Plasma markers of neurologic injury and systemic inflammation in individuals with self-reported neurologic post-acute sequelae of SARS-CoV-2 infection (PASC)
Authors: Peluso Michael J. , Sans Hannah M. , Forman Carrie A. , Nylander Alyssa N. , Ho Hsi-en , Lu Scott , Goldberg Sarah A. , Hoh Rebecca , Tai Viva , Munter Sadie E. , Chenna Ahmed , Yee Brandon C. , Winslow John W. , Petropoulos Christos J. , Martin Jeffrey N. , Kelly J. Daniel , Durstenfeld Matthew S. , Hsue Priscilla Y. , Hunt Peter W. , Greene Meredith , Chow Felicia C. , Hellmuth Joanna , Henrich Timothy J. , Glidden David V. , Deeks Steven G. 
Published: November 2021

Background

The biologic mechanisms underlying neurologic post-acute-sequelae of SARS-CoV-2 infection (PASC) are incompletely understood.

Methods

We measured markers of neuronal injury (glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and soluble markers of inflammation among a cohort of people with prior confirmed SARS-CoV-2 infection at early and late recovery following the initial illness (defined as less than and greater than 90 days, respectively). The primary clinical outcome was the presence of self-reported central nervous system (CNS) PASC symptoms during the late recovery timepoint. We compared fold-changes in marker values between those with and without CNS PASC symptoms using linear mixed effects models and examined relationships between neurologic and immunologic markers using rank linear correlations.

Results

Of 121 individuals, 52 reported CNS PASC symptoms. During early recovery, those who went on to report CNS PASC symptoms had elevations in GFAP (1.3-fold higher mean ratio, 95% CI 1.04-1.63, p=0.02), but not NfL (1.06-fold higher mean ratio, 95% CI 0.89-1.26, p=0.54). During late recovery, neither GFAP nor NfL levels were elevated among those with CNS PASC symptoms. Although absolute levels of NfL did not differ, those who reported CNS PASC symptoms demonstrated a stronger downward trend over time in comparison to those who did not report CNS PASC symptoms (p=0.041). Those who went on to report CNS PASC also exhibited elevations in IL-6 (48% higher during early recovery and 38% higher during late recovery), MCP-1 (19% higher during early recovery), and TNF-alpha (19% higher during early recovery and 13% higher during late recovery). GFAP and NfL correlated with levels of several immune activation markers during early recovery; these correlations were attenuated during late recovery.

Conclusions

Self-reported neurologic symptoms present >90 days following SARS-CoV-2 infection are associated with elevations in markers of neurologic injury and inflammation at early recovery timepoints, suggesting that early injury can result in long-term disease. The correlation of GFAP and NfL with markers of systemic immune activation suggests one possible mechanism that might contribute to these symptoms. Additional work is needed to better characterize these processes and to identify interventions to prevent or treat this condition.

Key Points

Question

Do individuals with and without self-reported neurologic symptoms following SARS-CoV-2 infection have different levels of biomarkers of neurologic injury or immune activationã

Findings

In this cohort study of 121 adults, individuals reporting neurologic symptoms beyond 90 days following SARS-CoV-2 infection had higher levels of glial fibrillary acidic protein but not neurofilament light chain. Levels of several markers of inflammation including interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 were also elevated.

Meaning

Post-acute neurologic symptoms following SARS-CoV-2 infection are associated with significant differences in levels of certain biomarkers. Further investigation may provide clues to the biologic pathways underlying these symptoms.