This pilot study indicates that increased concentrations of serum NfL in patients with COVID-19 may be a predictor of a severe disease course and increased mortality GFAp was also significantly associated with mortality. Increased NfL and GFAp concentration in patients with COVID-19 can be presumed to reflect affection of the nervous system. Although both the peripheral and central nervous system contain NfL, the correlation between CSF and blood is so strong that the majority of the NfL concentration must come from the CNS [18, 19]. Furthermore, GFAp is considered to be fairly specific to CNS [20]. The findings of high concentrations of NfL in non-survivors should be further studied in larger COVID-19 cohorts. Our findings are in line with another recent study of serum NfL concentrations in critically ill ICU patients where NfL concentrations were higher in COVID-19 patients than non-COVID-19 patients. Furthermore, higher NfL levels were associated with unfavorable short-term outcome [21].
Of other biomarkers available in this study, increased levels of procalcitonin were apparently associated with increased concentrations of NfL. However, this result is influenced by a few patients with very high measurements. Thus, the implications of these findings are not clear. Interestingly, NfL concentrations were not correlated with CRP and ferritin, often found to be associated hyperinflammation in COVID-19 patients, suggesting that the raised NfL concentrations merely reflect enhanced inflammation.
The association between clinical symptoms and NfL and GFAP in this study must be assessed with caution as the sample size was small. The patients with highest NfL values did all present with headache. Further neurological examination and evaluation was not available as they were all intubated shortly after admission. Furthermore, neuroimaging data were not available. The sample size was too small to draw other conclusions than fatal outcome. The lack of neurological examinations and of neuroimaging data does not allow to take in account the correlation with neurological involvement.
The identification of biomarkers in blood to assess nervous system manifestation will be important to monitor the severity of the disease and optimize treatment in COVID-19 patients. Measurement of NfL and GFAp in blood can be clinically useful methods to assess neurological affection in COVID-19, since this can easily be managed despite medical isolation procedures. Although NfL has been shown to be useful as diagnostic, prognostic and monitoring biomarker in a wide range of other neurological conditions [19, 22,23,24], more studies are needed to assess the applicability of NfL in COVID-19.
One could claim that the high concentrations of NfL could reflect medications used in ICU. However, a recent study of NfL and other blood biomarkers in patients undergoing inhalation general anesthesia showed a decrease in NfL concentrations after 5 h compared to baseline. This may suggest that the levels of NfL in COVID-19 patients treated in ICU might be even larger in magnitude but are masked by anesthesia-induced decreases [25].
The identification of biomarkers in blood to assess nervous system manifestation is important to monitor the severity of the disease and optimize treatment in COVID-19 patients. Measurement of NfL in blood can be a clinically useful tool to assess neurological affection in COVID-19. Although NfL has been shown to be useful as diagnostic, prognostic and monitoring biomarker in a wide range of other neurological conditions [19, 22,23,24], more studies are needed to assess the applicability of NfL in COVID-19.
In this pilot study, there are several limitations. First, the number of patients with full data sets available in this study was modest. Second, detailed and systematic neurological, neurophysiological and neuroradiological investigations were not possible to perform, since our patients were treated under medical isolation procedures at different units and several patients needed ventilatory support in ICUs. Thus, possible association between GFAp and NfL and specific CNS manifestations may have been undetected in this study. However, none of the patients with elevated NfL and GFAP levels had reported chronic neurological disorders. To expand our knowledge on the association between NfL and GFAp with neurological symptoms, we plan a follow-up study of COVID-19 patients up to a year after diagnosis including a systematic neurological assessment.
In conclusion, elevated concentrations of NfL and GFAp in COVID-19 patients seem to be potential prognostic markers in COVID-19. Further studies are essential to elucidate the pathogenesis and the clinical importance of how the COVID-19 disease affects the peripheral and CNS and how this can be measured and treated. Prospective neurologic and cognitive assessment of individuals with COVID-19 will also be crucial to understand the natural history of COVID-19 in the central nervous system and monitor for any long-term neurologic sequelae [26].