Acute TNFα levels predict cognitive impairment 6-9 months after COVID-19 infection.

BACKGROUND: A neurocognitive phenotype of post-COVID-19 infection has recently been described that is characterized by a lack of awareness of memory impairment (i.e., anosognosia), altered functional connectivity in the brain's default mode and limbic networks, and an elevated monocyte count. However, the relationship between these cognitive and brain functional connectivity alterations in the chronic phase with the level of cytokines during the acute phase has yet to be identified. AIM: Determine whether acute cytokine type and levels is associated with anosognosia and functional patterns of brain connectivity 6-9 months after infection. METHODS: We analyzed the predictive value of the concentration of acute cytokines (IL-1RA, IL-1ß, IL-6, IL-8, IFNγ, G-CSF, GM-CSF) (cytokine panel by multiplex immunoassay) in the plasma of 39 patients (mean age 59 yrs, 38-78) in relation to their anosognosia scores for memory deficits via stepwise linear regression. Then, associations between the different cytokines and brain functional connectivity patterns were analyzed by MRI and multivariate partial least squares correlations for the whole group. RESULTS: Stepwise regression modeling allowed us to show that acute TNFα levels predicted (R2 = 0.145; ß = -0.38; p = .017) and were associated (r = -0.587; p < .001) with scores of anosognosia for memory deficits observed 6-9 months post-infection. Finally, high TNFα levels were associated with hippocampal, temporal pole, accumbens nucleus, amygdala, and cerebellum connectivity. CONCLUSION: Increased plasma TNFα levels in the acute phase of COVID-19 predict the presence of long-term anosognosia scores and changes in limbic system functional connectivity.

Acute TNFα levels predict cognitive impairment 6-9 months after COVID-19 infection

Background A neurocognitive phenotype of post-COVID-19 infection has recently been described that is characterized by a lack of awareness of memory impairment (i.e., anosognosia), altered functional connectivity in the brain's default mode and limbic networks, and an elevated monocyte count. However, the relationship between these cognitive and brain functional connectivity alterations in the chronic phase with the level of cytokines during the acute phase has yet to be identified. Aim Determine whether acute cytokine type and levels is associated with anosognosia and functional patterns of brain connectivity 6-9 months after infection Methods We analyzed the predictive value of the concentration of acute cytokines (IL-1RA, IL-1β, IL-6, IL-8, IFNγ, G-CSF, GM-CSF) (cytokine panel by multiplex immunoassay) in the plasma of 39 patients (mean 59, 38-78) in relation to their anosognosia scores for memory deficits via stepwise linear regression. Then, associations between the different cytokines and brain functional connectivity patterns were analyzed by MRI and multivariate partial least squares correlations for the whole group. Results Stepwise regression modelling allowed us to show that acute TNFα levels predicted (R2 = 0.145;β =-0.38;p =.017) and were associated (r= -0.587;p<.001) with scores of anosognosia for memory deficits observed 6 to 9 months post-infection. Finally, high TNFα levels were associated with hippocampal, temporal pole, accumbens nucleus, amygdala, and cerebellum connectivity. Conclusion Increased plasma TNFα levels in the acute phase of COVID-19 predict the presence of long-term anosognosia scores and changes in limbic system functional connectivity.

Omicron breakthrough disease activity in the Swiss multiple sclerosis cohort study

Introduction: In patients with Multiple Sclerosis (pwMS), specific disease modifying treatments (DMTs) may compromise immune response following SARS-CoV-2 vaccination. Limited information is available, whether levels of anti-SARS-CoV-2 antibodies are linked to the risk of breakthrough infections in pwMS. Objective(s): To determine the rate of Omicron breakthrough infection and severity of COVID-19 in a cohort of MS patients treated with different DMTs and to estimate the impact of SARSCoV- 2-specific antibody level on breakthrough infection risk. Method(s): This study is nested within the Swiss MS Cohort, a nationwide multicenter study that has recruited 1585 pwMS. Patients who received two doses of SARS-CoV-2 vaccines before Omicron became the dominant variant in Switzerland on Dec-15, 2021 and had a follow-up thereafter were included. Data on SARS-CoV-2 infections, severity of COVID-19 according to the WHO scale and SARS-CoV-2 vaccines were collected by questionnaires. Anti-SARS-CoV-2-S antibody levels were measured after the second vaccine dose. Incidence of infections grouped by antibody level after second vaccination was visualized using Kaplan-Meier curves. Cox regression models were used to estimate the impact of antibody levels on the hazard of breakthrough infection during follow-up. Result(s): 242 pwMS (median age 49y [39,58], 162 (67%) female, 36 (15%) with progressive disease, median EDSS 2.5 [1.5,4.0]) were included. 22 (9%) had SARS-CoV-2 infection and 137 (57%) at least one additional vaccine dose prior to Omicron start. Since then, 57 breakthrough infections were reported. Severity of breakthrough disease on WHO scale ranged from 1-10: 7 were asymptomatic, 46 were symptomatic as outpatients, 3 were hospitalized and 1 died. Patients with antibody levels >150U/ml (n = 95, 39%) after second vaccination had a 64% reduced risk for Omicron breakthrough-infection compared to patients with antibody levels <0.7U/ml (n = 81, 33%) (HR 0.36, 95%CI=0.18- 0.71, p<0.01). This effect was maintained after adjustment for DMT at vaccination and time since second vaccination Conclusion(s): Humoral immune response after second SARSCoV- 2 vaccination is associated with Omicron breakthrough infection rate, a finding contrasting general populations, where antibody levels seem to have little impact on protecting from Omicron infection. Most breakthrough infections in our cohort were mild. Analyses on the effect of booster vaccinations on serology and infection rates will follow.

Monocytosis in the acute phase of SARS-CoV-2 infection predicts the presence of anosognosia for cognitive deficits in the chronic phase.

Reduced awareness of neuropsychological disorders (i.e., anosognosia) is a striking symptom of post-COVID-19 condition. Some leukocyte markers in the acute phase may predict the presence of anosognosia in the chronic phase, but they have not yet been identified. This study aimed to determine whether patients with anosognosia for their memory deficits in the chronic phase presented specific leukocyte distribution in the acute phase, and if so, whether these leukocyte levels might be predictive of anosognosia. First, we compared the acute immunological data (i.e., white blood cell differentiation count) of 20 patients who displayed anosognosia 6-9 months after being infected with SARS-CoV-2 (230.25 ± 46.65 days) versus 41 patients infected with SARS-Cov-2 who did not develop anosognosia. Second, we performed an ROC analysis to evaluate the predictive value of the leukocyte markers that emerged from this comparison. Blood circulating monocytes (%) in the acute phase of SARS-CoV-2 infection were associated with long-term post-COVID-19 anosognosia. A monocyte percentage of 7.35% of the total number of leukocytes at admission seemed to predict the presence of chronic anosognosia 6-9 months after infection.

CEREBRAL MICROBLEEDS IN PATIENTS WITH NEUROLOGICAL SYMPTOMS ASSOCIATED WITH COVID-19: DISTRIBUTION AND POSSIBLE PATHOPHYSIOLOGICAL MECHANISMS

Cerebral microbleeds (CMB) emerged as a possible complication of COVID-19. We aimed to assess CMB presence, distribution, and potential underlying pathophysiological mechanisms in hospitalised COVID-19 patients. In a cohort of 112 COVID-19 patients with neurological symptoms admitted to the Geneva University Hospital between March 2020 and May 2021, we assessed CMB distribution, and associations with clinical/ radiological variables. Neuroimaging was performed on a 1.5 T MRI with susceptibility-weighted images, 3D time-of-flight angiography, and 3D-contrast-enhanced fat-saturated T1 black blood VISTA sequences. Two neurologists rated CMB using the Microbleed Anatomic Rating Scale and white matter hyperintensities using the Age-Related White Matter Changes score. 53 patients (47.0%) had CMB;in 45.3% of cases, CMB were found in lobar regions with a predilection for temporal (58.3%) and frontal (29.2%) lobes. Deep CMB were present in 18.9%, with corpus callosum CMB found in 15.0%, in 35.9% CMB distribution was mixed. CMB presence was not related to intubation, pulmonary involvement, nor to radiologic signs of endothelitis. Patients with CMB were more likely to have a higher burden of white matter hyperintensities (OR 1.13, p=0.005, 95% CI: 1.03- 1.24), to have hypertension as a comorbidity (OR= 2.34, p= 0.04, 95% CI: 1.04 - 5.30) and to suffer from an acute stroke during hospitalisation (OR: 3.50 p= 0.012, 95% CI:1.31-9.18). In our sample, COVID-19 patients with neurological symptoms had a high burden of CMB. Their distribution suggests that they may be related to cardiovascular risk factors and cerebral amyloid angiopathy. CMB were also associated with an increased risk of acute stroke.

COVID-19 infections and vaccinations in the Swiss Multiple Sclerosis Cohort study

Background: COVID-19 disease course in MS has been described in various cohorts. Limited data is available on humoral immune responses following SARS-CoV-2 infection and vaccination. Objectives: To determine the rate of confirmed SARS-CoV-2 infection and severity of COVID-19 in a cohort of MS patients and to quantify SARS-CoV-2-specific antibody response. Methods: The study is nested within the Swiss MS Cohort, a nationwide multicenter study that has recruited 1504 persons with MS (pwMS) since 2012. PCR-confirmed SARS-CoV-2 infections, severity of COVID-19 according to the WHO clinical progression scale and immunizations with SARS-CoV-2 vaccines were captured by questionnaires used for interviews every 6 or 12 months. Anti-SARS-CoV-2 spike protein and nucleocapsid antibody levels will be determined by electrochemiluminescence immunoassay (ECLIA) (Elecsys, Anti-SARS-CoV-2, Roche Diagnostics) in sera of all participants. Results: Between February 2021 and April 2021, study questionnaires were completed for 253 pwMS (median age 47 years, 162 female). 211 pwMS (83%) had a relapsing, 25 (10%) a secondary progressive, 13 (5%) a primary progressive disease course and 4 (2%) a clinically isolated syndrome. Median disease duration was 12 years and median EDSS was 2.5. 218 (86%) pwMS were treated with DMTs: Ocrelizumab (27%), fingolimod (26%), dimethyl fumarate (15%), rituximab (10%), natalizumab (9%), other DMTs (13%). 15 (5.9%) of 253 pwMS had a positive SARSCoV- 2 PCR test since March 2020. In these pwMS, COVID-19 severity ranged from 1-10 on the WHO clinical progression scale: 1 pwMS was asymptomatic, 10 pwMS were symptomatic as outpatients (8 independently, 2 needed assistance), 3 pwMS were hospitalized (1 without oxygen therapy, 2 with oxygen by mask or nasal prongs) and 1 pwMS died. By April 2021, 24 and 38 pwMS received one and two doses of SARS-CoV-2 mRNA vaccines, respectively. Conclusions and outlook: Since start of the pandemic, rate of PCR-confirmed SARS-CoV-2 infection in our sample was slightly lower compared to incidence of laboratory-confirmed cases in Switzerland. The majority of pwMS had mild COVID-19. The study will continue until 2024 and by ECTRIMS 2021, we anticipate a doubling of completed questionnaires and to report preliminary results of serological measurements. This will allow us to present vaccine- and natural infection induced serological anti-SARS-CoV-2 responses in pwMS and assess differences related to various DMTs or COVID-19 severity.

COVID-19 related encephalopathy: The endotheliitis hypothesis

Objective: This study aims to compare the clinical characteristics of patients with COVID-19 related encephalopathy with and without radiological signs of intracranial gadolinium vessels enhancement. Background: The SARS-CoV-2 has been associated with neurological complications, including an acute encephalopathy. An unusual intracranial gadolinium vessels enhancement has been reported among these patients;however the prevalence, the clinical characteristics and the association with cerebrovascular complications have not been described yet. Design/Methods: Twenty-nine patients (66.9 ± 9.2 years;10% female) performed an MRI (with 3D T1-weighted black blood VISTA sequences) during acute onset of encephalopathy. The acute encephalopathy was defined by a delirium or a subsyndromal delirium with a pathobiological brain process in patients with a positive SARS-CoV-2 real-time reverse transcription polymerase chain reaction from a nasopharyngeal swab. Results: Twenty-three patients (79%) presented an intracranial gadolinium vessels enhancement, mainly in the vertebral arteries without sign of stenosis. Clinical characteristics were similar between patients with and without intracranial gadolinium enhancement, as well as the prevalence of acute stroke (9% versus 33%, respectively;p-value = 0.119) and microbleeds (52% versus 33%, respectively;p-value = 0.411). Among the 23 patients with an intracranial vessel gadolinium enhancement, 7 patients were treated by high-dose steroid (methylprednisolone 0.5g/d iv for 5 days) with a good clinical outcome. Conclusions: Patients with COVID-19 related encephalopathy present an increased prevalence of intracranial gadolinium vessels enhancement, suggestive of an endotheliitis that is not associated with stroke or microbleeds.

[Pathophysiology of COVID-19 related happy hypoxemia]

A significative proportion of patients with pulmonary-related COVID-19 initially present with << silent >> or << happy >> hypoxemia, a term denoting an absence of dyspnea or other respiratory distress symptoms in face of profound hypoxemia. COVID-19 is a multisystemic disease characterized by the diffusion of SARS-COV-2 through the blood and a widespread secondary immune response. Most of the organs are involved, including the brain and this translates into the development of acute encephalopathy and other complications. Silent hypoxemia and the consequent "vanishing dyspnea" represent a loss of warning signal and may be associated with a rapid clinical worsening and a fatal outcome. In this article, we will describe the physiological basis of ventilation and we will elucidate the different pathophysiological mechanisms underlying the phenomenon of silent hypoxemia in COVID-19.