Csf & Plasma Soluble Biomarkers in Neuro-Pasc: Preliminary Results from Covid Mind

Background: It is unknown whether individuals with neurological post-acute sequelae of COVID-19 (NeuroPASC) display altered levels of neuroimmune activity or neuronal injury. Method(s): Participants with new or worsened neurologic symptoms at least 3 months after laboratory-confirmed COVID-19 were enrolled in The COVID Mind Study at Yale. Never COVID controls (no history of COVID-19;nucleocapsid (N) antibody negative) were pre-pandemic or prospectively enrolled volunteers. CSF and plasma were assessed for neopterin and for IL-1beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, MCP-1, TNFalpha by bead-based multiplex assay;and for anti-SARS-CoV-2 N antibodies by Luminex-based multiplex assay in technical replicate, normalized against bovine serum albumin conjugated beads. Plasma concentrations of D-dimer, C-reactive protein, neurofilament light chain (NFL), and glial fibrillary acid protein (GFAP) were measured using high-sensitivity immunoassays. Group comparisons used non-parametric tests. Result(s): NeuroPASC participants (n=38) were studied 329 (median) days (range 81-742) after first positive test for acute COVID-19. Cognitive impairment (84%) and fatigue (82%) were the most frequent post-COVID symptoms. NeuroPASC and controls (n=22) were median 49 vs 52 yrs old (p=0.9), 74% vs 32% female (p< 0.001), 76% vs 23% white race (p< 0.001), and 6% vs 57% smokers (p< 0.001). CSF white blood cells/mL, CSF protein, and serum:CSF albumin ratio were normal in both groups. CSF TNFalpha (0.66 vs 0.55 pg/ul) and plasma IL12p40 were higher (103.3 vs 42.7);and MCP-1 (503 vs 697 pg/ul) and IL-6 (1.32 vs 1.84 pg/ul;p < 0.05 for IL-6) were lower in NeuroPASC vs controls (p< 0.05);but none of these differences were significant after adjusting for multiple comparisons. Plasma GFAP was elevated in NeuroPASC vs controls (54.4 vs 42.3 pg/ml;adjusted p< 0.03). There were no differences in the other biomarkers tested. 10/31 and 7/31 NeuroPASC had anti-N antibodies in CSF and plasma, respectively. Conclusion(s): When comparing NeuroPASC to never COVID controls, we found no evidence of neuroinflammation (normal CSF cell count, inflammatory cytokines) or blood-brain barrier dysfunction (normal albumin ratio), and no support for ongoing neuronal damage (normal plasma NFL). Future studies should include better gender and race matched controls and should explore the significance of a persistent CNS humoral immune response to SARS-CoV-2 and elevated plasma GFAP after COVID-19. (Figure Presented).

NO CSF BIOMARKER EVIDENCE OF PERSISTING CNS INFECTION AFTER SARS-CoV-2 INFECTION

Background: Neurocognitive symptoms are common in acute as well as convalescent (post-acute sequelae of COVID-19 [PASC]) COVID-19, but mechanisms of CNS pathogenesis are unclear. The aim of this study was to investigate cerebrospinal fluid (CSF) biomarker evidence of CNS infection, immune activation and neuronal injury in convalescent compared with acute infection. Method(s): We included 68 (35% female) patients >=18 years with CSF sampled during acute (46), 3-6 months after (22) SARS-CoV-2 infection or both (17), and 20 (70% female) healthy controls from longitudinal studies. The 22 patients sampled only at 3-6 months were recruited in a PASC protocol. CSF N-Ag was analyzed using an ultrasensitive antigen capture immunoassay platform (S-PLEX SARS-CoV-2 N Kit, Meso Scale Diagnostics, LLC. Rockville, MD). Additional analyses included CSF beta2-microglobulin (beta2M)], IFN-gamma, IL-6, TNF-alpha neurofilament light (NfL), and total and phosphorylated tau. Log-transformed CSF biomarkers were compared using ANOVA (Tukey post-hoc test). Result(s): Patients sampled during acute infection had moderate (27) or severe (19) COVID-19. In patients sampled at 3-6 months, corresponding initial severity was 10 (mild), 14 (moderate), and 15 (severe). At 3-6 months, 31/39 patients reported neurocognitive symptoms;8/17 patients also sampled during acute infection reported full recovery after 3-6 months. CSF biomarker results are shown in Figure 1. SARS-CoV-2 RNA was universally undetectable. N-Ag was detectable only during acute infection (32/35) but was undetectable in all follow up and control samples. Significantly higher CSF concentrations of beta2M (p< 0.0001), IFN-gamma (p=0.02), IL-6 (p< 0.0001) and NfL (p=0.04) were seen in acute compared to post-infection. Compared to controls, beta2M (p< .0001), IL-6 (p< 0.0001) and NfL (p=0.005) were significantly higher in acute infection. No biomarker differences were seen post-infection compared with controls. No differences were seen in CSF GFAp, t-tau or p-tau. Conclusion(s): We found no evidence of residual infection (RNA, N-Ag), inflammation (beta2M, IL-6, IFN-gamma, TNF-alpha), astrocyte activity (GFAp) or neuronal injury (NfL, tau) 3-6 months after initial COVID-19, while significantly higher concentrations of several markers were found during acute infection, suggesting that PASC may be a consequence of earlier injury rather than active CNS damage. CSF beta2M, IL-6, IFN-gamma and NfL were significantly lower after 3-6 months than during acute COVID-19 and not different from healthy controls. (Figure Presented).

An intersectional analysis of sociodemographic disparities in Covid-19 vaccination: A nationwide register-based study in Sweden.

BACKGROUND: Studies on sociodemographic disparities in Covid-19 vaccination uptake in the general population are still limited and mostly focused on older adults. This study examined sociodemographic differences in Covid-19 vaccination uptake in the total Swedish population aged 18-64 years. METHODS: National Swedish register data within the SCIFI-PEARL project were used to cross-sectionally investigate sociodemographic differences in Covid-19 vaccination among Swedish adults aged 18-64 years (n = 5,987,189) by 12 October 2021. Using logistic regression models, analyses were adjusted for sociodemographic factors, region of residence, history of Covid-19, and comorbidities. An intersectional analysis approach including several cross-classified subgroups was used to further address the complexity of sociodemographic disparities in vaccination uptake. FINDINGS: By 12 October 2021, 76·0% of the Swedish population 18-64 years old had received at least two doses of Covid-19 vaccine, an additional 5·5% had received only one dose, and 18·5% were non-vaccinated. Non-vaccinated individuals were, compared to vaccinated, more often younger, male, had a lower income, were not gainfully employed, and/or were born outside Sweden. The social patterning for vaccine dose two was similar, but weaker, than for dose one. After multivariable adjustments, findings remained but were attenuated indicating the need to consider different sociodemographic factors simultaneously. The intersectional analysis showed a large variation in vaccine uptake ranging from 32% to 96% in cross-classified subgroups, reflecting considerable sociodemographic heterogeneity in vaccination coverage. INTERPRETATION: Our study, addressing the entire Swedish population aged 18-64 years, showed broad sociodemographic disparities in Covid-19 vaccine uptake but also wide heterogeneities in coverage. The intersectional analysis approach indicates that focusing on specific sociodemographic factors in isolation and group average risks without considering the heterogeneity within such groups will risk missing the full variability of vaccine coverage. FUNDING: SciLifeLab / Knut & Alice Wallenberg Foundation, Swedish Research Council, Swedish government ALF agreement, FORMAS.

An intersectional analysis of sociodemographic disparities in Covid-19 vaccination: a nationwide register-based study in Sweden

Background Studies on sociodemographic disparities in Covid-19 vaccination uptake in the general population are still limited and mostly focused on older adults. This study examined sociodemographic differences in Covid-19 vaccination uptake in the total Swedish population aged 18-64 years. Methods National Swedish register data within the SCIFI-PEARL project were used to cross-sectionally investigate sociodemographic differences in Covid-19 vaccination among Swedish adults aged 18-64 years (n=5,987,189) as of 12 October 2021. Using logistic regression models, analyses were adjusted for sociodemographic factors, region of residence, history of Covid-19, and comorbidities. An intersectional analysis approach including several cross-classified subgroups was used to further address the complexity of sociodemographic disparities in vaccination uptake. Findings By 12 October 2021, 76·0% of the Swedish population 18-64 years old had received at least two doses of Covid-19 vaccine, an additional 5·5% had received only one dose, and 18·5% were non-vaccinated. Non-vaccinated individuals were, compared to vaccinated, more often younger, male, had a lower income, were not gainfully employed, and/or were born outside Sweden. The social patterning for vaccine dose two was similar, but weaker, than for dose one. After multivariable adjustments, findings remained but were attenuated indicating the need to consider different sociodemographic factors simultaneously. The intersectional analysis showed a large variation in vaccine uptake ranging from 32% to 96% in cross-classified subgroups, reflecting considerable sociodemographic heterogeneity in vaccination coverage. Interpretation Our study, addressing the entire Swedish population aged 18-64 years, showed broad sociodemographic disparities in Covid-19 vaccine uptake but also wide heterogeneities in coverage. The intersectional analysis approach indicates that focusing on specific sociodemographic factors in isolation and group average risks without considering the heterogeneity within such groups will risk missing the full variability of vaccine coverage. Funding SciLifeLab / Knut & Alice Wallenberg Foundation, Swedish Research Council, Swedish government ALF agreement, FORMAS.

CLINICAL OUTCOME in PEOPLE with COVID-19 by HIV-STATUS: A NATIONWIDE REGISTER STUDY

Background: It is still unclear whether people with HIV (PWH) are more likely to have severe outcome of COVID-19. We aimed to assess this association using nation-wide register data. Methods: We included all adults hospitalized with a primary diagnosis of COVID-19 (ICD-10;U07.1, U07.2) in Sweden between Feb 1, 2020, and Aug 31, 2021, identified from the National Patient Register. The study population was linked to the National HIV Quality Register (n= 8 032), the Swedish Intensive Care Register, the Swedish Cause of Death Register, and the LISA database for labour market studies. Using multivariate logistic regression models, we estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for severe COVID-19 (intensive care admission or 90-day mortality), by HIV-status. Results: We included 121 PWH and 64 764 HIV-negative individuals hospitalized with COVID-19. PWH were younger (median age 57y vs. 65y, p<0.001) and more likely to be men (68% vs. 57%, p=0.015) compared to HIV-negative. There was no difference in level of education, level of income or number of comorbidities. Most hospitalized PWH had undetectable HIV-RNA (93%) and high CD4 counts (median 560, IQR 376-780). Severe COVID-19 was identified in 17 (14%) PWH and 14 648 (23%) HIV-negative. Ten (8%) PWH and 10 217 (16%) HIV-negative died within 90 days. HIV status was not associated with higher odds of severe COVID-19 (aOR 0.88, 95% CI 0.52-1.49). Higher age was associated with severe COVID-19 in PWH (aOR 1.08, 95% CI 1.02-1.15). PWH with one or more comorbidities were four times more likely to have severe COVID-19 (aOR 4.3, 95% CI 1.1-16.7, ref PWH with no comorbidity). Neither level of income nor level of education or migrant status was associated with severe COVID-19 in PWH. Level of HIV-RNA, current CD4, nadir CD4, and mode of HIV-transmission was not associated with severe COVID-19. PWH admitted to the ICU were six times more likely treated with tocilizumab compared to HIV-negative admitted to the ICU (aOR 6.1, 95% CI 1.5-24.5), even after adjusting for regional differences in early adoption of tocilizumab use. There was no difference in the number treated with steroids (aOR 0.9, 95% CI 0.2-3.1). Conclusion: This nation-wide cohort study, including the entire Swedish adult population hospitalized with COVID-19, indicates that PWH with well-treated HIV-infection have similar odds of severe COVID-19 as HIV-negative individuals. PWH admitted to the ICU were more likely treated with tocilizumab compared to HIV-negative.

SARS-CoV-2 CSF N-ANTIGEN DETECTION IS ASSOCIATED with CNS INFLAMMATION in NEUROCOVID

Background: The underlying CNS pathogenesis in COVID-19 is not clear and viral RNA is rarely detected in cerebrospinal fluid (CSF). We measured viral antigen and biomarker profiles in CSF in relation to neurological symptoms and disease severity. Methods: We included 44 (32% female) hospitalized patients (26 moderate, 18 severe COVID-19) and 10 healthy controls (HC). 21 patients were neuroasymptomatic (NA), 23 neurosymptomatic (NS;encephalopathy=21, encephalitis=1, GBS=1). For antigen and cytokine analyses, a patient control (PC;n=41) group (COVID-negative with no sign of CNS infection in clinical CSF samples) was used. CSF nucleocapsid antigen (N-Ag) was analyzed using an ultrasensitive antigen capture immunoassay platform, S-PLEX direct detection assay, S-PLEX SARS-CoV-2 N Kit (MesoScale Diagnostics, LLC. Rockville, MD). Additional analyses included CSF neopterin, β2-microglobulin, cytokines and neurofilament light (NfL). Results: CSF N-Ag was detected in 31/35 patients (0/41 controls) while viral RNA was negative in all. CSF N-Ag was significantly correlated with CSF neopterin (r=0.38;p=0.03) and IFN-γ (r=0.42;p=0.01) adjusted for sampling day. No differences in CSF N-Ag concentrations were found between patient groups. All patient groups had markedly increased CSF neopterin, β2M, IL-6, IL-10 and TNF-α compared to controls, while IL-2, IL-1β and IFN-γ were significantly increased only in the NS group. CSF biomarkers were associated with time from symptom onset to CSF sampling. After adjusting for time of sampling, the NS group had significantly higher CSF IFN-γ (p=0.03), and showed a statistical trend towards significantly higher CSF neopterin, IL-6 and TNF-α (p=0.056-0.06) than the NA group. Additionally, age-adjusted CSF NfL was higher in the NS compared to the HC (p=0.01) group. No differences were seen in any CSF biomarkers in moderate compared to severe disease. Conclusion: Viral antigen is detectable in CSF in a majority of patients with COVID-19 despite the absence of detectable viral RNA, and is correlated to CNS immune activation markers. Patients with neurological symptoms had a more marked immune activation profile compared to NA patients, as well as signs of neuroaxonal injury compared to controls. These observations could not be attributed to a difference in COVID-19 severity. Our results highlight the importance of neurological symptoms and indicate that the CNS immune response and CNS pathogenesis can be initiated by viral components without direct viral invasion of the CNS.

Severe multisystem inflammatory syndrome (MIS-C/A) after confirmed SARS-CoV-2 infection: a report of four adult cases.

BACKGROUND: Multisystem inflammatory syndrome (MIS) triggered by a recent SARS-Cov-2 infection has been recognised worldwide. Although predominantly affecting children (MIS-C), similar presentations have been reported among adults (MIS-A). METHOD: A retrospective case series describing four critically ill patients with MIS-C/A diagnosed between January and April 2021 at Sahlgrenska University Hospital, Gothenburg, Sweden. Clinical presentation, laboratory and radiological findings, treatment and outcome are reported. RESULTS: Cases occurred in previously healthy patients with a history of laboratory-confirmed mild SARS-CoV-2 infection four to seven weeks earlier. The median age was 24 years (range 19-43) and 3/4 were male. All fulfilled suggested MIS-C/A criteria according to the US Centre for Disease Control and all required care at an intensive care unit. Treatment was initiated with intravenous immunoglobulin, interleukin-1-receptor antagonists, and pulse steroids in 3/4 cases which resulted in rapid clinical improvement. No severe complications were noticed in any case during a three-month follow-up period. CONCLUSION: MIS-C/A should be considered, irrespective of age, in patients with fever, hyperinflammation and multiple organ system involvements emerging weeks after COVID-19. Previously suggested treatment regimens for MIS-C seem to be applicable also for MIS-A.