Prognostic factors for disease activity in newly diagnosed teriflunomide-treated patients with multiple sclerosis: a nationwide Danish study.

BACKGROUND: Clinicians frequently rely on relapse counts, T2 MRI lesion load (T2L) and Expanded Disability Status Scale (EDSS) scores to guide treatment decisions for individuals diagnosed with multiple sclerosis (MS). This study evaluates how these factors, along with age and sex, influence prognosis during treatment with teriflunomide (TFL). METHODS: We conducted a nationwide cohort study using data from the Danish Multiple Sclerosis Registry.Eligible participants had relapsing-remitting MS or clinically isolated syndrome and initiated TFL as their first treatment between 2013 and 2019. The effect of age, pretreatment relapses, T2L and EDSS scores on the risk of disease activity on TFL were stratified by sex. RESULTS: In total, 784 individuals were included (57.4% females). A high number of pretreatment relapses (≥2) was associated with an increased risk of disease activity in females only (OR and (95% CI): 1.76 (1.11 to 2.81)). Age group 50+ was associated with a lower risk of disease activity in both sexes (OR females=0.28 (0.14 to 0.56); OR males=0.22 (0.09 to 0.55)), while age 35-49 showed a different impact in males and females (OR females=0.79 (0.50 to 1.23); OR males=0.42 (0.24 to 0.72)). EDSS scores and T2L did not show any consistent associations. CONCLUSION: A high number of pretreatment relapses was only associated with an increased risk of disease activity in females, while age had a differential impact on the risk of disease activity according to sex. Clinicians may consider age, sex and relapses when deciding on TFL treatment.

Extended interval dosing with ocrelizumab in multiple sclerosis.

BACKGROUND: This study investigates clinical and biomarker differences between standard interval dosing (SID) and extended interval dosing (EID) of ocrelizumab therapy in multiple sclerosis (MS). METHODS: This is a prospective, double-arm, open-label, multi-center study in Denmark. Participants diagnosed with MS on ocrelizumab therapy >12 months were included (n = 184). Clinical, radiological, and blood-based biomarker outcomes were evaluated. MRI disease activity, relapses, worsening of neurostatus, and No Evidence of Disease Activity-3 (NEDA-3) were used as a combined endpoint. RESULTS: Out of 184 participants, 107 participants received EID (58.2%), whereas 77 participants received SID (41.8%). The average extension was 9 weeks with a maximum of 78 weeks. When comparing EID to SID, we found higher levels of B-cells, lower serum concentrations of ocrelizumab, and similar levels of age-adjusted NFL and GFAP in the two groups. No difference in NEDA-3 between EID and SID was demonstrated (hazard ratio: 1.174, p = 0.69). Higher levels of NFL were identified in participants with disease activity. Body mass index correlated with levels of ocrelizumab and B-cells. CONCLUSION: Extending one treatment interval of ocrelizumab on average 9 weeks and up to 78 weeks did not result in clinical, radiological, or biomarker evidence of worsening compared with SID.

Low protection from breakthrough SARS-CoV-2 infection and mild disease course in ocrelizumab-treated patients with multiple sclerosis after three mRNA vaccine doses.

BACKGROUND: Our study investigated the rate of breakthrough SARS-CoV-2 infection and clinical outcomes in a cohort of multiple sclerosis (MS) patients who were treated with the anti-CD20 monoclonal antibody (Ab), ocrelizumab, before first, second and third BNT162b2 mRNA vaccinations. To correlate clinical outcomes with the humoral and cellular response. METHODS: The study was a prospective non-randomised controlled multicentre trial observational study. Participants with a diagnosis of MS who were treated for at least 12 months with ocrelizumab prior to the first BNT162b2 mRNA vaccination were prospectively followed up from January 2021 to June 2022. RESULTS: Out of 54 participants, 32 (59.3%) developed a positive SARS-CoV-2 PCR test in the study period. Mild infection was observed in all infected participants. After the third vaccination, the non-infected participants had higher mean Ab levels compared to the infected participants (54.3 binding antibody unit (BAU)/mL vs 26.5 BAU/mL, p=0.030). The difference in reactivity between spike-specific CD4+ and CD8+ T lymphocytes in the two groups was not significant. CONCLUSION AND RELEVANCE: The study results demonstrate rates of 59% in breakthrough infections after the third SARS-CoV-2 mRNA vaccination in ocrelizumab-treated patients with MS, without resulting in critical disease courses. These findings suggest the need for continuous development of prophylactic treatments when proved important in the protection of severe breakthrough infection.

Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment naïve relapsing MS patients.

OBJECTIVES: In a prospective phase IV trial of the first-line oral treatment dimethyl fumarate (DMF), we examined dynamics of neurofilament light (NFL) chain in serum, plasma and cerebrospinal fluid (CSF) samples collected over 12 months from relapsing-remitting multiple sclerosis (RRMS) patients. NFL changes were related to disease activity. METHODS: We examined NFL levels by single-molecule array in 88 CSF, 348 plasma and 131 sera from treatment-naïve RRMS patients (n=52), healthy controls (n=23) and a placebo group matched by age, sex and NFL (n=52). Plasma/sera were collected at baseline, and 1, 3, 6 and 12 months after DMF. CSF samples were collected at baseline and 12 months after DMF. RESULTS: NFL concentration in CSF, plasma and serum correlated highly (p<0.0001 for all), but plasma levels were only 76.9% of paired serum concentration. After 12 months of DMF treatment, NFL concentration decreased by 73%, 69% and 55% in the CSF, serum and plasma (p<0.0001, respectively). Significant reduction in blood was observed after 6 and 12 months treatment compared with baseline (p<0.01 and p<0.0001, respectively) and to placebo (p<0.0001). Patients with NFL above the 807.5 pg/mL cut-off in CSF had 5.0-times relative risk of disease activity (p<0.001). CONCLUSIONS: This study provides Class II evidence that first-line DMF reduces NFL in both blood and CSF after 6 months and normalises CSF levels in 73% of patients. High NFL concentration in CSF after a year reflected disease activity. NFL levels were higher in serum than in plasma, which should be considered when NFL is used as a biomarker.

[ALEMTUZUMAB: BENEFITS AND CHALLENGES OF A NEW THERAPY IN MULTIPLE SCLEROSIS]. / ALEMTUZUMAB: EGY ÚJ TERÁPIA ELONYEI ÉS KIHÍVÁSAI SCLEROSIS MULTIPLEXBEN.

The widening spectrum of MS treatment is partially due to increasing knowledge about the pathogenesis of MS. The humanized monoclonal antibody against CD52, alemtuzumab has been approved in Europe for the treatment of MS, which results in long-term depletion of B and T cells due to complement- and antibody-mediated cytotoxicity. Based on phase 2 and 3 clinical trials, alemtuzumob decreases the risk of sustained neurological deficit and progression compared to high-dose subcutaneous interferon-ß1a in patients with active relapsing-remitting MS, either treatment-naïve or with breakthrough disease. We review advantages and benefits of the treatment, discuss safety concerns, and present a case to describe practical issues.

High temperature requirement A1 and macrophage migration inhibitory factor in the cerebrospinal fluid; a potential marker of conversion from relapsing-remitting to secondary progressive multiple sclerosis.

BACKGROUND: Predictive and prognostic biomarkers for multiple sclerosis (MS) remain a significant gap in MS diagnosis and treatment monitoring. Currently, there are no timely markers to diagnose the transition to secondary progressive MS (SPMS). OBJECTIVE: This study aims to evaluate the discriminatory potential of the High temperature requirement serine protease (HTRA1)/Macrophage migration inhibitory factor (MIF) cerebrospinal fluid (CSF) ratio in distinguishing relapsing-remitting (RRMS) patients from SPMS patients. METHODS: The MIF and HTRA1 CSF levels were determined using ELISA in healthy controls (n = 23), RRMS patients before (n = 22) and after 1 year of dimethyl fumarate treatment (n = 11), as well as in SPMS patients before (n = 11) and after 2 years of mitoxantrone treatment (n = 7). The ability of the HTRA1/MIF ratio to discriminate the different groups was determined using receiver operating curve (ROC) analyses. RESULTS: The ratio was significantly increased in treatment naïve RRMS patients while decreased again in SPMS patients at baseline. Systemic administrated disease modifying treatment (DMT) only significantly affected the ratio in RRMS patients. ROC analysis demonstrated that the ratio could discriminate treatment naïve RRMS patients from SPMS patients with 91% sensitivity and 100% specificity. CONCLUSION: The HTRA1/MIF ratio is a strong candidate as a MS biomarker for SPMS conversion.

Comment: Reply to editorial letter on Limited value of a patient-reported triage algorithm in an outpatient epilepsy clinic.

This is a reply to the letter to the editor regarding the article "Limited value of a patient-reported triage algorithm in an outpatient epilepsy clinic" Dan Med J 2022;69(7):A12210915.

Progressive multifocal leukoencephalopathy in a patient with multiple myeloma: a case report and analysis of the FDA adverse event reporting system.

This paper demonstrates a case of progressive multifocal leukoencephalopathy (PML) in a patient with multiple myeloma (MM) treated with nine different MM therapies. This case report contributes to the already published 16 cases of PML in patients with MM. Additionally, this paper presents an analysis of cases from the United States Food and Drug Administration Adverse Event Report System database (n = 117) with a description of demographics and MM-specific therapies. Patients with MM, that developed PML, were treated with immunomodulatory drugs (97%), alkylating agents (52%), and/or proteasome inhibitors (49%). Prior to PML diagnosis, 72% of patients received two or more MM therapies. These results indicate that PML in MM is underreported and could be related to treatment with multiple immunosuppressive therapies rather than MM as a disease itself. Physicians should be aware of potential PML in the late stage of heavily treated MM patients.

Whole blood miRNAs in relapsing MS patients treated with dimethyl fumarate in the phase 4 TREMEND trial.

We investigated the impact of dimethyl fumarate (DMF), an oral therapy for relapsing multiple sclerosis (MS), on blood microRNA (miRNA) signatures and neurofilament light (NFL) levels. DMF normalized miR-660-5p and modulated various miRNAs associated with the NF-kB pathway. These alterations reached a peak 4-7 months after treatment. Notably, particular miRNAs correlated with high or low NFL levels, implying their potential role as markers of treatment efficacy. Our findings broaden the understanding of DMF's immunomodulatory effects and may aid in predicting treatment responses.

Discontinuation of dimethyl fumarate in multiple sclerosis - a nationwide study.

BACKGROUND: Adherence is a prerequisite for the efficacy of any drug, and previous studies have shown that non-adherence is associated with disease activity and increased health care cost in multiple sclerosis (MS). The aim of this study was to investigate rates and reasons for discontinuation of dimethyl fumarate (DMF) among people with MS on a national level and differences between clinics in Denmark. METHODS: This was a nationwide, registry and population study of patients treated with DMF. We calculated standard residuals (SR) demonstrate differences between clinics. For survival analysis regarding discontinuation rates and discontinuation due to specific AEs we used log-rank test Cox-proportional hazards and plotted Kaplan-Meier graphics. RESULTS: We included 2,448 people with MS, treated with DMF from 2013 to 2020. Average treatment duration was 26 months (5,382 treatment years). 49.2 % of patients who initiated treatment with DMF (n = 1205) were continuously treated. Reasons for discontinuation were adverse events (54.5 %, n = 656), active disease (26.1 %, n = 315), pregnancy (9.4 %, n = 113) or other reasons (13.2 %, n = 159). We compared SR to the mean regarding reasons for discontinuation and found significant differences between sites regarding gastrointestinal adverse events, flushing and lymphopenia. Discontinuation due to all adverse events, flushing and lymphopenia were more frequent in female than male patients. CONCLUSION: In this population-based study, we found major differences between the MS clinics in rates and reason for discontinuation of DMF. Our results suggest that management strategies during DMF treatment can reduce discontinuation rates.

Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis.

Importance: Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab. Objective: To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS. Design, Setting, and Participants: This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country. Exposure: Treatment with ocrelizumab or rituximab after 2015. Main outcomes and Measures: Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups. Results: Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses. Conclusion: In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials.

Predictors of treatment switching in the Big Multiple Sclerosis Data Network.

Background: Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods. Objective: The objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry. Methods: In this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect. Results: Every one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio [aHR] 1.08; 95% CI 1.07-1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08-1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48-2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79-8.41; reference = 1996-2006). Conclusion: Switching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices.

Limited value of a patient-reported triage algorithm in an outpatient epilepsy clinic.

INTRODUCTION: The hypothesis of this study was that the patient-reported outcome (PRO) triage algorithm may be used as a screening tool to discriminate between patients who do and do not need a visit in the outpatient epilepsy clinic. The purpose of this study was to evaluate the validity of the triage algorithm by comparing it to an assessment made by a neurologist subspecialised in epilepsy. METHODS: A neurologist reviewed the answers to the PRO questionnaires, and, based on the severity of the answers, the neurologist assessed whether or not the patients should be reclassified into another triage colour group. RESULTS: We found a significant difference between the triage of the neurologist and that of the PRO algorithm. The neurologist and PRO algorithm agreed regarding triage colour in 48.6% (37.4-59.9%) of the questionnaires (p less-than 0.0001). The neurologist and the PRO algorithm identified the same triage colour in 64.3% (38.8-83.7%) of the green baseline questionnaires (p less-than 0.0001), 46.7% (32.9-60.9%) of the yellow baseline questionnaires (p less-than 0.0001) and 38.5% (17.7-64.5%) of the red baseline questionnaires (p = 0.0016). CONCLUSIONS: The neurologist assessment reduced the number of patients in the yellow triage group and increased patient numbers in the green and the red triage groups compared with the PRO triage algorithm. Major differences between the expert assessment and the PRO results were found. Improvement of PRO triage is needed before it may be used as a clinical management tool for patients with epilepsy. FUNDING: none. TRIAL REGISTRATION: not relevant.

Managing antithrombotic treatment in a patient with atrial fibrillation and coronary stent with transient neurological symptoms in cerebral amyloid angiopathy.

We present the antithrombotic dilemma in a case with atrial fibrillation and a coronary stent and suspected transient ischemic attacks after diagnosed as a probable cerebral amyloid angiopathy and discuss plausible treatment options for the patient based on the available evidence.

Inflammatory profiles in plasma and cerebrospinal fluid of patients with neurosarcoidosis.

METHODS: Cerebrospinal fluid (CSF) and plasma levels of 38 biomarkers from 20 neurosarcoidosis (NS) patients were compared to healthy controls (HC). RESULTS: In CSF, 25 biomarkers were significantly elevated compared to HC: IFNγ, TNFα, TNFß, IL-2, IL-6, IL-10, IL-12B, IL-15, IL-16, CCL2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL22, CCL26, CXCL8, CXCL10, TNFR2, VEGF-A, PIGF, SAA, VCAM1, and ICAM1. In plasma, 12 biomarkers were significantly elevated compared to HC: IFNγ, TNFα, CCL2, CCL3, CCL4, CCL17, CXCL10, VEGFR1, PIGF, SAA, VCAM1, and ICAM1. CONCLUSION: NS patients have profoundly elevated cytokines, chemokines, vascular angiogenesis, and vascular injury biomarkers in CSF and plasma.

Risk factors for development of lymphopenia in dimethyl fumarate-treated patients with multiple sclerosis.

BACKGROUND: Dimethyl fumarate (DMF, Tecfidera®) is a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis. Lymphopenia is a frequent reason for discontinuation in fumarate-treated patients. Management strategies to minimize risk of lymphopenia are warranted. OBJECTIVE: The aims of this study were to investigate the correlation of body mass index (BMI), baseline absolute lymphocyte count (ALC), age and sex with risk of DMF-induced lymphopenia in MS patients. METHODS: The study was a retrospective cohort study of 452 MS patients who had been prescribed DMF at six clinics in two Danish regions between May 2014 and September 2017. Data on lymphocyte counts, BMI, age, sex, and reason for discontinuation of DMF were collected through the Danish Multiple Sclerosis Registry, with follow- up to two years after treatment start. RESULTS: 28.5% of patients had lymphopenia grade II or higher at some time in the first two years of DMF treatment. Increased risk of lymphopenia was observed in patients with baseline ALC of 1.00-1.49×109 cells/L (odds ratio, OR 5.48, p<0.0001) and 1.50-1.99×109 cells/L (OR 2.08, p = 0.0009). Reduced risk of lymphopenia was observed in patients with ALC of 2.00-2.49×109 cells/L (OR 0.51, p< 0.01) and ≥ 2.50×109 cells/L (0.12, p<0.0001). Patients aged ≥ 56 years had an increased risk of lymphopenia (OR 3.58, p<0.001), and patients with BMI ≥ 30 kg/m2 had a decreased risk of lymphopenia (OR 0.53, p value = 0.03). CONCLUSION: Low baseline ALC and older age were risk factors for DMF-induced lymphopenia, while BMI ≥ 30 kg/m2 and high baseline ALC were protective factors for developing lymphopenia in MS patients treated with DMF.

A prospective, one-year follow-up study of patients newly diagnosed with neurosarcoidosis.

METHODS: Twenty patients with newly diagnosed neurosarcoidosis were examined for multiple outcomes in an observational cohort study with 12-month follow-up. RESULTS: The patients' contrast-enhancing lesions on MRI scans reduced during treatment (p < 0.0001). The mean modified Rankin Score improved from 3.0 to 1.8 (p < 0.0001), and 75% of patients experienced clinically important improvement. Patients improved on the Symbol Digit Modalities Test (p < 0.0001) and on SF-36 Physical (p = 0.003) and Mental Component Summary scores (p = 0.03). Proportions of patients with substantial fatigue (75%) and high depression score (35%) were unchanged. CONCLUSIONS: 12-month immunosuppression improved several outcomes, and 75% of patients experienced clinically important improvement.

MIF in the cerebrospinal fluid is decreased during relapsing-remitting while increased in secondary progressive multiple sclerosis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is involved in the function of both the innate and adaptive immune systems and in neuroprotection and has recently been implicated in multiple sclerosis (MS). OBJECTIVES: Determination of MIF levels in the cerebrospinal fluid (CSF) of patients with distinct subtypes of MS and the cellular localization of MIF in human brain tissue. METHODS: The levels of MIF were investigated in CSF from patients with clinically isolated syndrome (CIS) (n = 26), relapsing-remitting MS (RRMS) (n = 22), secondary progressive MS (SPMS) (n = 19), and healthy controls (HCs) (n = 24), using ELISA. The effect of disease-modifying therapies in the RRMS and SPMS cohorts were examined. Cellular distribution of MIF in the human brain was studied using immunochemistry and the newly available OligoInternode database. RESULTS: MIF was significantly decreased in treatment-naïve CIS and RRMS patients compared to HCs but was elevated in SPMS. Interestingly, MIF levels were sex-dependent and significantly lower in women with CIS and RRMS. MIF expression in the human brain was localized to neurons, astrocytes, pericytes, and oligo5 oligodendrocytes but not in microglia. CONCLUSION: The finding that MIF was decreased in newly diagnosed CIS and RRMS patients but was high in patients with SPMS may suggest that MIF levels in CSF are regulated by local MIF receptor expression that affects the overall MIF signaling in the brain and may represent a protective mechanism that eventually fails.

Persistently reduced humoral and sustained cellular immune response from first to third SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients.

OBJECTIVE: To examine humoral and cellular response in multiple sclerosis patients on anti-CD20 therapy after third BNT162b2 mRNA SARS-CoV-2 vaccination. METHODS: A prospective longitudinal study design from first throughout third vaccination in Danish and American MS centers. All participants were treated with ocrelizumab. Antibody (Ab) levels were assessed before and after third vaccination using SARS-CoV-2 IgG II Quant assay (Abbott Laboratories). B- and T-lymphocytes enumeration was done with BD Multitest™6-color TBNK reagent. Spike-specific T-cell responses were measured through PBMC stimulation with spike peptide pools (JPT Peptide Technologies). RESULTS: We found that 14.0%, 37.7%, and 33.3% were seropositive after first, second and third vaccination. The median Ab-levels were 74.2 BAU/mL (range: 8.5-2427) after second vaccination, as well as 43.7 BAU/ml (range: 7.8-366.1) and 31.3 BAU/mL (range: 7.9-507.0) before and after third vaccination, respectively. No difference was found in levels after second and third vaccination (p = 0.1475). Seropositivity dropped to 25.0% of participants before the third vaccination, a relative reduction of 33.3% (p = 0.0020). No difference was found between frequencies of spike reactive CD4+and CD8+ T-cells after second (0.65 ± 0.08% and 0.95 ± 0.20%, respectively) and third vaccination (0.99 ± 0.22% and 1.3 ± 0.34%, respectively). CONCLUSION: In this longitudinal cohort we found no significant increased humoral or cellular response with administration of a third SARS-CoV-2 mRNA vaccination. These findings suggest the need for clinical strategies to include allowance of B cell reconstitution before repeat vaccination and/or provision of pre-exposure prophylactic monoclonal antibodies.

Serum levels of neurofilament light chain, neuron-specific enolase and S100 calcium-binding protein B during acute bacterial meningitis: a prospective cohort study.

PURPOSE: Acute bacterial meningitis (ABM) is a severe disease with an overall poor outcome. Neurofilament (NFL) has shown to be a promising biomarker of neuroaxonal injury in various neurological disorders but has not been investigated in ABM. The aims of this study were (i) to obtain a temporal profile of NFL, neuron-specific enolase (NSE) and S100B in serum during ABM, and (ii) to evaluate their use as biomarkers of severity (Glasgow coma score) and prognosis (Glasgow Outcome Score, GOS and death) in severe ABM. METHODS: Fifteen adults with severe community-acquired ABM who were admitted to the intensive care unit (ICU) and fulfilled the inclusion criteria were included. Lumbar puncture and blood tests were performed on admission, and blood tests were performed three times daily during the ICU stay. GOS was obtained day 30. RESULTS: Serum NFL was significantly elevated in ABM patients compared to healthy controls, both at admission and throughout the observation period (p < .01). NFL increased significantly from day 1 up to day 3-6 (p < .0001), peaking day 6. NSE increased significantly from admission up to day 3 (p < .01). At day 5-6, the serum values were not significantly different from values at admission. The highest median serum value of S100B was observed at admission (0.10 µg/L, IQR 0.06-0.14), significantly decreasing day 4-6 (p < .05). None of the investigated biomarkers revealed significant correlation with severity and prognosis. CONCLUSION: This study represents a first clinical observation of the temporal profile of NFL in serum, in severe ABM. No correlation with severity or prognosis.