Abstract
BackgroundNeurologic 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 wished to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID‐19.MethodPatients 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 analyzed plasma concentrations of neurofilament light‐chain (NfL), glial fibrillary acidic protein (GFAp), and growth differentiation factor 15 (GDF‐15).ResultWe recruited 100 patients with mild (n = 24), moderate (n = 28), and severe (n = 48) COVID‐19 who were followed for a median of (IQR) 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 included fatigue (n = 40), “brain‐fog” (n = 29), and changes in cognition (n = 25). We found no relation between persistent neurological symptoms and CNS injury biomarkers in the acute phase.ConclusionThe normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicate that post‐acute COVID‐19 neurological sequelae are not accompanied by ongoing CNS injury. Although injury biomarkers commonly increase in severe acute COVID‐19, further investigations into the causes of post‐infectious sequelae are needed.
Highlights
Central nervous system (CNS) involvement has been described in coronavirus disease 2019 (COVID-19) patients since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) pandemic.[1,2] Headache, fatigue, dysgeusia, and anosmia are common in both mild and severe cases of COVID-19, while signs of CNS dysfunction, and inflammatory CNS disorders have primarily been reported in patients with severe COVID-19 [2,3,4,5]
We have prospectively examined the dynamic changes in plasma biomarkers of CNS injury (GFAp and neurofilament light chain (NfL)) and persistent neurological symptoms in a cohort of patients with mild, moderate, or severe COVID-19 during the acute phase of the disease, and in subsequent follow-up in comparison with uninfected controls to determine the long-term CNS impact of COVID-19
When assessing the impact of the degree of CNS injury during the acute phase using binary logistic regression, we found that higher biomarker concentrations were not related to any of the symptoms reported at follow-up (Table S3)
Summary
Central nervous system (CNS) involvement has been described in coronavirus disease 2019 (COVID-19) patients since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) pandemic.[1,2] Headache, fatigue, dysgeusia, and anosmia are common in both mild and severe cases of COVID-19, while signs of CNS dysfunction, (including encephalopathy) and inflammatory CNS disorders (including encephalitis) have primarily been reported in patients with severe COVID-19 [2,3,4,5]. Several mechanisms have been proposed as contributing to the neuropathogenesis of SARS-CoV-2. Conclusive evidence of active viral infection of the CNS is still lacking, other effects of SARS-CoV2 infection, including CNS immune activation secondary to systemic inflammatory responses, microvascular injuries, thromboembolic events, or unspecific hypoxic/toxic consequences of severe disease, may all contribute to the neurological manifestations of COVID-19 [1]. We concluded that changes in these CNS damage biomarkers were more pronounced in hospitalized patients compared to nonhospitalized individuals and healthy controls [8]. Results confirming this have subsequently been reported in other studies [9,10]. We sought to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID-19
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