Showing papers by "Sebastian Weis published in 2022"

Small Extracellular Vesicles from Peripheral Blood of Aged Mice Pass the Blood-Brain Barrier and Induce Glial Cell Activation

Abstract: Extracellular vesicles (EVs), including small EVs (sEVs), are involved in neuroinflammation and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Yet, increased neuroinflammation can also be detected in the aging brain, and it is associated with increased glial activation. Changes in EV concentration are reported in aging tissues and senescence cells, suggesting a role of EVs in the process of aging. Here, we investigated the effect of peripheral sEVs from aged animals on neuroinflammation, specifically on glial activation. sEVs were isolated from the peripheral blood of young (3 months) and aged (24 months) C57BL/6J wildtype mice and injected into the peripheral blood from young animals via vein tail injections. The localization of EVs and the expression of selected genes involved in glial cell activation, including Gfap, Tgf-β, Cd68, and Iba1, were assessed in brain tissue 30 min, 4 h, and 24 h after injection. We found that sEVs from peripheral blood of aged mice but not from young mice altered gene expression in the brains of young animals. In particular, the expression of the specific astrocyte marker, Gfap, was significantly increased, indicating a strong response of this glial cell type. Our study shows that sEVs from aged mice can pass the blood-brain barrier (BBB) and induce glial cell activation.

Effect of Automated Telephone Infectious Disease Consultations to Nonacademic Hospitals on 30-Day Mortality Among Patients With Staphylococcus aureus Bacteremia

Abstract: Key Points Question Do unsolicited telephone infectious disease consultations for nonacademic hospitals improve 30-day all-cause mortality in patients with Staphylococcus aureus bacteremia? Findings In this cluster randomized crossover clinical trial of 386 participants in 21 centers in Thuringia, Germany, no effect was found from the telephone consultations on 30-day all-cause mortality. Further explorative analyses revealed potential, modest improvements in quality-of-care indicators. Meaning This trial found that telephone consultations did not have an effect on survival despite improvements in some quality-of-care indicators, suggesting that bedside consultations should remain the stand of care.

Persistent T-Cell Reactivity in a Seronegative Patient after SARS-CoV-2 Infection and One Vaccination

Abstract: We present here a 64-year-old male participant of the CoNAN study who experienced a PCR-confirmed mild SARS-CoV-2 infection but did not develop any measurable antibody response. Additionally, after vaccination with ChAdOx1 (AstraZeneca, Cambridge, UK) 11 months later, no antibodies were detected in six serological tests three weeks after the vaccination. When we assessed T-helper (Th) cell immunity, SARS-CoV-2-specific Th cells produced detectable amounts of IFNγ and TNF six weeks after the infection. A robust T-cell immunity remained detectable at least until six months after the infection and was boosted by the vaccination thereafter. This case report points out that an assessment of a prior infection or a vaccine response based solely on antibody detection might have limitations in individual patients.

Impact of the COVID-19 pandemic on influenza and respiratory syncytial virus antibody titres in the community: a prospective cohort study in Neustadt, Thuringia, Germany

Abstract: The coronavirus disease 2019 (COVID-19) pandemic, and the subsequent infection control measures, has led to a substantial shift in the spectrum of respiratory tract infections. In many regions, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was or still is the most common viral respiratory pathogen while the circulation of influenza and respiratory syncytial virus (RSV) was decreased [1–3]. There is some evidence from the past that an interruption of viral circulation for several years may reduce the immunity of the population and lead to a consecutive severe season, as observed in the 2017–2018 season that was dominated by influenza B lineage Yamagata, which was barely present in the previous 5 years [4, 5]. The lack of circulation of influenza and RSV during the COVID-19 pandemic did not result in a substantial drop in respective antibody levels in the community over 12 months https://bit.ly/3qXVLId

ImmunoSep (Personalised Immunotherapy in Sepsis) international double-blind, double-dummy, placebo-controlled randomised clinical trial: study protocol

Abstract: Introduction Sepsis is a major cause of death among hospitalised patients. Accumulating evidence suggests that immune response during sepsis cascade lies within a spectrum of dysregulated host responses. On the one side of the spectrum there are patients whose response is characterised by fulminant hyperinflammation or macrophage activation-like syndrome (MALS), and on the other side patients whose immune response is characterised by immunoparalysis. A sizeable group of patients are situated between the two extremes. Recognising immune endotype is very important in order to choose the appropriate immunotherapeutic approach for each patient resulting in the best chance to improve the outcome. Methods and analysis ImmunoSep is a randomised placebo-controlled phase 2 clinical trial with a double-dummy design in which the effect of precision immunotherapy on sepsis phenotypes with MALS and immunoparalysis is studied. Patients are stratified using biomarkers. Specifically, 280 patients will be 1:1 randomly assigned to placebo or active immunotherapy as adjunct to standard-of-care treatment. In the active immunotherapy arm, patients with MALS will receive anakinra (recombinant interleukin-1 receptor antagonist) intravenously, and patients with immunoparalysis will receive subcutaneous recombinant human interferon-gamma. Τhe primary endpoint is the comparative decrease of the mean total Sequential Organ Failure Assessment score by at least 1.4 points by day 9 from randomisation. Ethics and dissemination The protocol is approved by the German Federal Institute for Drugs and Medical Devices; the National Ethics Committee of Greece and by the National Organization for Medicines of Greece; the Central Committee on Research Involving Human Subjects and METC Oost Netherland for the Netherlands; the National Agency for Medicine and Medical Products of Romania; and the Commission Cantonale d’éthique de la recherche sur l’être human of Switzerland. The results will be submitted for publication in peer-reviewed journals. Trial registration number NCT04990232.

Tidy up - The unfolded protein response in sepsis

Abstract: Pathogens, their toxic byproducts, and the subsequent immune reaction exert different forms of stress and damage to the tissue of the infected host. This stress can trigger specific transcriptional and post-transcriptional programs that have evolved to limit the pathogenesis of infectious diseases by conferring tissue damage control. If these programs fail, infectious diseases can take a severe course including organ dysfunction and damage, a phenomenon that is known as sepsis and which is associated with high mortality. One of the key adaptive mechanisms to counter infection-associated stress is the unfolded protein response (UPR), aiming to reduce endoplasmic reticulum stress and restore protein homeostasis. This is mediated via a set of diverse and complementary mechanisms, i.e. the reduction of protein translation, increase of protein folding capacity, and increase of polyubiquitination of misfolded proteins and subsequent proteasomal degradation. However, UPR is not exclusively beneficial since its enhanced or prolonged activation might lead to detrimental effects such as cell death. Thus, fine-tuning and time-restricted regulation of the UPR should diminish disease severity of infectious disease and improve the outcome of sepsis while not bearing long-term consequences. In this review, we describe the current knowledge of the UPR, its role in infectious diseases, regulation mechanisms, and further clinical implications in sepsis.

In-hospital mortality of patients with severe bloodstream infection: only the tip of the iceberg.

Abstract: Many studies on severe infections use in-hospital mortality, 14-day mortality, or 30-day mortality, as classic endpoints. However, in the era of high-performance intensive care, these endpoints no longer seem appropriate. Modern intensive-care medicine has massively reduced early mortality in patients with sepsis.1 Although this reduction is gratifying, it should not obscure the fact that these patients are still far from being healed.

Behandlung von Staphylococcus-aureus-Blutstrominfektionen

Abstract: Die Blutstrominfektion mit Staphylococcus aureus (SAB) stellt eine eigene klinische Entität dar. Aufgrund ihrer Häufigkeit und der hohen assoziierten Morbidität und Mortalität gelten besondere Anforderungen an das klinische Management. So ist im Gegensatz zu koagulasenegativen Staphylokokken, schon der einmalige Nachweis von Staphylococcus (S.) aureus in der Blutkultur als behandlungsbedürftige Infektion anzusehen. Es erfolgt die Einteilung in komplizierte vs. unkomplizierte Blutstrominfektion mit Auswirkung auf die empfohlene Therapiedauer (2 vs. 4 bis 6 Wochen). Die Durchführung einer transösophagealen Echokardiographie zum Ausschluss einer Endokarditis ist in den allermeisten Fällen indiziert. Aufgrund häufig klinisch stummer septischer Metastasen kann eine Positronenemissionstomographie mit Computertomographie (PET-CT) zur Fokussuche erwogen werden. Bei Methicillin-sensiblem S. aureus (MSSA) werden Flucloxacillin und Cefazolin als Basistherapie eingesetzt, bei Methicillin-resistentem S. aureus (MRSA) je nach Fokus und Komorbidität Vancomycin oder Daptomycin. Bei einliegendem Fremdmaterial sollte eine Kombination der Basistherapie mit Rifampicin oder Fosfomycin erwogen werden. Eine Fokussanierung durch Abszessdrainage oder Entfernung von infizierten intravaskulären Kathetern, intrakardialen Devices oder ggf. künstlichen Gelenken ist wichtig. Infektiologische Konsile verbessern die Behandlungsqualität und Mortalität bei SAB. Aktuelle offene Fragen behandeln die Identifikation der Subpopulation, die von einer Kombinationstherapie profitiert, die Effektivität und den Zeitpunkt einer Oralisierung der antibiotischen Therapie im Verlauf sowie eine mögliche Verkürzung der Gesamttherapiedauer. In diesem Übersichtsbeitrag fassen wir die aktuellen Standards zur Diagnostik und Therapie von Patienten mit SAB zusammen und stellen aktuelle relevante Studien zu diesem Krankheitsbild vor.

Non-patient related SARS-CoV-2 exposure to colleagues and household members impose the highest infection risk for hospital employees with and without patient contact in a German university hospital: follow-up of the prospective Co-HCW Seroprevalence study

Abstract: Background: The Co-HCW study is a prospective, longitudinal single center observational study on the SARS-CoV-2 seroprevalence and infection status in staff members of Jena University Hospital (JUH) in Jena, Germany. Material and Methods: This follow-up study covers the observation period from 19th May 2020 to 22nd June 2021. At each out of three voluntary study visits, participants filled out a questionnaire on individual SARS-CoV-2 exposure. In addition, serum samples to assess specific SARS-CoV-2 antibodies were collected. Participants with antibodies against nucleocapsid and/or spike protein without previous vaccination and/or a reported positive SARS-CoV-2 PCR test were regarded as participants with detected SARS-CoV-2 infection. Multivariable logistic regression modeling was applied to identify potential risk factors for infected compared to non-infected participants. Results: Out of 660 participants that were included during the first study visit, 406 participants (61.5%) were eligible for final analysis as they did not change the COVID-19 risk area (high-risk n=76; intermediate-risk n=198; low-risk n=132) during the study. Forty-four participants (10.8%, 95% confidence interval (95%CI) 8.0%-14.3%) had evidence of a current or past SARS-CoV-2 infection detected by serology (n=40) and/or PCR (n=28). No association of any SARS-CoV-2 infection with the COVID-19 risk group according to working place could be detected. But exposure to a SARS-CoV-2 positive household member (adjusted OR (AOR) 4.46, 95%CI 2.06-9.65) or colleague (AOR 2.30, 95%CI 1.10-4.79) significantly increased the risk of a SARS-CoV-2 infection. Conclusion. Our results demonstrate that non-patient-related SARS-CoV-2 exposure imposed the highest infection risk in hospital staff members of JUH.

Development of a new antigen-based microarray platform for screening and detection of human IgG antibodies against SARS-CoV-2

Abstract: Strategies to contain the current SARS-CoV-2 pandemic rely, beside vaccinations, also on molecular and serological testing. For any kind of assay development, screening for the optimal antigen is essential. Here we describe the verification of a new protein microarray with different commercially available preparations significant antigens of SARS-CoV-2 that can be used for the evaluation of the performance of these antigens in serological assays and for antibody screening in serum samples. Antigens of other pathogens that are addressed by widely used vaccinations were also included. To evaluate the accuracy of 21 different antigens or antigen preparations on the microarray, receiver operating characteristics (ROC) curve analysis using ELISA results as reference were performed. Except for a single concentration, a diagnostic sensitivity of 1 was determined for all antigen preparations. A diagnostic specificity, as well as an area under the curve (AUC) of 1 was obtained for 16 of 21 antigen preparations. For the remaining five, the diagnostic specificity ranged from 0.942 to 0.981 and AUC from 0.974 to 0.999. The optimized assay was subsequently also applied to determine the immune status of previously tested individuals and/or to detect the immunization status after COVID-19 vaccination. Microarray evaluation of the antibody profiles of COVID-19 convalescent and post vaccination sera showed that the IgG response differed between these groups, and that the choice of the test antigen is crucial for the assay performance. Furthermore, the results showed that the immune response is highly individualized, depended on several factors (e.g., age or sex), and was not directly related to the severity of disease. The new protein microarray provides an ideal method for the parallel screening of many different antigens of vaccine-preventable diseases in a single sample and for reliable and meaningful diagnostic tests, as well as for the development of safe and specific vaccines.

Persistent humoral and CD4+ TH cell immunity after mild SARS-COV-2 infection—The CoNAN long-term study

Abstract: Understanding persistent cellular and humoral immune responses to SARS-CoV-2 will be of major importance to terminate the ongoing pandemic. Here, we assessed long-term immunity in individuals with mild COVID-19 up to 1 year after a localized SARS-CoV-2 outbreak. CoNAN was a longitudinal population-based cohort study performed 1.5 months, 6 months, and 12 months after a SARS-CoV-2 outbreak in a rural German community. We performed a time series of five different IgG immunoassays assessing SARS-CoV-2 antibody responses on serum samples from individuals that had been tested positive after a SARS-CoV-2 outbreak and in control individuals who had a negative PCR result. These analyses were complemented with the determination of spike-antigen specific TH cell responses in the same individuals. All infected participants were presented as asymptomatic or mild cases. Participants initially tested positive for SARS-CoV-2 infection either with PCR, antibody testing, or both had a rapid initial decline in the serum antibody levels in all serological tests but showed a persisting TH cell immunity as assessed by the detection of SARS-CoV-2 specificity of TH cells for up to 1 year after infection. Our data support the notion of a persistent T-cell immunity in mild and asymptomatic cases of SARS-CoV-2 up to 1 year after infection. We show that antibody titers decline over 1 year, but considering several test results, complete seroreversion is rare. Trial registration German Clinical Trials Register DRKS00022416.

PERSISTENT IMMUNITY AFTER MILD SARS CoV-2 INFECTION - THE CoNAN-LONG TERM STUDY -

Abstract: Objectives: Understanding persistent cellular and humoral immune responses to SARS-CoV-2 will be of major importance to terminate the ongoing pandemic. Here we assessed long-term immunity in individuals with mild COVID-19 up to one year after a localized SARS-CoV-2 outbreak. Methods: CoNAN was a longitudinal population-based cohort study performed 1.5 months, 6 months and 12 months after a SARS-CoV-2 outbreak in a rural German community. We performed a time series of five different IgG immunoassays assessing SARS-CoV-2 antibody responses on serum samples from individuals that had been tested positive after a SARS-CoV-2 outbreak as well as in control individuals who had a negative PCR result. These analyses were complemented with the determination of spike-antigen specific TH cell responses in the same individuals. Results: All infected participants presented as asymptomatic or mild cases. Participants initially tested positive for SARS-CoV-2 infection either with PCR, antibody testing, or both had a rapid initial decline in the serum antibody levels in all serological test but showed a persisting and robust TH cell immunity as assessed by the detection of SARS-CoV-2 specificity of TH cells for up to one year after infection. Conclusion: Our data support the notion of a robust T cell immunity in mild and asymptomatic cases of SARS-CoV-2 up to one year after infection. We show that antibody titers decline over one year, but considering several test results, complete seroconversion is rare. Trial Registration: German Clinical Trials Register DRKS00022416.