.6 [8.2–11.2] for the oldest group (Table 1).
Table 1
Baseline characteristics of study participants stratified by COVID-19 status
Non COVID-19 ( n = 72)
COVID-19 ( n = 28)
Female ( N, %)
59 (81.9)
25 (89.3)
Male ( N, %)
13 (18.1)
3 (10.7)
Age group 18–35 years ( N, %)
20 (27.7)
13 (46.4)
Age group 36–50 years ( N, %)
28 (38.9)
9 (32.14)
Age group 51–65 years ( N, %)
24 (33.3)
6 (21.4)
Respiratory symptoms ( N, %)
17 (60.7)
Neurological symptoms ( N, %)
21 (75.0)
Notes: respiratory symptoms included cough and shortness of breath; neurological symptoms included headache and anosmia
Since sNFL levels are highly dependent on age [ 8] the association between COVID-19 status and sNFL was determined using a multivariable linear regression model with COVID-19 status, age and sex as independent variables. This analysis revealed that COVID-19 status was significantly associated with sNfL ( b = 1.87; p = 0.005) when controlling for age and sex (Table 2). In COVID-19 patients with two sNfL measurements ( n = 16, time span between the measurements was median 35 days, range 29–36 days), sNfL levels were highly correlated ( r = 0.96).
Table 2
Multivariable linear regression analysis of sex, age and COVID-19 status on sNfL
Sex (female)
− 0.02
− 0.00
Age group 18–35 years
Reference category
Age group 36–50 years
< 0.001
Age group 51–65 years
< 0.001
Notes: n = 100. Nagelkerke’s R 2 = 0.45; b regression coefficient, SE B standard error (regression coefficient), β standardized regression coefficient, p significance value
NfL is a highly specific structural protein of neurons and elevated levels of sNfL are recognized as measures of acute or chronic neuro-axonal damage [ 5]. Our results from a study in health care workers without known co-morbidities indicate that mild-to-moderate COVID-19 is associated with increased sNfL levels. Neurologic symptoms and complications in patients with SARS-CoV-2 infection have been reported by the first available studies during SARS-CoV-2 pandemic [ 1, 2]. However, these studies are restricted to hospitalized patients and, therefore, represent a population more likely to have severe neurological manifestations for a variety of reasons. Our results indicate for the first time that COVID-19 may affect the neuro-axonal integrity also in adults with a mild-to-moderate course of the disease. This new evidence for a more general neuro-destructive capability of SARS-CoV-2 also in mild-to-moderate COVID-19 patients should raise awareness for potential long-term neurologic sequelae following COVID-19. Of note, our study includes only a limited number of patients. In addition, information on participants’ age was collected using very broad categories and we cannot exclude that there were age differences between COVID-19 patients and controls not accounted for in the statistical adjustment using age groups. To draw further conclusions, additional studies on sNfL and COVID-19 are needed.


Open Access funding provided by Projekt DEAL.

Compliance with ethical standards

Conflicts of interest

Nothing to disclose.

Ethical approval

The Ethics Committee of the University of Regensburg approved the study (file-number: 20-1767-101).
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creativecommons.​org/​licenses/​by/​4.​0/​.

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