Plasma Markers of Neurologic Injury and Inflammation in People With Self-Reported Neurologic Postacute Sequelae of SARS-CoV-2 Infection

Abstract

Background and ObjectivesThe biologic mechanisms underlying neurologic postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are incompletely understood.MethodsWe measured markers of neurologic 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 after the initial illness (defined as less than and greater than 90 days, respectively). The primary clinical outcome was the presence of self-reported CNS PASC symptoms during the late recovery time point. 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.ResultsOf 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 with those who did not report CNS PASC symptoms (p = 0.041). Those who went on to report CNS PASC also exhibited elevations in interleukin 6 (48% higher during early recovery and 38% higher during late recovery), monocyte chemoattractant protein 1 (19% higher during early recovery), and tumor necrosis factor α (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.DiscussionSelf-reported neurologic symptoms present approximately 4 months after SARS-CoV-2 infection are associated with elevations in markers of neurologic injury and inflammation at earlier time points. Some inflammatory pathways seem to be involved months after acute infection. Additional work will be needed to better characterize these processes and to identify interventions to prevent or treat this condition.

Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID

“…Although CMV seropositivity was not completely protective against Long COVID in our study, the differential effects of CMV serostatus on acute versus Long COVID suggests that assessment of CMV serostatus may be important in future mechanistic evaluations of COVID-19. Indeed, since CMV seropositivity is associated with increased systemic inflammation, but a decreased risk of Long COVID, adjusting for CMV serostatus actually strengthened our previously reported associations between systemic inflammation and Long COVID symptoms (3, 33). This finding suggests that sources of inflammation unrelated to CMV are most likely driving PASC risk in COVID-19 survivors and highlights the importance of the source of inflammation - as opposed to simply systemic inflammation itself - in mediating the risk of PASC.…”

“…We previously identified significant correlations between various markers of inflammation and LC symptoms, such as IL-6 and TNFα (3, 33, 34). As a result, we examined the relationship between EBV and CMV antibody results in a subset of 143 participants (24 with HIV) who had circulating biomarker data as measured on the HD-X Simoa platform available including markers of neuronal injury, inflammation and immune activation (glial fibrillary acidic protein [GFAP, a marker of astrocyte activation], neurofilament light chain [NFL, a marker of neuronal injury], monocyte Chemoattractant Protein-1 [MCP-1], IFNγ, IL-6, IL-10, TNFα, and IP-10).…”

“…We and others have previously reported associations between several of these markers ( e.g . IL-6, TNFα) and LC symptoms (Durstenfeld et al, 2022a, 2022b; Peluso et al, 2021a, 2022a; Phetsouphanh et al, 2022). The lack of association between EBV serology and these markers suggest that there are additional important etiological factors driving PASC and LC symptoms that are not directly related to EBV reactivation.…”

Combining Deep Phenotyping of Serum Proteomics and Clinical Data via Machine Learning for COVID-19 Biomarker Discovery

“…Given the involvement of both inflammation [ 3 ] and cardiac injury (triggered both by direct [ 68 ] and indirect mechanisms [ 69 ]) in the pathophysiology of COVID-19, two commercial panels containing 92 “inflammation” and “cardiometabolic” biomarkers were employed. Since a large number of neurological manifestations (e.g., headache, confusion, neuroinflammatory, and cerebrovascular disease) have been described to occur in the acute and chronic phase of COVID-19 [ 20 , 70 ], we additionally employed a commercial panel containing 92 “neurology” biomarkers.…”

“…Last, several neurological (e.g., anosmia and ageusia) and psychiatric symptoms have been described in COVID-19 patients, most of which are independent from a direct affection of the central nervous system (CNS) by the virus but are considered to be secondary to the immune reaction [ 18 , 19 ]. CNS involvement is also relevant for the post-acute sequelae of SARS-CoV-2 infection (PASC), a spectrum of symptoms experienced by COVID-19 patients that persist after the resolution of the infection, which is characterized by the high prevalence of neurologic symptoms [ 19 , 20 ]. However, novel studies investigating the evidence of CNS involvement in COVID-19 patients are needed [ 21 ].…”