Second, we relied on self-report to ascertain the presence of symptoms, and many symptoms are not clearly attributable to a neurologic cause. The authors acknowledge the contributions of the UCSF Clinical and Translational Science Unit, Core Immunology Laboratory, and AIDS Specimen Bank. In addition to symptom data collected at the time of the visit, we also used data collected retrospectively at the time of enrollment regarding the presence or absence of neurologic symptoms during the acute phase of infection to examine changes in biomarkers at early and late follow-up. Plasma was isolated using centrifugation of heparinized blood and stored at 80 C. Late recovery visits took place at a median of 123 (IQR 114135) days postinfection. The authors were grateful to the LIINC study participants and to the clinical staff who provided care to these individuals during their acute illness period and during their recovery. GFAP levels weakly correlated with MCP-1 (r = 0.21, p = 0.02) and IL-6 (r = 0.18, p = 0.054) at the early time point and with IL-6 at the late time point (r = 0.19, p = 0.043). For this reason, more detailed studies that include CSF analyses will be critical. For hospitalized participants, medical records were requested and reviewed by a study physician. Some inflammatory pathways seem to be involved months after acute infection. All assays were performed according to the manufacturer's instructions, and assay performance was consistent with the manufacturer's specifications. Although the purpose of this analysis was to explore the inflammatory pathways related to CNS PASC and not to define clinical factors associated with this condition, we performed several adjusted analyses to assess how these clinical factors could be involved with the inflammatory pathways. Because the proportion of individuals with preexisting autoimmune disease (most commonly thyroiditis) differed between groups, we adjusted for this and the results were largely unchanged (eTable 8). Lines and paragraphs break automatically. DOI: https://doi.org/10.1212/NXI.0000000000200003, Cross-Sectional Measurements and Longitudinal Trends in Neurologic Marker Levels Among Those With and Without CNS PASC, Cross-Sectional Measurements and Longitudinal Trends in Cytokine Levels Among Those With and Without CNS PASC, Cross-Sectional Measurements and Longitudinal Trends in Chemokine Levels and Antibodies Among Those With and Without CNS PASC, Relationships Between Biomarkers of Neurologic Injury and Systemic Inflammation in the Full Cohort, Technical article: updated estimates of the prevalence of post-acute symptoms among people with coronavirus (COVID-19) in the UK [online], High-dimensional characterization of post-acute sequelae of COVID-19, Global incidence of neurological manifestations among patients hospitalized with COVID-19-A report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium, Neurological Manifestations of COVID-19: a systematic review and current update, Longitudinal analyses reveal immunological misfiring in severe COVID-19, An inflammatory cytokine signature predicts COVID-19 severity and survival, Inflammatory cytokine patterns associated with neurological diseases in coronavirus disease 2019, Longterm disruption of cytokine signalling networks is evident in patients who required hospitalization for SARSCoV2 infection, Measurement of the glial fibrillary acidic protein and its breakdown products GFAP-BDP biomarker for the detection of traumatic brain injury compared to computed tomography and magnetic resonance imaging, Blood neurofilament light: a critical review of its application to neurologic disease, Plasma biomarkers of neurodegeneration and neuroinflammation in hospitalized COVID-19 patients with and without new neurological symptoms [online], Biomarkers for central nervous system injury in cerebrospinal fluid are elevated in COVID-19 and associated with neurological symptoms and disease severity, Association of neuronal injury blood marker neurofilament light chain with mild-to-moderate COVID-19, Blood neurofilament light concentration at admittance: a potential prognostic marker in COVID-19, Quantification of neurological blood-based biomarkers in critically ill patients with coronavirus disease 2019, Elevation of neurodegenerative serum biomarkers among hospitalized COVID-19 patients [online], Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19, Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes, SARS-CoV-2 is associated with changes in brain structure in UK Biobank, 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study, Immediate and long-term consequences of COVID-19 infections for the development of neurological disease, 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records, Persistent symptoms and association with inflammatory cytokine signatures in recovered coronavirus disease 2019 patients, Markers of immune activation and inflammation in individuals with postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection, Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19, Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up. 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Replication of these findings in larger and more diverse cohorts may be a first step toward identifying interventions for their prevention and/or management. Although it is likely that the severity of acute infection is 1 contributor to the development of PASC, the determination of who will have ongoing elevations in markers of neurologic injury and/or who will go on to experience CNS PASC during late recovery seems to be more complex than identifying those who report neurologic symptoms during the acute phase of illness. Participants were queried regarding the presence of 32 symptoms, including 8 neurologic symptoms (eTable 1, links.lww.com/NXI/A727). We investigated the associations between self-reported neurologic symptoms and plasma biomarkers of neurologic injury and systemic inflammation during early and late recovery periods after laboratory-confirmed SARS-CoV-2 infection. ), Weill Institute for Neurosciences (F.C.C. One possibility is that they represent residual inflammation from the period of acute infection that is slower to resolve among those with PASC. Elevations in IL-6 and TNF persisted through approximately 4 months of recovery. It suggests that CNS PASC might reflect 1 extreme on a spectrum of illness. Winslow, and C.J. Of those hospitalized, 23 (85%) required supplemental oxygen and 3 (11%) required mechanical ventilation. Although we collected data related to comorbidities known to be important in both acute COVID-19 and PASC (e.g., diabetes, lung disease, obesity), we did not obtain complete medical and psychiatric histories as part of the study and we did not have available psychiatric symptom data for this analysis; affective symptoms may also co-occur and be inter-related.29 Fourth, we measured a limited set of biomarkers, and there are likely to be others that are important in the pathophysiology of this condition. If you are uploading a letter concerning an article: We next compared the levels of each biomarker measured during late recovery between those with and without self-reported CNS PASC at this visit (Figures 13, eTables 3 and 4, links.lww.com/NXI/A727). 'MacMoody'. IFN = interferon; IL = interleukin; PASC = postacute sequelae of SARS-CoV-2 infection; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TNF = tumor necrosis factor. The authors thank Dr. Isabel Rodriguez-Barraquer, Dr. Bryan Greenhouse, and Dr. Rachel Rutishauser for their contributions to the LIINC leadership team. A secondary analysis examined any neurologic symptom, which included the following in addition to the central neurologic symptoms: problems with smell or taste, smelling an odor that is not really present, and numbness/tingling (eTable 2, links.lww.com/NXI/A727). GFAP = glial fibrillary acidic protein; NfL = neurofilament light chain; PASC = postacute sequelae of SARS-CoV-2 infection; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. p values reflect group comparisons during early and late recovery as well as comparison of change over time between groups. Early recovery represents a median of 52 days postSARS-CoV-2 symptom onset (or positive PCR); late recovery represents a median of 123 days postSARS-CoV-2 symptom onset (or positive PCR). Because of the relationship between age and levels of NfL,31 we performed an age-adjusted analysis which did not change the primary results (no new relationship between NfL and PASC was identified) (eTable 6, links.lww.com/NXI/A727). We log-transformed all biomarkers to reduce the influence of outliers and to permit interpretation of fold changes. Methods We 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). More guidelines and information on Disputes & Debates, Neurology: Neuroimmunology & Neuroinflammation Glidden reports grants and/or personal fees from Merck and Co. and Gilead Biosciences outside the submitted work. Viral tropism for human astrocytes has been demonstrated in vivo,44 postmortem brain samples from patients with COVID-19 have shown preferential infection of astrocytes,45 and a case-control study of brain samples uncovered altered gene expression in some astrocytes.46 Astrocyte dysfunction, as reflected in increased plasma GFAP observed here, could relate to the emerging cognitive PASC complaints, which can encapsulate attention and working memory deficits. Our measurements were all taken in blood, and although there are established relationships between blood and CSF measurements of these markers in other disease conditions, these have yet to be established for COVID-19 and were not seen in at least 1 study.19 Furthermore, although they are of mechanistic interest regardless of their cells of origin, the markers we measured are not CNS-specific and may be generated peripherally. Our rationale for and methods of symptom ascertainment have been described in detail elsewhere.30. Five (4%) reported asymptomatic SARS-CoV-2 infection. Read any comments already posted on the article prior to submission. Third, it is difficult to disentangle neurologic symptoms from other non-neurologic symptoms which might co-occur, and it is possible that differences in these markers are driven by more severe PASC in general rather than neurologic symptoms specifically. GFAP and NfL correlated with levels of several immune activation markers during early recovery; these correlations were attenuated during late recovery. Plasma was assayed according to the manufacturer's recommended 1:4 dilution for all assays except IFN-, which was assayed at the recommended 1:2 dilution, and SARS-CoV2 IgG, which was diluted 1:1,000. The primary clinical outcome was the presence of self-reported CNS PASC symptoms during the late recovery time point. 
At late follow-up, those with any neurologic PASC had higher levels of IL-6 and TNF. To examine relationships between the neurologic markers and markers of inflammation, we performed nonparametric pairwise analyses at early and late recovery time points (Figure 4). The analysis of all samples was performed in 23 separate batch runs in singlicate within a week period per assay, using the same kit lot for each assay. Those who went on to report CNS PASC also had higher levels of cytokines IL-6 (1.48-fold higher mean ratio, 95% CI 1.121.96, p = 0.006; Figure 2A), TNF (1.19-fold higher mean ratio, 95% CI 1.061.34, p = 0.003; Figure 2B), and the chemokine MCP-1 (1.19-fold higher mean ratio, 95% CI 1.011.40, p = 0.034; Figure 3A), compared with those who did not report CNS PASC. Symptoms that preceded and were unchanged after SARS-CoV-2 infection were recorded as absent. Background and Objectives The biologic mechanisms underlying neurologic postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are incompletely understood. The Article Processing Charge was funded by the authors. Together, these observations lend support to the possibility of early injury that might resolve while clinical symptoms persist. This analysis builds on several observations we and others have made suggesting that markers of systemic inflammation may be important in driving PASC.24,25 Although we previously observed associations between such markers and broadly defined PASC (i.e., any 1 of 32 COVID-19attributed symptoms), it is notable that the strength of these associations was more pronounced in the current analysis using a more specific PASC outcome (i.e., any 1 of 5 CNS PASC symptoms). This study included 121 individuals with primary outcome data (Table 1), 92 of whom (76%) had a paired early recovery sample for analysis. Go to Neurology.org/NN for full disclosures. Your organization or institution (if applicable), e.g. ), Departments of Neurology and Medicine (Infectious Diseases), and Memory and Aging Center (J.H. There is an urgent need to understand the pathophysiology that underlies the postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), a set of conditions characterized by persistent symptoms in some individuals recovering from coronavirus disease 2019 (COVID-19).1 Although a spectrum of symptoms is reported among individuals experiencing PASC, neurologic symptoms are particularly common.1,-,3 Limited data are available on the biologic predictors and correlates of these symptoms. In a prior analysis using the broadest possible case definition of PASC (i.e., presence of any 1 of 32 COVID-19attributed symptoms), we found that subtle differences in levels of inflammatory markers predicted the presence of persistent symptoms >90 days after COVID-19.25 In the current report, we investigated a more specific outcome measure defined by 8 self-reported neurologic symptoms. Although the definition is not optimal, we believe that our case definition appropriately captures this condition as it is currently understood. areas brain eloquent awake craniotomy neuros comprehension speech craneofaringioma turca Early recovery represents a median of 52 days postSARS-CoV-2 symptom onset (or positive PCR); late recovery represents a median of 123 days postSARS-COV-2 symptom onset (or positive PCR). Go to Neurology.org/NN for full disclosures. If you are responding to a comment that was written about an article you originally authored: This risks misattribution of symptoms to neurologic causes and therefore misclassification of individuals as having CNS PASC. The primary analytes were plasma GFAP and NfL measured using the GFAP Discovery and NF-light Advantage kit assays, respectively (Quanterix). Plasma biomarker measurements were performed using the fully automated HD-X Simoa platform at 2 time points: early recovery (median 52 days) and late recovery (median 123 days). Funding information is provided at the end of the article. h2s induced gyri flattened ), University of California, San Francisco; Icahn School of Medicine at Mount Sinai (H.H. This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Regardless, we believe that the observations made here provide important preliminary clues as to potentially important biological pathways to inform more detailed neurologic evaluations and potential therapeutic studies. SARS-CoV-2 receptor-binding domain (RBD) immunoglobulin (Ig) G was also assayed. Those performing the assays were blinded to clinical information. Data reflect nonparametric correlations between markers at early and late recovery time points. The timing of the late recovery visit was similar between those with and without CNS PASC (123 [IQR 117137] and 124 [IQR 113134] days, respectively). This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. No participant experienced an acute neurologic event (e.g., stroke, seizure) during their hospitalization. In addition to the previous measures of inflammation, we evaluated markers of neurologic injury among those with and without this more specific PASC phenotype. Early recovery represents a median of 52 days postSARS-CoV-2 symptom onset (or positive PCR); late recovery represents a median of 123 days postSARS-CoV-2 symptom onset (or positive PCR). We found that those reporting CNS PASC symptoms approximately 4 months after initial infection had earlier elevations in several biomarkers, including GFAP, IL-6, and TNF, suggesting that the acute infection resulted in direct CNS tissue injury and systemic inflammation, both of which might conceivably be causally related to the development of CNS PASC symptoms.
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