Publications by authors named "Oliver Witzke"

206 Publications

Impaired Humoral Response in Renal Transplant Recipients to SARS-CoV-2 Vaccination with BNT162b2 (Pfizer-BioNTech).

Viruses 2021 04 25;13(5). Epub 2021 Apr 25.

Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has a major impact on transplant recipients, with mortality rates up to 20%. Therefore, the effect of established messenger RNA (mRNA)-based SARS-CoV-2 vaccines have to be evaluated for solid organ transplant patients (SOT) since they are known to have poor responses after vaccination. We investigated the SARS-CoV-2 immune response via SARS-CoV-2 IgG detection in 23 renal transplant recipients after two doses of the mRNA-based SARS-CoV-2 vaccine BNT162b2 following the standard protocol. The antibody response was evaluated once with an anti-SARS-CoV-2 IgG CLIA 15.8 +/- 3.0 days after the second dose. As a control, SARS-CoV-2 IgG was determined in 23 healthcare workers (HCW) and compared to the patient cohort. Only 5 of 23 (22%) renal transplant recipients were tested positive for SARS-CoV-2 IgG antibodies after the second dose of vaccine. In contrast, all 23 (100%) HCWs were tested positive for antibodies after the second dose. Thus, the humoral response of renal transplant recipients after two doses of the mRNA-based vaccine BNT162b2 (Pfizer-BioNTech, Kronach, Germany) is impaired and significantly lower compared to healthy controls (22% vs. 100%; = 0.0001). Individual vaccination strategies might be beneficial in these vulnerable patients.
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http://dx.doi.org/10.3390/v13050756DOI Listing
April 2021

SARS-CoV-2 Seroprevalence in Healthcare Workers in Germany: A Follow-Up Study.

Int J Environ Res Public Health 2021 04 25;18(9). Epub 2021 Apr 25.

Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 179, 45147 Essen, Germany.

SARS-CoV-2 is a worldwide challenge for the medical sector. Healthcare workers (HCW) are a cohort vulnerable to SARS-CoV-2 infection due to frequent and close contact with COVID-19 patients. However, they are also well trained and equipped with protective gear. The SARS-CoV-2 IgG antibody status was assessed at three different time points in 450 HCW of the University Hospital Essen in Germany. HCW were stratified according to contact frequencies with COVID-19 patients in (I) a high-risk group with daily contacts with known COVID-19 patients (n = 338), (II) an intermediate-risk group with daily contacts with non-COVID-19 patients (n = 78), and (III) a low-risk group without patient contacts (n = 34). The overall seroprevalence increased from 2.2% in March-May to 4.0% in June-July to 5.1% in October-December. The SARS-CoV-2 IgG detection rate was not significantly different between the high-risk group (1.8%; 3.8%; 5.5%), the intermediate-risk group (5.1%; 6.3%; 6.1%), and the low-risk group (0%, 0%, 0%). The overall SARS-CoV-2 seroprevalence remained low in HCW in western Germany one year after the outbreak of COVID-19 in Germany, and hygiene standards seemed to be effective in preventing patient-to-staff virus transmission.
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http://dx.doi.org/10.3390/ijerph18094540DOI Listing
April 2021

Glycyrrhizin Effectively Inhibits SARS-CoV-2 Replication by Inhibiting the Viral Main Protease.

Viruses 2021 04 2;13(4). Epub 2021 Apr 2.

Department of Infectious Diseases, West German Centre of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany.

The outbreak of SARS-CoV-2 developed into a global pandemic affecting millions of people worldwide. Despite one year of intensive research, the current treatment options for SARS-CoV-2 infected people are still limited. Clearly, novel antiviral compounds for the treatment of SARS-CoV-2 infected patients are still urgently needed. Complementary medicine is used along with standard medical treatment and accessible to a vast majority of people worldwide. Natural products with antiviral activity may contribute to improve the overall condition of SARS-CoV-2 infected individuals. In the present study, we investigated the antiviral activity of glycyrrhizin, the primary active ingredient of the licorice root, against SARS-CoV-2. We demonstrated that glycyrrhizin potently inhibits SARS-CoV-2 replication in vitro. Furthermore, we uncovered the underlying mechanism and showed that glycyrrhizin blocks the viral replication by inhibiting the viral main protease M that is essential for viral replication. Our data indicate that the consumption of glycyrrhizin-containing products such as licorice root tea of black licorice may be of great benefit for SARS-CoV-2 infected people. Furthermore, glycyrrhizin is a good candidate for further investigation for clinical use to treat COVID-19 patients.
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http://dx.doi.org/10.3390/v13040609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066091PMC
April 2021

Humoral Response to SARS-CoV-2-Vaccination with BNT162b2 (Pfizer-BioNTech) in Patients on Hemodialysis.

Vaccines (Basel) 2021 Apr 8;9(4). Epub 2021 Apr 8.

Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.

mRNA-based SARS-CoV-2 vaccines offer a preventive strategy against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections that is of interest in the care of patients on hemodialysis (HDP). We measured humoral immune responses in 72 HDP after standard vaccination with two doses of the mRNA-based SARS-CoV-2 vaccine BNT162b2 (Pfizer-BioNTech). Antibody responses were evaluated with an anti-SARS-CoV-2 IgG ChemiLuminescent ImmunoAssay (CLIA) two weeks after the second dose. In addition, SARS-CoV-2 IgG was determined in a control of 16 healthy healthcare workers (HCW). The control group of HCW has shown a strong antibody response with a median (MD (Q1; Q3)) antibody titer of 800.0 AU/mL (520.5; 800.0). In comparison to HCW, HDP under 60 years of age responded equally (597.0 AU/mL (410.5; 800.0), = 0.051). However, the antibody responses of the HDP negatively correlated with age (r = 0.2954 < 0.0001), leading to significantly lower antibody titers in HDP over 60 years (280.0 AU/mL (45.7; 477.0), < 0.0001). To thoroughly understand the immunogenicity of the new mRNA-based vaccines in HDP, longitudinal data on the effectiveness and durability of antibody responses are needed. Modifications of immunization schedules should be considered in HDP with low or without antibody responsiveness after standard vaccination to boost immune reactivity and prolong protective effects in these vulnerable patients.
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http://dx.doi.org/10.3390/vaccines9040360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070660PMC
April 2021

No association of genetic variants in TLR4, TNF-α, IL10, IFN-γ, and IL37 in cytomegalovirus-positive renal allograft recipients with active CMV infection-Subanalysis of the prospective randomised VIPP study.

PLoS One 2021 16;16(4):e0246118. Epub 2021 Apr 16.

Department of Nephrology, University Clinic Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.

Background: Cytomegalovirus (CMV) infection is amongst the most important factors complicating solid organ transplantation. In a large prospective randomized clinical trial, valganciclovir prophylaxis reduced the occurrence of CMV infection and disease compared with preemptive therapy in CMV-positive renal allograft recipients (VIPP study; NCT00372229). Here, we present a subanalysis of the VIPP study, investigating single nucleotide polymorphisms (SNPs) in immune-response-related genes and their association with active CMV infection, CMV disease, graft loss or death, rejection, infections, and leukopenia.

Methods: Based on literature research ten SNPs were analyzed for TLR4, three for IFN-γ, six for IL10, nine for IL37, and two for TNF-α. An asymptotic independence test (Cochran-Armitage trend test) was used to examine associations between SNPs and the occurrence of CMV infection or other negative outcomes. Statistical significance was defined as p<0.05 and Bonferroni correction for multiple testing was performed.

Results: SNPs were analyzed on 116 blood samples. No associations were found between the analyzed SNPs and the occurrence of CMV infection, rejection and leukopenia in all patients. For IL37 rs2723186, an association with CMV disease (p = 0.0499), for IL10 rs1800872, with graft loss or death (p = 0.0207) and for IL10 rs3024496, with infections (p = 0.0258) was observed in all patients, however did not hold true after correction for multiple testing.

Conclusion: The study did not reveal significant associations between the analyzed SNPs and the occurrence of negative outcomes in CMV-positive renal transplant recipients after correction for multiple testing. The results of this association analysis may be of use in guiding future research efforts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246118PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051780PMC
April 2021

CD107a (LAMP-1) Cytotoxic CD8 T-Cells in Lupus Nephritis Patients.

Front Med (Lausanne) 2021 23;8:556776. Epub 2021 Mar 23.

Department of Infectious Diseases, West German Centre of Infectious Diseases, University Duisburg-Essen, Essen, Germany.

Cytotoxic CD8 T-cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the role of CD107a (LAMP-1) on cytotoxic CD8 T-cells in SLE-patients in particular with lupus nephritis. Peripheral blood of SLE-patients ( = 31) and healthy controls ( = 21) was analyzed for the expression of CD314 and CD107a by flow cytometry. Kidney biopsies of lupus nephritis patients were investigated for the presence of CD8 and C107a cells by immunohistochemistry and immunofluorescence staining. The percentages of CD107a on CD8 T-cells were significantly decreased in SLE-patients as compared to healthy controls (40.2 ± 18.5% vs. 47.9 ± 15.0%, = 0.02). This was even more significant in SLE-patients with inactive disease. There was a significant correlation between the percentages of CD107aCD8 T-cells and SLEDAI. The evaluation of lupus nephritis biopsies showed a significant number of CD107aCD8 T-cells mainly located in the peritubular infiltrates. The intrarenal expression of CD107a was significantly correlated with proteinuria. These results demonstrate that CD8 T-cells of patients with systemic lupus erythematosus have an altered expression of CD107a which seems to be associated with disease activity. The proof of intrarenal CD107aCD8 suggests a role in the pathogenesis of lupus nephritis.
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http://dx.doi.org/10.3389/fmed.2021.556776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021690PMC
March 2021

Disinfection of SARS-CoV-2 Contaminated Surfaces of Personal Items with UVC-LED Disinfection Boxes.

Viruses 2021 03 31;13(4). Epub 2021 Mar 31.

West German Centre of Infectious Diseases, Department of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted from person to person by close contact, small aerosol respiratory droplets, and potentially via contact with contaminated surfaces. Herein, we investigated the effectiveness of commercial UVC-LED disinfection boxes in inactivating SARS-CoV-2-contaminated surfaces of personal items. We contaminated glass, metal, and plastic samples representing the surfaces of personal items such as smartphones, coins, or credit cards with SARS-CoV-2 formulated in an organic matrix mimicking human respiratory secretions. For disinfection, the samples were placed at different distances from UVC emitting LEDs inside commercial UVC-LED disinfection boxes and irradiated for different time periods (up to 10 min). High viral loads of SARS-CoV-2 were effectively inactivated on all surfaces after 3 min of irradiation. Even 10 s of UVC-exposure strongly reduced viral loads. Thus, UVC-LED boxes proved to be an effective method for disinfecting SARS-CoV-2-contaminated surfaces that are typically found on personal items.
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http://dx.doi.org/10.3390/v13040598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065986PMC
March 2021

Reactivations of Latent Viral Infections Are Associated with an Increased Thr389 p70S6k Phosphorylation in Peripheral Lymphocytes of Renal Transplant Recipients.

Viruses 2021 03 6;13(3). Epub 2021 Mar 6.

West German Centre of Infectious Diseases, Department of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany.

Reactivations of BK polyoma virus (BKPyV) and human cytomegalovirus (HCMV) frequently cause life- and graft-threatening complications after renal transplantation. Both viruses are dependent on the mTOR pathway for replication. In this study we investigated the association of viral replication with mTOR activity in peripheral lymphocytes of renal transplant recipients. A flow-cytometry based assay for the measurement of Thr389 p70S6k phosphorylation, a surrogate marker of the mTOR pathway was established. Forty-eight adult renal transplant recipients were recruited to measure p70S6k activity in their peripheral blood mononuclear cells. This data set in conjunction with information concerning previous replication of BKPyV and HCMV was examined for correlations. Episodes of BKPyV replication were significantly associated with increased p70S6k phosphorylation in CD4 T lymphocytes ( = 0.0002) and CD19 B lymphocytes ( = 0.0073). HCMV infection of patients with a high-risk HCMV constellation of donor and recipient (D+/R-) was associated with increased p70S6k phosphorylation in CD19 B lymphocytes ( = 0.0325). These associations were found to be independent of the trough levels of the immunosuppressive drugs. Conclusion: P70S6k phosphorylation in peripheral lymphocytes is associated with BKPyV reactivations and to a lesser extent with HCMV infections in renal transplant recipients.
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http://dx.doi.org/10.3390/v13030424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000484PMC
March 2021

Convalescent plasma treatment of critically ill intensive care COVID-19 patients.

Transfusion 2021 Mar 30. Epub 2021 Mar 30.

Department of Infectious Diseases, West German Centre of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, Essen, Germany.

Background: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be life-threatening, and specific antiviral drugs are currently not available. However, first studies indicated that convalescent plasma treatment might improve the clinical outcome of coronavirus disease 2019 (COVID-19) patients.

Study Design And Methods: In the current study, we investigated the efficacy of convalescent plasma treatment in eight COVID-19 patients. All the patients were critically ill, and seven of them were SARS-CoV-2 RNA-positive when starting treatment. SARS-CoV-2-specific antibodies were determined by an enzyme-linked immunosorbent assay detecting immunoglobulin G (IgG) antibodies against the S1 protein (Euroimmun), and the neutralizing titers were determined with a cell-culture-based neutralization assay. Plasma treatment started between 4 and 23 days after the onset of symptoms. The patients were usually treated by three plasma units, each containing 200-280 ml, which was applied at day 1, 3, and 5.

Results: Donor sera had on average lower IgG antibody ratios and neutralizing titers than the COVID-19 patients before the onset of treatment (median ratio of 5.8 and neutralizing titer of 1:320 vs. 7.5 and 1:640, respectively). Nevertheless, we observed an increase of antibody ratios in seven and of neutralizing titers in five patients after treatment; which did, however, not correlate with patient survival. Plasma treatment was effective in three patients, but five deceased despite treatment. Patients who deceased had a later treatment onset than survivors and finally died from multiple organ failure.

Conclusion: Our data indicate that the efficacy of convalescent plasma treatment of critically ill COVID-19 patients who already had developed strong antiviral immune responses and organ complications is limited.
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http://dx.doi.org/10.1111/trf.16392DOI Listing
March 2021

Observational cohort study of neurological involvement among patients with SARS-CoV-2 infection.

Ther Adv Neurol Disord 2021 26;14:1756286421993701. Epub 2021 Feb 26.

Department of Neurology and Center for Translational and Behavioral Neurosciences (C-TNBS), University Medicine Essen, Hufelandstraße 55, Essen, 45147, Germany.

Background: A growing number of reports suggest that infection with SARS-CoV-2 often leads to neurological involvement; however, data on the incidence and severity are limited to mainly case reports and retrospective studies.

Methods: This prospective, cross-sectional study of 102 SARS-CoV-2 PCR positive patients investigated the frequency, type, severity and risk factors as well as underlying pathophysiological mechanisms of neurological involvement (NIV) in COVID-19 patients.

Results: Across the cohort, 59.8% of patients had NIV. Unspecific NIV was suffered by 24.5%, mainly general weakness and cognitive decline or delirium. Mild NIV was found in 9.8%; most commonly, impaired taste or smell. Severe NIV was present in 23.5%; half of these suffered cerebral ischaemia. Incidence of NIV increased with respiratory symptoms of COVID-19. Mortality was higher with increasing NIV severity. Notably, 83.3% with severe NIV had a pre-existing neurological co-morbidity. All cerebrospinal fluid (CSF) samples were negative for SARS-CoV-2 RNA, and SARS-CoV-2 antibody quotient did not suggest intrathecal antibody synthesis. Of the patients with severe NIV, 50% had blood-brain barrier (BBB) disruption and showed a trend of elevated interleukin levels in CSF. Antibodies against neuronal and glial epitopes were detected in 35% of the patients tested.

Conclusion: Cerebrovascular events were the most frequent severe NIV and severe NIV was associated with high mortality. Incidence of NIV increased with respiratory symptoms and NIV and pre-existing neurological morbidities were independent risk factors for fatality. Inflammatory involvement due to BBB disruption and cytokine release drives NIV, rather than direct viral invasion. These findings might help physicians define a further patient group requiring particular attention during the pandemic.
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http://dx.doi.org/10.1177/1756286421993701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934032PMC
February 2021

Norovirus Infections in Kidney Transplant Recipients.

Transplantation 2021 Mar 2. Epub 2021 Mar 2.

Department of Nephrology, Universitätsmedizin Essen, University Duisburg-Essen, Essen, Germany Department of Infectious Diseases, West German Centre of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, Essen, Germany Centre of Translational Medicine, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, Germany Institute for Virology, Universitätsmedizin Essen, University Duisburg-Essen, Essen, Germany.

Background: Norovirus (NoV) infection frequently progresses to chronic disease after kidney transplant (KTx). This study aims to assess potential risk factors helping to determine patients at risk of chronic NoV infection and to analyse the effect of NoV on allograft outcome. Additionally, we assessed the effectiveness of intravenous immunoglobulin (IVIg) therapy for chronic NoV infection.

Methods: The study enrolled 60 KTx patients requiring hospitalization because of NoV infection. Clinical parameters, severity of NoV infection and potential risk factors were evaluated. Outcome parameters were clinical symptoms, rehospitalizations, persistent shedding of virus and effects on allograft function.

Results: Patients were divided into 2 groups: 29 had acute NoV infection only, 31 progressed to chronic NoV infection. Chronic NoV infection was defined as a recurrence of clinical symptoms plus redetection of NoV in stool. Lymphocyte-depleting induction therapy and diabetes mellitus were independent risk factors for chronic infection. For patients with chronic NoV infection, length of stay in hospital was significantly prolonged (p= 0.024). Allograft function remained impaired in the chronic NoV group 6 and 12 months after initial admission.IVIg was administered to 18 patients with chronic NoV infection. No further clinical symptoms of NoV infection occurred in 13 (72%) of these patients. However, NoV was still detectable in stool specimens from 10 (77%) of these patients.

Conclusions: Chronic NoV infection is associated with reduced allograft function. Administration of IVIg to patients with chronic NoV infection seems beneficial in achieving freedom from clinical symptoms, despite limited effects on shedding of virus.
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http://dx.doi.org/10.1097/TP.0000000000003708DOI Listing
March 2021

Characterization of follicular T helper cells and donor-specific T helper cells in renal transplant patients with de novo donor-specific HLA-antibodies.

Clin Immunol 2021 May 24;226:108698. Epub 2021 Feb 24.

Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany. Electronic address:

T follicular helper (T) cells are a heterogeneous subset of immunocompetent T helper (T) cells capable of augmenting B cell responses in lymphoid tissues. In transplantation, exposure to allogeneic tissue activates T cells increasing the risk of the emergence of de novo donor-specific HLA-antibodies (dnDSA). These can cause antibody-mediated rejection (AMR) and allograft loss. Follicular regulatory T (T) cells counteract T cell activity. Here, we investigated the implications of T and T cells on dnDSA formation after renal transplantation (RTX). Considering T cells to be CXCR5 and IL-21, we found by flow cytometry that patients with dnDSA produced IL-21 more abundantly compared to healthy volunteers. In in vitro alloreactivity assays, patients with dnDSA featured an enhanced alloreactive T cell pool in response to donor-specific HLA antigens. Besides, longitudinal investigations suggested enhanced alloreactivity shortly after transplantation increasing the risk of dnDSA development. Taken together, in spite of continuous immunosuppression we report a strong IL-21 response in T cells and an expanded reservoir of donor-specific memory T cells in patients with dnDSA. This warrants further investigations if aberrant T cell activation may precede the formation of dnDSA promoting AMR.
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http://dx.doi.org/10.1016/j.clim.2021.108698DOI Listing
May 2021

[Acute kidney injury].

Nephrologe 2021 18;16(2):65. Epub 2021 Feb 18.

Klinik für Infektiologie, Westdeutsches Zentrum für Infektiologie, Universitätsmedizin Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Deutschland.

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http://dx.doi.org/10.1007/s11560-021-00489-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890778PMC
February 2021

von Willebrand Factor Multimer Formation Contributes to Immunothrombosis in Coronavirus Disease 2019.

Crit Care Med 2021 05;49(5):e512-e520

Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Herne, Germany.

Objectives: Prevention and therapy of immunothrombosis remain crucial challenges in the management of coronavirus disease 2019, since the underlying mechanisms are incompletely understood. We hypothesized that endothelial damage may lead to substantially increased concentrations of von Willebrand factor with subsequent relative deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13).

Design: Prospective controlled cross-over trial.

Setting: Blood samples of patients with confirmed coronavirus disease 2019 and healthy controls were obtained in three German hospitals and analyzed in a German hemostaseologic laboratory.

Patients: Seventy-five patients with confirmed coronavirus disease 2019 of mild to critical severity and 30 healthy controls.

Measurements And Main Results: von Willebrand factor antigen, ADAMTS13, and von Willebrand factor multimer formation were analyzed. von Willebrand factor antigen was 4.1 times higher in COVID-19 patients compared with healthy controls (p < 0.0001), whereas ADAMTS13 activities were not significantly different (p = 0.18). The ADAMTS13/von Willebrand factor antigen ratio was significantly lower in COVID-19 than in the control group (24.4 ± 20.5 vs 82.0 ± 30.7; p < 0.0001). Fourteen patients (18.7%) undercut a critical ratio of 10 as described in thrombotic thrombocytopenic purpura. Gel analysis of multimers resembled a thrombotic thrombocytopenic purpura pattern with loss of the largest multimers in 75% and a smeary triplet pattern in 39% of the patients. The ADAMTS13/von Willebrand factor antigen ratio decreased continuously from mild to critical disease (analysis of variance p = 0.026). Furthermore, it differed significantly between surviving patients and those who died from COVID-19 (p = 0.001) yielding an area under the curve of 0.232 in receiver operating characteristic curve curve analysis.

Conclusion: COVID-19 is associated with a substantial increase in von Willebrand factor levels, which can exceed the ADAMTS13 processing capacity resulting in the formation of large von Willebrand factor multimers indistinguishable from thrombotic thrombocytopenic purpura. The ADAMTS13/von Willebrand factor antigen ratio is an independent predictor of severity of disease and mortality. These findings provide a rationale to consider plasma exchange as a therapeutic option in COVID-19 and to include von Willebrand factor and ADAMTS13 in the diagnostic workup.
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http://dx.doi.org/10.1097/CCM.0000000000004918DOI Listing
May 2021

COVID-19 immune signatures reveal stable antiviral T cell function despite declining humoral responses.

Immunity 2021 02;54(2):340-354.e6

Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany. Electronic address:

Cellular and humoral immunity to SARS-CoV-2 is critical to control primary infection and correlates with severity of disease. The role of SARS-CoV-2-specific T cell immunity, its relationship to antibodies, and pre-existing immunity against endemic coronaviruses (huCoV), which has been hypothesized to be protective, were investigated in 82 healthy donors (HDs), 204 recovered (RCs), and 92 active COVID-19 patients (ACs). ACs had high amounts of anti-SARS-CoV-2 nucleocapsid and spike IgG but lymphopenia and overall reduced antiviral T cell responses due to the inflammatory milieu, expression of inhibitory molecules (PD-1, Tim-3) as well as effector caspase-3, -7, and -8 activity in T cells. SARS-CoV-2-specific T cell immunity conferred by polyfunctional, mainly interferon-γ-secreting CD4 T cells remained stable throughout convalescence, whereas humoral responses declined. Immune responses toward huCoV in RCs with mild disease and strong cellular SARS-CoV-2 T cell reactivity imply a protective role of pre-existing immunity against huCoV.
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http://dx.doi.org/10.1016/j.immuni.2021.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871825PMC
February 2021

[Thrombotic microangiopathy].

Nephrologe 2021 Feb 3:1-10. Epub 2021 Feb 3.

Klinik für Infektiologie, Westdeutsches Zentrum für Infektiologie, Universitätsmedizin Essen, Universität Duisburg-Essen, Essen, Deutschland.

Thrombotic microangiopathy (TMA) is characterized by an endothelium injury-associated formation of platelet clots in arterial and venous microvessels. Concomitant ischemia causes severe organ dysfunction and can be acutely life threatening. The underlying etiology of TMA shows a very heterogeneous disease spectrum. In addition to thrombotic thrombocytopenic purpura, which is characterized by a greatly reduced activity of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), infection-associated classical hemolytic uremic syndrome (HUS) and complement-mediated atypical HUS (aHUS), further very rare diseases or secondary forms can be present. The differential diagnostic classification is pivotal as different treatment approaches are necessary. Initiation of novel specific pharmacotherapy methods has greatly improved the prognosis of TMA.
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http://dx.doi.org/10.1007/s11560-021-00487-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856846PMC
February 2021

SARS-CoV-2-specific humoral and cellular immunity in two renal transplants and two hemodialysis patients treated with convalescent plasma.

J Med Virol 2021 05 9;93(5):3047-3054. Epub 2021 Feb 9.

Department of Infectious Diseases, West German Centre of Infectious Diseases, Universitätsmedizin Essen, University of Duisburg-Essen, Essen, Germany.

When patients with chronic kidney disease are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) they can face two specific problems: virus-specific immune responses may be impaired and remdesivir, an antiviral drug described to shorten recovery, is contraindicated. Antiviral treatment with convalescent plasma (CP) could be an alternative treatment option. In this case report, we present two kidney transplant recipients and two hemodialysis patients who were infected with SARS-CoV-2 and received CP. Antibodies against the receptor-binding domain in the S1 subunit of the SARS-CoV-2 spike protein were determined sequentially by immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) and neutralization assay and specific cellular responses by interferon-gamma ELISpot. Before treatment, in both kidney transplant recipients and one hemodialysis patient antibodies were undetectable by ELISA (ratio < 1.1), corresponding to low neutralizing antibody titers (≤1:40). ELISpot responses in the four patients were either weak or absent. After CP treatment, we observed an increase of SARS-CoV-2-specific antibodies (IgG ratio and neutralization titer) and of specific cellular responses. After intermittent clinical improvement, one kidney transplant recipient again developed typical symptoms on Day 12 after treatment and received a second cycle of CP treatment. Altogether, three patients clinically improved and could be discharged from the hospital. However, one 83-year-old multimorbid patient deceased. Our data suggest that the success of CP therapy may only be temporary in patients with chronic kidney disease; which requires close monitoring of viral load and antiviral immunity and possibly an adaptation of the treatment regimen.
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http://dx.doi.org/10.1002/jmv.26840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014298PMC
May 2021

Sex-Associated Differences in Cytomegalovirus Prevention: Prophylactic Strategy is Potentially Associated With a Strong Kidney Function Impairment in Female Renal Transplant Patients.

Front Pharmacol 2020 21;11:534681. Epub 2020 Dec 21.

Department of Biology, Systems Immunology Lab, Humboldt-Universität zu Berlin, Berlin, Germany.

Post-transplantation cytomegalovirus (CMV) syndrome can be prevented using the antiviral drug (val)ganciclovir. (Val)ganciclovir is typically administered following a prophylactic or a pre-emptive strategy. The prophylactic strategy entails early universal administration, the pre-emptive strategy, early treatment in case of infection. However, it is not clear which strategy is superior with respect to transplantation outcome; sex-specific effects of these prevention strategies are not known. We have retrospectively analyzed 540 patients from the multi-centre Harmony study along eight pre-defined visits: 308 were treated according to a prophylactic, 232 according to a pre-emptive strategy. As expected, we observed an association of prophylactic strategy with lower incidence of CMV syndrome, delayed onset and lower viral loads compared to the pre-emptive strategy. However, in female patients, the prophylactic strategy was associated with a strong impairment of glomerular filtration rate one year post-transplant (difference: -11.8 ± 4.3 ml min·1.73 m, = 0.006). Additionally, we observed a tendency of higher incidence of acute rejection and severe BK virus reactivation in the prophylactic strategy group. While the prophylactic strategy was more effective for preventing CMV syndrome, our results suggest for the first time that the prophylactic strategy might lead to inferior transplantation outcomes in female patients, providing evidence for a strong association with sex. Further randomized controlled studies are necessary to confirm this potential negative effect.
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http://dx.doi.org/10.3389/fphar.2020.534681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845412PMC
December 2020

Generation of HBsAg-reactive T- and B-cells following HBV vaccination in serological non-responders under hemodialysis treatment.

Eur J Immunol 2021 May 9;51(5):1278-1281. Epub 2021 Feb 9.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany.

HBV vaccination is recommend for hemodialysis patients, but only 50-60% of the patients show seroconversion. HBV vaccine-induced generation of HBV reactive T and B cells could be detected regardless of their capacity to mount a serological response, indicating that patients without seroconversion are potentially protected by their HBV-reactive T cell pool.
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http://dx.doi.org/10.1002/eji.202048756DOI Listing
May 2021

Coronavirus Disease 2019 Associated Risk Score, Behavior, and Symptom Prevalence in German Transplant Recipients.

Transplant Proc 2020 Dec 16. Epub 2020 Dec 16.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, BIH Center for Regenerative Therapies, and Institute of Medical Immunology, Berlin, Germany; Ruhr-University Bochum, Marien Hospital Herne, Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Herne, Germany. Electronic address:

Background: Transplant recipients are prone to developing severe infections because of immunosuppression. Therefore, studying the manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in transplant recipients is of particular importance.

Methods: One hundred twelve transplant patients consecutively visiting the outpatient department of 2 German transplant centers were included in this study after providing written informed consent. The patients were interviewed about coronavirus disease 2019 (COVID-19) symptoms and history. Nasopharyngeal swabs were analyzed by SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR). SARS-CoV-2 IgG and IgA were measured concomitantly in patient sera by enzyme-linked immunosorbent assay.

Results: The risk of severe COVID-19 according to 2 recent scores differed among the analyzed patients. All patients were well educated about their presumed higher risk of a severe COVID-19 and described performing self-isolation wherever possible. Nevertheless, 20 patients reported contact with someone suspected of having COVID-19 or who tested positive shortly thereafter (18%). Despite this relatively high exposure, no clinically relevant case of COVID-19 was reported. Though SARS-CoV-2 IgG and IgA were found in 3 patients (3%); 2 patients were asymptomatic and only 1 had mild COVID-19 symptoms and positive RT-PCR 4 weeks earlier. There were no occult SARS-CoV-2 infections, as demonstrated by negative PCR tests.

Conclusion: Despite the high exposure level, the incidence of COVID-19 remained very low. Because of the differences in COVID-19 risk, balancing risk exposure and quality of life should be recommended.
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http://dx.doi.org/10.1016/j.transproceed.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833920PMC
December 2020

Orbital aspergillosis: a case report and review of the literature.

BMC Ophthalmol 2021 Jan 8;21(1):22. Epub 2021 Jan 8.

Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Background: Orbital aspergillosis is a rare sight- and life-threatening fungal infection affecting immunocompromised or otherwise healthy patients. It is often misdiagnosed due to its unspecific clinical and radiologic appearance. Therapeutic delay can have dramatic consequences. However, progress in microbiological diagnostic techniques and therapeutic experience from case series help improve the management of this disease.

Case Presentation: A 78-year-old immunocompetent woman presented at an eye clinic for subacute swelling, reddening, and ptosis of her left upper eyelid. Based on radiologic and histologic considerations, she was treated for idiopathic orbital inflammation, but her condition worsened. After a second biopsy of the orbital mass, aspergillosis was diagnosed. Her condition improved promptly after initiation of an oral voriconazole treatment. Additionally, using a polymerase chain reaction (PCR) assay, A. fumigatus was identified on tissue of both biopsies and its azole susceptibility was examined simultaneously.

Conclusions: In the case described here, oral antifungal treatment was sufficient for the therapy of invasive orbital aspergillosis. Performing fungal PCR on orbital tissue can accelerate the diagnostic process and should be performed in ambiguous cases of slowly growing orbital mass. Finally, interdisciplinary management is the key to optimal treatment of orbital tumours and infections.
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http://dx.doi.org/10.1186/s12886-020-01773-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792050PMC
January 2021

Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid.

Immunity 2021 01 23;54(1):164-175.e6. Epub 2020 Dec 23.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany. Electronic address:

Patients suffering from Coronavirus disease 2019 (COVID-19) can develop neurological sequelae, such as headache and neuroinflammatory or cerebrovascular disease. These conditions-termed here as Neuro-COVID-are more frequent in patients with severe COVID-19. To understand the etiology of these neurological sequelae, we utilized single-cell sequencing and examined the immune cell profiles from the cerebrospinal fluid (CSF) of Neuro-COVID patients compared with patients with non-inflammatory and autoimmune neurological diseases or with viral encephalitis. The CSF of Neuro-COVID patients exhibited an expansion of dedifferentiated monocytes and of exhausted CD4 T cells. Neuro-COVID CSF leukocytes featured an enriched interferon signature; however, this was less pronounced than in viral encephalitis. Repertoire analysis revealed broad clonal T cell expansion and curtailed interferon response in severe compared with mild Neuro-COVID patients. Collectively, our findings document the CSF immune compartment in Neuro-COVID patients and suggest compromised antiviral responses in this setting.
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http://dx.doi.org/10.1016/j.immuni.2020.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831653PMC
January 2021

Effect of everolimus-based drug regimens on CMV-specific T-cell functionality after renal transplantation: 12-month ATHENA subcohort-study results.

Eur J Immunol 2021 Apr 28;51(4):943-955. Epub 2020 Dec 28.

Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.

Post-transplant cytomegalovirus (CMV) infections and increased viral replication are associated with CMV-specific T-cell anergy. In the ATHENA-study, de-novo everolimus (EVR) with reduced-exposure tacrolimus (TAC) or cyclosporine (CyA) showed significant benefit in preventing CMV infections in renal transplant recipients as compared to standard TAC + mycophenolic acid (MPA). However, immunomodulatory mechanisms for this effect remain largely unknown. Ninety patients from the ATHENA-study completing the 12-month visit on-treatment (EVR + TAC n = 28; EVR + CyA n = 19; MPA + TAC n = 43) were included in a posthoc analysis. Total lymphocyte subpopulations were quantified. CMV-specific CD4 T cells were determined after stimulation with CMV-antigen, and cytokine-profiles and various T-cell anergy markers were analyzed using flow cytometry. While 25.6% of MPA + TAC-treated patients had CMV-infections, no such events were reported in EVR-treated patients. Absolute numbers of lymphocyte subpopulations were comparable between arms, whereas the percentage of regulatory T cells was significantly higher with EVR + CyA versus MPA + TAC (p = 0.019). Despite similar percentages of CMV-specific T cells, their median expression of CTLA-4 and PD-1 was lower with EVR + TAC (p < 0.05 for both) or EVR + CyA (p = 0.045 for CTLA-4) compared with MPA + TAC. Moreover, mean percentages of multifunctional CMV-specific T cells were higher with EVR + TAC (27.2%) and EVR + CyA (29.4%) than with MPA + TAC (19.0%). In conclusion, EVR-treated patients retained CMV-specific T-cell functionality, which may contribute to enhanced protection against CMV infections.
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http://dx.doi.org/10.1002/eji.202048855DOI Listing
April 2021

COVID-19-Induced ARDS Is Associated with Decreased Frequency of Activated Memory/Effector T Cells Expressing CD11a.

Mol Ther 2020 12 8;28(12):2691-2702. Epub 2020 Oct 8.

Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr University Bochum, Hölkeskampring 40, 44625 Herne, Germany.

Preventing the progression to acute respiratory distress syndrome (ARDS) in COVID-19 is an unsolved challenge. The involvement of T cell immunity in this exacerbation remains unclear. To identify predictive markers of COVID-19 progress and outcome, we analyzed peripheral blood of 10 COVID-19-associated ARDS patients and 35 mild/moderate COVID-19 patients, not requiring intensive care. Using multi-parametric flow cytometry, we compared quantitative, phenotypic, and functional characteristics of circulating bulk immune cells, as well as SARS-CoV-2 S-protein-reactive T cells between the two groups. ARDS patients demonstrated significantly higher S-protein-reactive CD4 and CD8 T cells compared to non-ARDS patients. Of interest, comparison of circulating bulk T cells in ARDS patients to non-ARDS patients demonstrated decreased frequencies of CD4 and CD8 T cell subsets, with activated memory/effector T cells expressing tissue migration molecule CD11a. Importantly, survival from ARDS (4/10) was accompanied by a recovery of the CD11a T cell subsets in peripheral blood. Conclusively, data on S-protein-reactive polyfunctional T cells indicate the ability of ARDS patients to generate antiviral protection. Furthermore, decreased frequencies of activated memory/effector T cells expressing tissue migratory molecule CD11a observed in circulation of ARDS patients might suggest their involvement in ARDS development and propose the CD11a-based immune signature as a possible prognostic marker.
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http://dx.doi.org/10.1016/j.ymthe.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543694PMC
December 2020

The role of soluble mediators in the clinical course of EBV infection and B cell homeostasis after kidney transplantation.

Sci Rep 2020 11 11;10(1):19594. Epub 2020 Nov 11.

Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Epstein-Barr virus (EBV) reactivation can lead to serious complications in kidney transplant patients, including post-transplant lymphoproliferative disorder (PTLD). Here, we have assessed the impact of EBV on B cell homeostasis at cellular and humoral level. In a multicenter study monitoring 540 kidney transplant patients during the first post-transplant year, EBV reactivation was detected in 109 patients. Thirteen soluble factors and B cell counts were analyzed in an EBV sub-cohort (N = 54) before, at peak and after EBV clearance and compared to a control group (N = 50). The B cell activating factor (BAFF) was significantly elevated among EBV patients. No additional soluble factors were associated with EBV. Importantly, in vitro experiments confirmed the proliferative effect of BAFF on EBV-infected B cells, simultaneously promoting EBV production. In contrast, elevated levels of BAFF in EBV patients did not lead to B cell expansion in vivo. Moreover, diminished positive inter-correlations of soluble factors and alterations of the bi-directional interplay between B cell and soluble factors were observed in EBV patients at peak and after clearance. Our data suggest that such alterations may counteract the proliferative effect of BAFF, preventing B cell expansion. The role of these alterations in lymphoma development should be analyzed in future studies.
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http://dx.doi.org/10.1038/s41598-020-76607-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658229PMC
November 2020

Time and personnel requirements for antimicrobial stewardship in small hospitals in a rural area in Germany.

J Infect Public Health 2020 Dec 26;13(12):1946-1950. Epub 2020 Oct 26.

Zentrum für Hygiene, Evangelische Kliniken Gelsenkirchen, Munckelstr. 27, 45879 Gelsenkirchen, Germany. Electronic address:

Background: In order to control their anti-infectives consumption, hospitals are required to provide multidisciplinary teams comprising among others an infectiologist, a microbiologist and a pharmacist. Small hospitals though often do not dispose of the defaulted personnel. This study illustrates a solution for an antimicrobial stewardship program (ASP) in small community hospitals in a rural area in Germany.

Methods: Four hospitals of ca. 200 beds each, jointly hired an antimicrobial stewardship expert to start a common ASP. This expert did rounds on every ward once a week, mostly as chard reviews with the physician in charge. Outside the rounds, he could be consulted by mail. Working time and number of visited patients were documented. Anti-infectives consumption, incidence of Clostridioides difficile infections (CDI) and mortality rates were retrieved from routinely collected data. The intervention period (01/2018-12/2018) was compared to the preintervention period (01/2017-12/2017).

Results: 3321 patients were visited in the intervention period. In average, 20 patients were seen per day and 20 min were needed per patient/ chard. About 65% of the expert's working time was needed for rounds, 15% for driving between the hospitals. The anti-infectives consumption of the 4 hospitals in the preintervention period amounted to 50 defined daily doses per 100 occupied bed days. The total consumption was reduced by 10% and of quinolones by 36%. The incidence of hospital-acquired CDI receded from 0.14 to 0.07 cases per 100 patient days (-50%, p = 0.001). The overall in-hospital mortality did not change.

Conclusions: A single expert was able to implement a successfull ASP in 4 hospitals. While multidisciplinary antimicrobial stewardship teams are ideal for tertiary care hospitals, small hospitals need a more practical solution. This survey shows that one expert can be sufficient for several small hospitals even with the distances in a rural setting.
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http://dx.doi.org/10.1016/j.jiph.2020.10.001DOI Listing
December 2020

Cellular Immunity in COVID-19 Convalescents with PCR-Confirmed Infection but with Undetectable SARS-CoV-2-Specific IgG.

Emerg Infect Dis 2021 01 15;27(1). Epub 2020 Oct 15.

We investigated immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among a group of convalescent, potential blood donors in Germany who had PCR-confirmed SARS-CoV-2 infection. Sixty days after onset of symptoms, 13/78 (17%) study participants had borderline or negative results to an ELISA detecting IgG against the S1 protein of SARS-CoV-2. We analyzed participants with PCR-confirmed infection who had strong antibody responses (ratio >3) as positive controls and participants without symptoms of SARS-CoV-2 infection and without household contact with infected patients as negative controls. Using interferon-γ ELISpot, we observed that 78% of PCR-positive volunteers with undetectable antibodies showed T cell immunity against SARS-CoV-2. We observed a similar frequency (80%) of T-cell immunity in convalescent donors with strong antibody responses but did not detect immunity in negative controls. We concluded that, in convalescent patients with undetectable SARS-CoV-2 IgG, immunity may be mediated through T cells.
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http://dx.doi.org/10.3201/2701.203772DOI Listing
January 2021