Publications by authors named "Sascha David"

93 Publications

Role of endothelial microRNA 155 on capillary leakage in systemic inflammation.

Crit Care 2021 02 22;25(1):76. Epub 2021 Feb 22.

Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.

Background: Capillary leakage is a key contributor to the pathological host response to infections. The underlying mechanisms remain incompletely understood, and the role of microRNAs (MIR) has not been investigated in detail. We hypothesized that specific MIRs might be regulated directly in the endothelium thereby contributing to vascular leakage.

Methods: SmallRNA sequencing of endotoxemic murine pulmonary endothelial cells (ECs) was done to detect regulated vascular MIRs. In vivo models: transgenic zebrafish (flk1:mCherry/l-fabp:eGFP-DPB), knockout/wildtype mouse (B6.Cg-Mir155tm1.1Rsky/J); disease models: LPS 17.5 mg/kgBW and cecal ligation and puncture (CLP); in vitro models: stimulated human umbilical vein EC (HUVECs), transendothelial electrical resistance.

Results: Endothelial MIR155 was identified as a promising candidate in endotoxemic murine pulmonary ECs (25 × upregulation). Experimental overexpression in a transgenic zebrafish line and in HUVECs was sufficient to induce spontaneous vascular leakage. To the contrary, genetic MIR155 reduction protects against permeability both in vitro and in endotoxemia in vivo in MIR155 heterozygote knockout mice thereby improving survival by 40%. A tight junction protein, Claudin-1, was down-regulated both in endotoxemia and by experimental MIR155 overexpression. Translationally, MIR155 was detectable at high levels in bronchoalveolar fluid of patients with ARDS compared to healthy human subjects.

Conclusions: We found that MIR155 is upregulated in the endothelium in mouse and men as part of a systemic inflammatory response and might contribute to the pathophysiology of vascular leakage in a Claudin-1-dependent manner. Future studies have to clarify whether MIR155 could be a potential therapeutic target.
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http://dx.doi.org/10.1186/s13054-021-03500-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901081PMC
February 2021

[Extracorporeal Strategies in Sepsis Treatment: Role of Therapeutic Plasma Exchange].

Anasthesiol Intensivmed Notfallmed Schmerzther 2021 Feb 19;56(2):101-110. Epub 2021 Feb 19.

Background:  Mortality in sepsis remains high. Various techniques for extracorporeal cytokine removal have been investigated as additional therapeutic measures in sepsis and septic shock.

Objectives:  To summarize a selection of extracorporeal blood purification techniques, with a special focus on therapeutic plasma exchange, and their current evidence in clinical use.

Methods:  Non-systematic literature review.

Results:  Various extracorporeal blood purification techniques with different levels of evidence regarding cytokine removal, vasopressor sparing effects and reduction of mortality are currently in clinical use. Most extensively studied modalities include high-volume hemofiltration/dialysis with and without high cut-off filters a well as hemoadsorption techniques (including CytoSorb, and polymyxin-B filters). Despite partly encouraging observations regarding removal of inflammatory cytokines and hemodynamic stabilization, results from randomized studies did not show an effect on survival. Due to use of donor plasma as substitution fluid, therapeutic plasma exchange represents the only modality able to additionally replace protective and consumed factors.

Conclusions:  The use of extracorporeal blood purification methods cannot be recommended for sepsis patients outside of clinical trials given the current lack of evidence of their efficacy. Future investigations should aim to homogenize the studied patient collective in respect to clinical sepsis severity, time point of intervention and different inflammatory (sub-)phenotypes.
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http://dx.doi.org/10.1055/a-1105-0572DOI Listing
February 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

Adjuvant therapeutic plasma exchange in septic shock.

Intensive Care Med 2021 Jan 20. Epub 2021 Jan 20.

Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl-Neuberg-Street 1, 30625, Hannover, Germany.

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http://dx.doi.org/10.1007/s00134-020-06339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816555PMC
January 2021

Circulating cardiovascular microRNAs in critically ill COVID-19 patients.

Eur J Heart Fail 2021 Jan 9. Epub 2021 Jan 9.

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

Aims: Coronavirus disease 2019 (COVID-19) is a still growing pandemic, causing many deaths and socio-economic damage. Elevated expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry receptor angiotensin-converting enzyme 2 on cardiac cells of patients with heart diseases may be related to cardiovascular burden. We have thus analysed cardiovascular and inflammatory microRNAs (miRs), sensitive markers of cardiovascular damage, in critically ill, ventilated patients with COVID-19 or influenza-associated acute respiratory distress syndrome (Influenza-ARDS) admitted to the intensive care unit and healthy controls.

Methods And Results: Circulating miRs (miR-21, miR-126, miR-155, miR-208a, and miR-499) were analysed in a discovery cohort consisting of patients with mechanically-ventilated COVID-19 (n = 18) and healthy controls (n = 15). A validation study was performed in an independent cohort of mechanically-ventilated COVID-19 patients (n = 20), Influenza-ARDS patients (n = 13) and healthy controls (n = 32). In both cohorts, RNA was isolated from serum and cardiovascular disease/inflammatory-relevant miR concentrations were measured by miR-specific TaqMan PCR analyses. In both the discovery and the validation cohort, serum concentration of miR-21, miR-155, miR-208a and miR-499 were significantly increased in COVID-19 patients compared to healthy controls. Calculating the area under the curve using receiver operating characteristic analysis miR-155, miR-208a and miR-499 showed a clear distinction between COVID-19 and Influenza-ARDS patients.

Conclusion: In this exploratory study, inflammation and cardiac myocyte-specific miRs were upregulated in critically ill COVID-19 patients. Importantly, miR profiles were able to differentiate between severely ill, mechanically-ventilated Influenza-ARDS and COVID-19 patients, indicating a rather specific response and cardiac involvement of COVID-19.
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http://dx.doi.org/10.1002/ejhf.2096DOI Listing
January 2021

Comparison of anticoagulation strategies for veno-venous ECMO support in acute respiratory failure.

Crit Care 2021 01 4;24(1):701. Epub 2021 Jan 4.

Department of Anaesthesiology and Critical Care Medicine, University Hospital Bonn, Bonn, Germany.

Background: Extracorporeal membrane oxygenation (ECMO) support in acute respiratory failure may be lifesaving, but bleeding and thromboembolic complications are common. The optimal anticoagulation strategy balancing these factors remains to be determined. This retrospective study compared two institutional anticoagulation management strategies focussing on oxygenator changes and both bleeding and thromboembolic events.

Methods: We conducted a retrospective observational cohort study between 04/2015 and 02/2020 in two ECMO referral centres in Germany in patients receiving veno-venous (VV)-ECMO support for acute respiratory failure for > 24 h. One centre routinely applied low-dose heparinization aiming for a partial thromboplastin time (PTT) of 35-40 s and the other routinely used a high-dose therapeutic heparinization strategy aiming for an activated clotting time (ACT) of 140-180 s. We assessed number of and time to ECMO oxygenator changes, 15-day freedom from oxygenator change, major bleeding events, thromboembolic events, 30-day ICU mortality, activated clotting time and partial thromboplastin time and administration of blood products. Primary outcome was the occurrence of oxygenator changes depending on heparinization strategy; main secondary outcomes were the occurrence of severe bleeding events and occurrence of thromboembolic events. The transfusion strategy was more liberal in the low-dose centre.

Results: Of 375 screened patients receiving VV-ECMO support, 218 were included in the analysis (117 high-dose group; 101 low-dose group). Disease severity measured by SAPS II score was 46 (IQR 36-57) versus 47 (IQR 37-55) and ECMO runtime was 8 (IQR 5-12) versus 11 (IQR 7-17) days (P = 0.003). There were 14 oxygenator changes in the high-dose group versus 48 in the low-dose group. Freedom from oxygenator change at 15 days was 73% versus 55% (adjusted HR 3.34 [95% confidence interval 1.2-9.4]; P = 0.023). Severe bleeding events occurred in 23 (19.7%) versus 14 (13.9%) patients (P = 0.256) and thromboembolic events occurred in 8 (6.8%) versus 19 (19%) patients (P = 0.007). Mortality at 30 days was 33.3% versus 30.7% (P = 0.11).

Conclusions: In this retrospective study, ECMO management with high-dose heparinization was associated with lower rates of oxygenator changes and thromboembolic events when compared to a low-dose heparinization strategy. Prospective, randomized trials are needed to determine the optimal anticoagulation strategy in patients receiving ECMO support.
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http://dx.doi.org/10.1186/s13054-020-03348-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780376PMC
January 2021

Absence of SARS-CoV-2 RNA in COVID-19-associated intestinal endothelialitis.

Intensive Care Med 2021 Jan 3. Epub 2021 Jan 3.

Institute for Intensive Care Medicine, University Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1007/s00134-020-06326-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778861PMC
January 2021

Activated Clotting Time (ACT) for Monitoring of Low-Dose Heparin: Performance Characteristics in Healthy Adults and Critically Ill Patients.

Clin Appl Thromb Hemost 2020 Jan-Dec;26:1076029620975494

Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany.

Dose adjustment of unfractionated heparin (UFH) anticoagulation is an important factor to reduce hemorrhagic events. High doses of heparin can be monitored by Activated Clotting Time (ACT). Because of limited information about the monitoring of low-dose heparin we assessed monitoring by ACT, aPTT and anti-Xa. Blood samples from healthy volunteers (n = 54) were treated ex vivo with increasing UFH doses (0-0.4 IU/ml). Samples from ICU-patients (n = 60), were drawn during continuous UFH infusion. Simultaneous ACT measurements were performed using iSTAT and Hemochron. In UFH treated blood, iSTAT and Hemochron showed a significant change of ACT at ≥0.075 IU/ml and ≥0.1 IU/ml UFH, respectively. In ICU-patients no relationship between ACT and either UFH dose, aPTT and anti-Xa was observed. Hemochron was affected by antithrombin and platelet count. iSTAT was sensitive to CRP and hematocrit. A moderate correlation was identified between UFH dose and aPTT (R = 0.196) or anti-Xa (R = 0.162). In heparin-spiked blood, ACT is sensitive to heparin at levels of ≥0.1 IU/ml heparin. In ICU-patients, ACT did not correlate with UFH dose or other established methods. Both systems were differently influenced by certain parameters.
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http://dx.doi.org/10.1177/1076029620975494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758671PMC
December 2020

Immunoglobulin Deficiency as an Indicator of Disease Severity in Patients with COVID-19.

Am J Physiol Lung Cell Mol Physiol 2020 Nov 25. Epub 2020 Nov 25.

Nephrologie, Medizinische Hochschule Hannover.

Despite the pandemic status of COVID-19, there is limited information about host risk factors and treatment beyond supportive care. Immunoglobulin G (IgG) could be a potential treatment target. Our aim was to determine the incidence of IgG deficiency and associated risk factors in a cohort of 62 critical ill COVID-19 patients admitted to two German ICUs (72.6% male, median age: 61 years). 13 (21.0%) of the patients displayed IgG deficiency (IgG <7 g/L) at baseline (predominant for the IgG1, IgG2, and IgG4 subclasses). IgG-deficient patients had worse measures of clinical disease severity than those with normal IgG levels (shorter duration from disease onset to ICU admission, lower ratio of PaO to FiO, higher Sequential Organ Failure Assessment score, and higher levels of ferritin, neutrophil-to-lymphocyte ratio and serum creatinine). IgG-deficient patients were also more likely to have sustained lower levels of lymphocyte counts and higher levels of ferritin throughout the hospital stay. Furthermore, IgG-deficient patients compared to those with normal IgG levels displayed higher rates of acute kidney injury (76.9% vs. 26.5%; p=0.005) and death (46.2% vs. 14.3%; p=0.012), longer ICU (28 [6-48] vs. 12 [3-18] days; p=0.012) and hospital length of stay (30 [22-50] vs. 18 [9-24] days; p=0.004). Multivariable logistic regression showed increasing odds of 90-day overall mortality associated with IgG-deficiency (OR 12.8, 95% CI 1.5-108.4; p=0.019). IgG deficiency might be common in critically ill COVID-19 patients, and warrants investigation as both a marker of disease severity as well as a potential therapeutic target.
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http://dx.doi.org/10.1152/ajplung.00359.2020DOI Listing
November 2020

F-FDG PET/CT of off-target lymphoid organs in CD19-targeting chimeric antigen receptor T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma.

Ann Nucl Med 2021 Jan 11;35(1):132-138. Epub 2020 Nov 11.

Department of Hematology, Hemostasis, Oncology and Stem-Cell Transplantation, Hannover, Germany.

Objective: The interplay between systemic inflammation, activity of lymphoid organs and lymphoma activity in CD19-targeting chimeric antigen receptor (CAR)-T-cell immunotherapy, and its significance for response and toxicity, is not well defined.

Methods: Using serial F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), metabolic parameters of lymphoma and lymphoid organs were analyzed in ten patients receiving Tisagenlecleucel (an autologous CD19 CAR-T cell product) for relapsed or refractory diffuse large B-cell lymphoma. The prevalence and severity of toxicity (e.g., neurotoxicity) were noted.

Results: Achieving remission required early metabolic response (P = 0.0476). Early suppression of metabolic activity of lymphoid organs (spleen, P = 0.0368; lymph nodes, P = 0.0470) was associated with poor outcome. Lymphoma metabolic activity was significantly higher in patients with neurotoxicity (P = 0.0489).

Conclusions: Early metabolic changes in lymphoma lesions and off-target lymphoid organs parallel medium-term response to CAR-T-cell therapy. PET can identify patients at risk for severe toxicity.
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http://dx.doi.org/10.1007/s12149-020-01544-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796875PMC
January 2021

Effect of Therapeutic Plasma Exchange on Immunoglobulin Deficiency in Early and Severe Septic Shock.

J Intensive Care Med 2020 Oct 16:885066620965169. Epub 2020 Oct 16.

Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.

Background: Deficiency of immunoglobulins of the classes IgG, IgG1, IgA and IgM is associated with severity of disease and mortality in sepsis and septic shock. Therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) has recently gained attention as an adjunctive therapeutic option in early septic shock. We hypothesized that TPE might modulate immunoglobulin deficiencies besides sole elimination of circulating injurious molecules.

Methods: We conducted a prospective single center study with TPE in 33 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4μg/kg/min). Clinical and biochemical data, including measurement of immunoglobulin subgroups IgG, IgG1, IgM and IgA were obtained before and after TPE. The following immunoglobulin cut-off values were used to analyze subgroups with low immunoglobulin concentrations at baseline (IgG ≤ 6.5, IgG1 ≤ 3, IgM ≤ 1.5 and IgA ≤ 0.35 g/L).

Results: At inclusion, median (IQR) SOFA score was 18 (15-20) and NE dose was 0.8 (0.6-1.2) μg/kg/min. The majority of patients demonstrated profound reductions in immunoglobulins levels of all classes. Globally, immunoglobulin levels were not significantly changed after a single TPE session. However, in patients with low baseline immunoglobulin levels a significant increase in all classes was observed (IgG 1.92 (0.96-3) g/L (+41%), IgG1 2.1 (1.46-2.32) g/L (+96%), IgA 0.44 (0.12-0.62) g/L (59%) and IgM 0.18 (0.14-0.34) g/L (+55%), p < 0.001 for comparison to patients above cut-off).

Conclusions: The majority of early and severe septic shock patients had reduced immunoglobulin levels and a single TPE could attenuate immunoglobulin deficiencies of all classes. The clinical relevance of this observation has to be investigated in a proper designed trial.
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http://dx.doi.org/10.1177/0885066620965169DOI Listing
October 2020

Direct evidence of SARS-CoV-2 in gut endothelium.

Intensive Care Med 2020 Nov 11;46(11):2081-2082. Epub 2020 Sep 11.

Institute for Intensive Care Medicine, University Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1007/s00134-020-06237-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483488PMC
November 2020

[Extracorporeal techniques for blood purification in sepsis: an update].

Internist (Berl) 2020 Oct;61(10):1010-1016

Klinik für Nieren- und Hochdruckerkrankungen, Medizinische Hochschule Hannover, Hannover, Deutschland.

Background: Despite ongoing development, mortality in sepsis remains considerable. Various techniques for extracorporeal cytokine removal have been described, but evidence remains conflicting.

Objectives: The aim of this article is to summarize currently used extracorporeal blood purification techniques and their evidence.

Methods: Non-systematic literature review RESULTS: There are currently various blood purification techniques used with different levels of evidence regarding cytokine removal, vasopressor sparing effects and reduction of mortality, including high-volume dialysis with and without high cut-off filters, special adsorption filters (including CytoSorb®, CytoSorbents Europe, Berlin, Germany, and polymyxin‑B filters). There is development regarding therapeutic plasma exchange. For some blood purification techniques such as combined plasma filtration and adsorption, multicentric randomized studies found a negative effect on survival.

Conclusions: Despite a theoretical rationale, the use of blood purification methods cannot be recommended for sepsis patients due to the lack of evidence of their efficacy. Heterogeneous inflammatory responses in sepsis render conduction of larger trials difficult. Thus, future studies should cautiously identify appropriate sepsis subtypes to be included. Available techniques should be chosen as individualized complementary treatments and not as competing systems.
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http://dx.doi.org/10.1007/s00108-020-00862-5DOI Listing
October 2020

Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis.

Elife 2020 08 24;9. Epub 2020 Aug 24.

Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.

Endothelial Tie2 signaling plays a pivotal role in vascular barrier maintenance at baseline and after injury. We previously demonstrated that a sharp drop in Tie2 expression observed across various murine models of critical illnesses is associated with increased vascular permeability and mortality. Matrix metalloprotease (MMP)-14-mediated Tie2 ectodomain shedding has recently been recognized as a possible mechanism for Tie2 downregulation in sepsis. Here, we identified the exact MMP14-mediated Tie2 ectodomain cleavage sites and could show that pharmacological MMP14 blockade in experimental murine sepsis exerts barrier protective and anti-inflammatory effects predominantly through the attenuation of Tie2 cleavage to improve survival both in a pre-treatment and rescue approach. Overall, we show that protecting Tie2 shedding might offer a new therapeutic opportunity for the treatment of septic vascular leakage.
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http://dx.doi.org/10.7554/eLife.59520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447424PMC
August 2020

Corrigendum to: Maintenance Immunosuppression Is Associated With Better Outcome in the 2017/2018 Influenza Epidemic.

Open Forum Infect Dis 2020 Feb 12;7(2):ofaa027. Epub 2020 Feb 12.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

[This corrects the article DOI: 10.1093/ofid/ofz381.].
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http://dx.doi.org/10.1093/ofid/ofaa027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372958PMC
February 2020

Reappearance of effector T cells is associated with recovery from COVID-19.

EBioMedicine 2020 Jul 7;57:102885. Epub 2020 Jul 7.

Institute of Immunology, Hannover Medical School, Germany; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany. Electronic address:

Background: Elucidating the role of T cell responses in COVID-19 is of utmost importance to understand the clearance of SARS-CoV-2 infection.

Methods: 30 hospitalized COVID-19 patients and 60 age- and gender-matched healthy controls (HC) participated in this study. We used two comprehensive 11-colour flow cytometric panels conforming to Good Laboratory Practice and approved for clinical diagnostics.

Findings: Absolute numbers of lymphocyte subsets were differentially decreased in COVID-19 patients according to clinical severity. In severe disease (SD) patients, all lymphocyte subsets were reduced, whilst in mild disease (MD) NK, NKT and γδ T cells were at the level of HC. Additionally, we provide evidence of T cell activation in MD but not SD, when compared to HC. Follow up samples revealed a marked increase in effector T cells and memory subsets in convalescing but not in non-convalescing patients.

Interpretation: Our data suggest that activation and expansion of innate and adaptive lymphocytes play a major role in COVID-19. Additionally, recovery is associated with formation of T cell memory as suggested by the missing formation of effector and central memory T cells in SD but not in MD. Understanding T cell-responses in the context of clinical severity might serve as foundation to overcome the lack of effective anti-viral immune response in severely affected COVID-19 patients and can offer prognostic value as biomarker for disease outcome and control.

Funding: Funded by State of Lower Saxony grant 14-76,103-184CORONA-11/20 and German Research Foundation, Excellence Strategy - EXC2155"RESIST"-Project ID39087428, and DFG-SFB900/3-Project ID158989968, grants SFB900-B3, SFB900-B8.
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http://dx.doi.org/10.1016/j.ebiom.2020.102885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338277PMC
July 2020

Therapeutic plasma exchange in acute on chronic liver failure.

J Clin Apher 2020 Aug 24;35(4):316-327. Epub 2020 Jun 24.

Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.

Background: Acute on chronic liver failure (ACLF) has been identified as a distinct syndrome due to acute decompensation of liver cirrhosis accompanied by extra-hepatic organ failure, primarily caused by an overwhelming systemic immune response. Therapeutic plasma exchange (TPE) has been demonstrated in a randomized controlled trial to improve transplant free survival in acute liver failure. Here we investigated if TPE might have comparable beneficial effects in patients with ACLF.

Methods: Thirty-one patients with ACLF that were treated with TPE were enrolled into this retrospective analysis and 1:1 matched to an ACLF cohort treated with standard medical therapy (SMT) only.

Results: Patients considered for a bridge to recovery (n = 21 each group) approach had a 30-day mortality >90% that was not improved by TPE (P = .185). Deaths occurred in the SMT group at significant earlier time points compared to the patients treated with TPE (mortality at 5 days: 33.3% for TPE and 66.7% for SMT, P = .048). However, patients who received TPE as a bridge to transplant strategy (n = 10) survived in 60% of cases and demonstrated 24 hours after study inclusion a stabilization of organ dysfunction (organ failures at inclusion: 4 (3-5) vs 24 hours after inclusion: 3 (2-4), P = .031 and CLIF-C-ACLF score: 64 (49-76) vs 54 (49-66), P = .043) not seen in SMT patients.

Conclusions: Although these retrospective data need to be interpreted with caution, they suggest that TPE in ACLF patients is feasible but not suitable as a bridge to recovery strategy. In selected patients TPE might assist as bridge to transplant.
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http://dx.doi.org/10.1002/jca.21799DOI Listing
August 2020

First do no harm-beware the risk of therapeutic plasma exchange in severe COVID-19.

Crit Care 2020 06 18;24(1):363. Epub 2020 Jun 18.

Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany.

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http://dx.doi.org/10.1186/s13054-020-03070-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301767PMC
June 2020

Donor-derived IL-17A and IL-17F deficiency triggers Th1 allo-responses and increases gut leakage during acute GVHD.

PLoS One 2020 6;15(4):e0231222. Epub 2020 Apr 6.

Institute of Immunology, Hannover Medical School, Hannover, Germany.

IL-17A and IL-17F cytokines are important regulators of acute graft-versus-host-disease (GVHD). However, contrary effects of these cytokines in inflammatory diseases have been reported. To investigate the effects of donor-derived IL-17A and IL-17F on GVHD, we made use of single (Il17a-/- or Il17f-/-) and double deficient (Il17af-/-) allogeneic donor CD4+ T cells. We could demonstrate that transplantation of Il17af-/- CD4+ donor T cells led to aggravated GVHD. However, this phenotype was not observed after transplantation of single, Il17a-/- or Il17f-/-, deficient CD4+ T cells, suggesting redundant effects of IL-17A and IL-17F. Moreover, Il17af-/- cell recipients showed an increase of systemic IFNγ, indicating a heightened pro-inflammatory state, as well as infiltration of IFNγ-secreting CD4+ T cells in the recipients' intestinal tract. These recipients exhibited significant gut leakage, and markedly macrophage infiltration in the gastrointestinal epithelial layer. Moreover, we saw evidence of impaired recovery of gut epithelial cells in recipients of Il17af-/- CD4+ T cells. In this study, we show that IL-17A/F double deficiency of donor CD4+ T cells leads to accelerated GVHD and therefore highlight the importance of these cytokines. Together, IL-17 cytokines might serve as a brake to an intensified Th1 response, leading to the exacerbated gut damage in acute GVHD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231222PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135231PMC
July 2020

Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock.

Crit Care 2020 03 2;24(1):71. Epub 2020 Mar 2.

Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany.

Background: A dysbalanced coagulation system is part of the pathological host response to infection in sepsis. Activation of pro-coagulant pathways and attenuation of anti-coagulant activity ultimately lead to microvascular stasis and consequent organ failure. No treatment approaches specifically targeting this axis are available. We explored the effects of therapeutic plasma exchange (TPE) on microvascular coagulation dysbalance in septic shock.

Methods: We conducted a prospective single-center study enrolling 31 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4 μg/kg/min). Clinical and biochemical data, including measurement of protein C; a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13); and von Willebrand factor antigen (vWF:Ag), were obtained before and after TPE against fresh frozen plasma.

Results: Antithrombotic acting proteins such as antithrombin-III (ATIII) and protein C were markedly reduced in septic patients, but their activity increased after TPE (ATIII, 51% (41-61) vs. 63% (48-70), p = 0.029; protein C, 47% (38-60) vs. 62% (54-69), p = 0.029). Median ADAMTS13 activity was increased by TPE from 27 (21-42) % before to 47 (38-62) % after TPE (p < 0.001). In contrast, vWF:Ag was elevated and could be reduced by TPE (353 (206-492) IU/dL vs. 170 (117-232) IU/dL, p < 0.001). Regression analysis yielded a correlation between ADAMTS13 activity and platelet count (p = 0.001, R = 0.316).

Conclusions: Septic shock was associated with activation of pro-coagulant pathways and simultaneous depletion of anti-coagulant factors. TPE partially attenuated this dysbalance by removing pro- and by replacing anti-coagulant factors.

Trial Registration: ClinicalTrials.gov, NCT03065751. Retrospectively registered on 28 February 2017.
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http://dx.doi.org/10.1186/s13054-020-2799-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053051PMC
March 2020

Extracorporeal cytokine removal in severe CAR-T cell associated cytokine release syndrome.

J Crit Care 2020 06 19;57:124-129. Epub 2020 Feb 19.

Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany. Electronic address:

Purpose: Life-threatening complications of CD-19 Chimeric antigen receptor - T (CAR-T) cells such as the cytokine release syndrome (CRS)) have been reported. Treatment is limited to IL-6 blockade and steroids although global removal of elevated soluble inflammatory factors might be more effective.

Methods: Clinical course of a CRS patient treated with extracorporeal cytokine adsorption (Cytosorb®). A panel of 48 cytokines, chemokines and endothelial markers has been analyzed longitudinally. Ex vivo stimulation of endothelial cells to visualize (immunocytochemistry) and quantify (ECIS, TER) endothelial barrier effects.

Results: Following CAR-T cell application a 65 years old male developed grade 4 CRS with refractory shock (3 vasopressors) and severe capillary leakage (+37 L/24 h resuscitation). Treatment included IL-6 blockade, methylprednisolone and additionally Cytosorb hemoperfusion. While multiple soluble inflammatory factors were elevated and most of them decreased by more than 50% following Cytosorb, markers of endothelial injury increased steadily (e.g. Angpt-2/Angpt-1) leading to profound endothelial activation and leakage in ex vivo assays.

Conclusion: This is the first reported use of cytokine adsorption for CRS showing efficacy in absorption of various cytokines but not endothelial growth factors. A randomized controlled trial to evaluate additional Cytosorb treatment in CRS is currently recruiting at our institution (NCT04048434).
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http://dx.doi.org/10.1016/j.jcrc.2020.02.010DOI Listing
June 2020

Non-occlusive mesenteric ischemia (NOMI): evaluation of 2D-perfusion angiography (2D-PA) for early treatment response assessment.

Abdom Radiol (NY) 2020 10;45(10):3342-3351

Department of Diagnostic and Interventional Radiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Purpose: To evaluate the feasibility of 2D-perfusion angiography (2D-PA) for the analysis of intra-procedural treatment response after intra-arterial prostaglandin E1 therapy in patients with non-occlusive mesenteric ischemia (NOMI).

Methods: Overall, 20 procedures in 18 NOMI patients were included in this retrospective case-control study. To evaluate intra-procedural splanchnic circulation changes, post-processing of digital subtraction angiography (DSA) series was performed. Regions of interest (ROIs) were placed in the superior mesenteric artery (SMA; reference), the portal vein (PV; ROI), as well as the aorta next to the origin of the SMA (ROI). Peak density (PD), time to peak (TTP), and area under the curve (AUC) were assessed, and parametric ratios 'target ROI/reference ROI' were computed and compared within treatment and control group. Additionally, a NOMI score was assessed pre- and post-treatment compared to 2D-PA.

Results: Vasodilator therapy leads to a significant decrease of the 2D-PA-derived values PD (p = 0.04) and AUC (p = 0.03). These findings correlated with changes of the simplified NOMI score, both for overall (4 to 1, p < 0.0001) and for each category. Prostaglandin application caused a significant increase of the AUC (p = 0.04) and TTP was accelerated without reaching statistical significance (p = 0.13). When compared to a control group, all 2D-PA values in the NOMI group (pre- and post-intervention) differed significantly (p < 0.05) with longer TTP and lower AUC and PD .

Conclusion: 2D-PA offers an objective approach to analyze immediate flow and perfusion changes following vasodilatory therapies of NOMI patients and may be a valuable tool for assessing treatment response.
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http://dx.doi.org/10.1007/s00261-020-02457-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455582PMC
October 2020

Soluble neprilysin, NT-proBNP, and growth differentiation factor-15 as biomarkers for heart failure in dialysis patients (SONGBIRD).

Clin Res Cardiol 2020 Aug 30;109(8):1035-1047. Epub 2020 Jan 30.

Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Background: Dialysis patients are at increased risk of HF. However, diagnostic utility of NT-proBNP as a biomarker is decreased in patients on dialysis. GDF-15 and cNEP are biomarkers of distinct mechanisms that may contribute to HF pathophysiology in such cohorts. The aim of this study was to determine whether growth differentiation factor-15 (GDF-15) and circulating neprilysin (cNEP) improve the diagnosis of congestive heart failure (HF) in patients on dialysis.

Methods And Results: We compared circulating concentrations of NT-proBNP, GDF-15, and cNEP along with cNEP activity in patients on chronic dialysis without (n = 80) and with HF (n = 73), as diagnosed by clinical parameters and post-dialysis echocardiography. We used correlation, linear and logistic regression as well as receiver operating characteristic (ROC) analyses. Compared to controls, patients with HF had higher median values of NT-proBNP (16,216 [interquartile range, IQR = 27739] vs. 2883 [5866] pg/mL, p < 0.001), GDF-15 (7512 [7084] vs. 6005 [4892] pg/mL, p = 0.014), but not cNEP (315 [107] vs. 318 [124] pg/mL, p = 0.818). Median cNEP activity was significantly lower in HF vs. controls (0.189 [0.223] vs. 0.257 [0.166] nmol/mL/min, p < 0.001). In ROC analyses, a multi-marker model combining clinical covariates, NT-proBNP, GDF-15, and cNEP activity demonstrated best discrimination of HF from controls (AUC = 0.902, 95% CI 0.857-0.947, p < 0.001 vs. base model AUC = 0.785).

Conclusion: We present novel comparative data on physiologically distinct circulating biomarkers for HF in patients on dialysis. cNEP activity but not concentration and GDF-15 provided incremental diagnostic information over clinical covariates and NT-proBNP and may aid in diagnosing HF in dialysis patients.
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http://dx.doi.org/10.1007/s00392-020-01597-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376515PMC
August 2020

"Better be awake"-a role for awake extracorporeal membrane oxygenation in acute respiratory distress syndrome due to Pneumocystis pneumonia.

Crit Care 2019 12 23;23(1):418. Epub 2019 Dec 23.

Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany.

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http://dx.doi.org/10.1186/s13054-019-2703-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927178PMC
December 2019

Dual Pharmacological Inhibition of Angiopoietin-2 and VEGF-A in Murine Experimental Sepsis.

J Vasc Res 2020 14;57(1):34-45. Epub 2019 Nov 14.

Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany,

Background: Sepsis is a pathological host response to infection leading to vascular barrier breakdown due to elevated levels of angiopoietin-2 (Angpt-2) and vascular endothelial growth factor-A (VEGF-A). Here, we tested a novel heterodimeric bispecific monoclonal IgG1-cross antibody of Angpt-2 and VEGF - termed "A2V."

Methods: Cecal ligation and puncture was used to induce murine polymicrobial sepsis. Organs and blood were harvested for fluorescence immunohistochemistry and RT-PCR, and survival was recorded. In vitro endothelial cells were stimulated with plasma from septic shock patients costimulated with A2V or IgG antibody followed by immunocytochemistry and real-time transendothelial electrical resistance.

Results: Septic mice treated with A2V had a reduced induction of the endothelial adhesion molecule ICAM-1, leading to a trend towards less transmigration of inflammatory cells (A2V: 42.2 ± 1.0 vs. IgG 48.5 ± 1.7 Gr-1+ cells/HPF, p = 0.08) and reduced tissue levels of inflammatory cytokines (e.g., IL-6 mRNA: A2V 9.4 ± 3.2 vs. IgG 83.9 ± 36.7-fold over control, p = 0.03). Endothelial permeability was improved in vivo and in vitro in stimulated endothelial cells with septic plasma. Survival was improved by 38% (p = 0.02).

Conclusion: Dual inhibition of Angpt-2 and VEGF-A improves murine sepsis morbidity and mortality, making it a potential therapeutic against vascular barrier breakdown.
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http://dx.doi.org/10.1159/000503787DOI Listing
September 2020

Maintenance Immunosuppression Is Associated With Better Outcome in the 2017/2018 Influenza Epidemic.

Open Forum Infect Dis 2019 Oct 24;6(10):ofz381. Epub 2019 Sep 24.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Background: The impact of immunosuppression on outcomes in influenza is insufficiently understood. We analyzed the morbidity and mortality of immunocompetent (IC) vs immunosuppressed (IS) patients with influenza A and B in the 2017/2018 season.

Methods: Patients with proven influenza in a German tertiary care hospital were analyzed for hospitalization, intensive care unit (ICU) admission, and mortality. Causes for IS were organ and bone marrow transplantation, AIDS, chemotherapy, and medical immunosuppression.

Results: In total, 227 patients were included in this analysis (IC, n = 118 [52%]; IS, n = 109 [48%]). Hospitalization (71% vs 91%; < .001) and ICU admission (7% vs 23%; = .001) were less frequent in the IS compared with the IC group. IC patients had a higher need for invasive ventilation (20% vs 5%; = .001), vasopressors (19% vs 4%; < .001), and renal replacement therapy (15% vs 3%; = .002). Influenza-associated cardiomyopathy was found in 18% of IC vs 2% of IS patients ( < .001). The 30-day in-hospital mortality was 6.6%, 10.2% in the IC group and 2.8% in the IS group (hazard ratio IS group, 0.259; 95% confidence interval [CI], 0.113-0.855; = .023). Immunosuppression was associated with reduced mortality (odds ratio, 0.25; 95% CI, 0.07-0.91; = .036).

Conclusions: We observed that IS was not associated with a worse outcome in this influenza cohort. Due to the presence of both confounding and referral and selection bias, the conclusion that immunosuppression reduces mortality cannot be drawn. Prospective studies investigating the influence of baseline immunosuppression on severity of influenza infection are desirable.
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http://dx.doi.org/10.1093/ofid/ofz381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785702PMC
October 2019

Nonocclusive Mesenteric Ischemia and Interventional Local Vasodilatory Therapy: A Meta-Analysis and Systematic Review of the Literature.

J Intensive Care Med 2020 Feb 23;35(2):128-139. Epub 2019 Oct 23.

Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.

Background: Intensive care patients with nonocclusive mesenteric ischemia (NOMI) show mortality rates of 70% to 90%. Besides emergency surgery, different interventional local vasodilatory treatment (LVT) attempts have been described. We performed a systematic review and a meta-analysis to evaluate feasibility, efficacy, and tolerability of LVT in patients with life-threatening NOMI.

Methods: Searches of PubMed, EMBASE, Web of Science, and Cochrane Library databases were performed until February 2019. Measured outcomes included immediate technical success rates (as indicated by mesenteric vasodilation on angiography or clinical improvement) and adverse events (AEs). Therapeutic efficacy was measured by the assessment of overall mortality.

Results: Twelve studies (335 patients, 245 received LVT) from 1977 to 2018 were included. All studies were retrospective (4 comparative and 8 noncomparative). Different intra-arterial vasodilators (4× papaverine, 6× prostaglandin E1, 1× tolazoline/heparin, 1× tolazoline + iloprost) were reported. Initial technical success rate was 75.9% (95% confidence interval [CI], 55.1%-89%, = .017) with an AE rate of 2.9% (95% CI: 1.3%-6.6%; = .983). Overall mortality in LVT patients was 40.3% (95% CI: 28.7%-53%, = .134). In 4 studies, outcomes were compared between patients receiving LVT to those who received standard of care (odds ratio for death in LVT patients was 0.261 [95% CI: 0.095-0.712, = .009]).

Conclusions: Local vasodilatory treatment appears to be safe in patients with NOMI and might have the potential to at least partially reverse mesenteric vasoconstriction features in control angiographies. However, with no randomized and prospective studies available yet, the overall quality of published studies has to be considered as low; therefore, it is not possible to draw generalizable conclusions from the present data concerning clinical end points. Its application might hold promise as a rescue treatment strategy and deserves further evaluation in randomized controlled trials.
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http://dx.doi.org/10.1177/0885066619879884DOI Listing
February 2020

Binding to carboxypeptidase M mediates protective effects of fibrinopeptide Bβ.

Transl Res 2019 11 26;213:124-135. Epub 2019 Jul 26.

Department of Nephrology and Hypertension, Medical School Hannover, Germany.

During fibrinolysis a 28-amino-acid peptide is generated besides other degradation products of fibrin. This peptide, called Bβ which is cleaved by plasmin from the end of the fibrin Bβ-chain, is protective in myocardial and renal ischemia/reperfusion injury and improves the outcome in experimental sepsis. Bβ has been shown to mediate different beneficial effects in endothelial cells through binding to vascular endothelial-cadherin. Here, we provide in vitro and in vivo evidence that Bβ has additional cell protective activity in tubular cells, which is caused by a distinct mechanism. As vascular endothelial-cadherin is not expressed by tubular cells we used ligand-receptor capture technology LRC-TriCEPS to search for tubular cell surface receptors and identified carboxypeptidase M (CBPM) as a novel binding partner of Bβ. Silencing CBPM with siRNA reduced the protective potential of Bβ against tubular cell stress. Bβ inhibited the enzymatic activity of CBPM and modified the impact of CBPM on bradykinin signaling. We conclude that beneficial properties of Bβ are not restricted to endothelial cells but are also active in epithelial cells where cytoprotection depends on CBPM binding.
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http://dx.doi.org/10.1016/j.trsl.2019.07.008DOI Listing
November 2019