Publications by authors named "Alexander Uhrig"

9 Publications

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CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity.

Infection 2021 Apr 6. Epub 2021 Apr 6.

Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117, Berlin, Germany.

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons.
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April 2021

Evaluation of PEEP and prone positioning in early COVID-19 ARDS.

EClinicalMedicine 2020 Nov 11;28:100579. Epub 2020 Oct 11.

Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: In face of the Coronavirus Disease (COVID)-19 pandemic, best practice for mechanical ventilation in COVID-19 associated Acute Respiratory Distress Syndrome (ARDS) is intensely debated. Specifically, the rationale for high positive end-expiratory pressure (PEEP) and prone positioning in early COVID-19 ARDS has been questioned.

Methods: The first 23 consecutive patients with COVID-19 associated respiratory failure transferred to a single ICU were assessed. Eight were excluded: five were not invasively ventilated and three received veno-venous ECMO support. The remaining 15 were assessed over the first 15 days of mechanical ventilation. Best PEEP was defined by maximal oxygenation and was determined by structured decremental PEEP trials comprising the monitoring of oxygenation, airway pressures and trans-pulmonary pressures. In nine patients the impact of prone positioning on oxygenation was investigated. Additionally, the effects of high PEEP and prone positioning on pulmonary opacities in serial chest x-rays were determined by applying a semiquantitative scoring-system. This investigation is part of the prospective observational PA-COVID-19 study.

Findings: Patients responded to initiation of invasive high PEEP ventilation with markedly improved oxygenation, which was accompanied by reduced pulmonary opacities within 6 h of mechanical ventilation. Decremental PEEP trials confirmed the need for high PEEP (17.9 (SD ± 3.9) mbar) for optimal oxygenation, while driving pressures remained low. Prone positioning substantially increased oxygenation (<0.01).

Interpretation: In early COVID-19 ARDS, substantial PEEP values were required for optimizing oxygenation. Pulmonary opacities resolved during mechanical ventilation with high PEEP suggesting recruitment of lung volume.

Funding: German Research Foundation, German Federal Ministry of Education and Research.
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November 2020

Heterogeneous approach to nebulization of antimicrobial agents in mechanically ventilated adults in a German tertiary care hospital: a cross-sectional survey.

Eur J Clin Microbiol Infect Dis 2021 Feb 3;40(2):419-421. Epub 2020 Sep 3.

Department for Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany.

There is lack of standardization of practices and limited evidence on efficacy and safety of nebulization of antimicrobials. We sought to determine inhalation practices in one tertiary care hospital by performing a cross-sectional survey. Eleven adult ICUs were included in the analysis. Three units followed established protocols. Ventilation circuit filters were exchanged at least daily in all but one units. Dosages of aminoglycosides and CMS depended on indication and unit. Nebulization of antimicrobials was generally regarded as safe and efficacious. Our data indicate that approach to nebulization of antimicrobials may be heterogeneous even in a single center.
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February 2021

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment.

Cell 2020 09 5;182(6):1419-1440.e23. Epub 2020 Aug 5.

Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Lung Research (DZL).

Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRCD11c inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DR monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.
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September 2020

CytoResc - "CytoSorb" Rescue for critically ill patients undergoing the COVID-19 Cytokine Storm: A structured summary of a study protocol for a randomized controlled trial.

Trials 2020 Jun 26;21(1):577. Epub 2020 Jun 26.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Objectives: Approximately 8 - 10 % of COVID-19 patients present with a serious clinical course and need for hospitalization, 8% of hospitalized patients need ICU-treatment. Currently, no causal therapy is available and treatment is purely supportive. The main reason for death in critically ill patients is acute respiratory failure. However, in a number of patients a severe hyperinflammatory response with excessively elevated proinflammatory cytokines causes vasoplegic shock resistant to vasopressor therapy. A new polystyrene-based hemoadsorber (CytoSorb®, Cytosorbents Inc., New Jersey, USA) has been shown to adsorb effectively cytokines and other middle molecular weight toxins this way reducing their blood concentrations. This has been routinely used in clinical practice in the EU for other conditions where a cytokine storm occurs and an observational study has just been completed on COVID-19 patients. We hypothesized that the extracorporeal elimination of cytokines in critically ill COVID-19 patients with suspected hyperinflammation and shock may stabilize hemodynamics and improve outcome. The primary endpoint is time until resolution of vasoplegic shock, which is a well implemented, clinically relevant endpoint in critical care studies.

Trial Design: Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of "CytoSorb" to standard of care without "CytoSorb".

Participants: Patients are recruited from the Intensive Care Units (ICUs) of 7 participating centers in Germany (approximately 10 ICUs). All patients aged 18- 80 with positive polymerase chain reaction (PCR) test for SARS-CoV-2, a C-reactive protein (CRP) ≥ 100 mg/l, a Procalcitonin (PCT) < 2 ng/l, and suspected cytokine storm defined via a vasoplegic shock (Norepinephrine > 0.2 μg/min/kg to achieve a Mean Arterial Pressure ≥ 65mmHg). Patients are included irrespective of indication for renal replacement therapy. Suspected or proven bacterial cause for vasoplegic shock is a contraindication.

Intervention And Comparator: Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional "CytoSorb" therapy via a shaldon catheter for 3-7 days. Filter exchange is done every 24 hours. If patients receive antibiotics, an additional dose of antibiotics is administered after each change of "CytoSorb" filter in order to prevent underdosing due to "CytoSorb" treatment.

Main Outcomes: Primary outcome is time to resolution of vasoplegic shock (defined as no need for vasopressors for at least 8 hours in order to sustain a MAP ≥ 65mmHg) in days. Secondary outcomes are 7 day mortality after fulfilling the inclusion criteria, mortality until hospital discharge, Interleukin-6 (IL-6) measurement on day 1 and 3, need for mechanical ventilation, duration of mechanical ventilation, duration of ICU-stay, catecholamine dose on day 1/2/3 after start of "CytoSorb" and acute kidney injury.

Randomization: An electronic randomization will be performed using the study software secuTrial® administered by the Clinical Study Center (CSC) of the Charité - Universitätsmedizin Berlin, Germany. Randomization is done in blocks by 4 stratified by including center.

Blinding (masking): The trial will be non-blinded for the clinicians and patients. The statistician will receive a blinded data set, so that all analyses will be conducted blinded.

Numbers To Be Randomized (sample Size): As this is a pilot study with the goal to examine the feasibility of the study design as well as the intervention effect, no formal sample size calculation was conducted. A total number of approximately 80-100 patients is planned (40-50 patients per group). Safety assessment is done after the inclusion of each 10 patients per randomization group.

Trial Status: Please see the study protocol version from April 24 2020. Recruitment of patients is still pending.

Trial Registration: The study was registered on April 27 2020 in the German Registry of Clinical Trials (DRKS) under the number DRKS00021447.

Full Protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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June 2020

Studying the pathophysiology of coronavirus disease 2019: a protocol for the Berlin prospective COVID-19 patient cohort (Pa-COVID-19).

Infection 2020 Aug 13;48(4):619-626. Epub 2020 Jun 13.

Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Campus Virchow Klinikum, Augustenburgerplatz 1, 13353, Berlin, Germany.

Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions.

Methods: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up.

Results: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany.

Conclusion: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents.

Trial Registration: Registered at the German registry for clinical studies (DRKS00021688).
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August 2020

Standard operating procedures for antibiotic therapy and the occurrence of acute kidney injury: a prospective, clinical, non-interventional, observational study.

Crit Care 2014 Jun 12;18(3):R120. Epub 2014 Jun 12.

Introduction: Acute kidney injury (AKI) occurs in 7% of hospitalized and 66% of Intensive Care Unit (ICU) patients. It increases mortality, hospital length of stay, and costs. The aim of this study was to investigate, whether there is an association between adherence to guidelines (standard operating procedures (SOP)) for potentially nephrotoxic antibiotics and the occurrence of AKI.

Methods: This study was carried out as a prospective, clinical, non-interventional, observational study. Data collection was performed over a total of 170 days in three ICUs at Charité - Universitaetsmedizin Berlin. A total of 675 patients were included; 163 of these had therapy with vancomycin, gentamicin, or tobramycin; were >18 years; and treated in the ICU for >24 hours. Patients with an adherence to SOP >70% were classified into the high adherence group (HAG) and patients with an adherence of <70% into the low adherence group (LAG). AKI was defined according to RIFLE criteria. Adherence to SOPs was evaluated by retrospective expert audit. Development of AKI was compared between groups with exact Chi2-test and multivariate logistic regression analysis (two-sided P <0.05).

Results: LAG consisted of 75 patients (46%) versus 88 HAG patients (54%). AKI occurred significantly more often in LAG with 36% versus 21% in HAG (P = 0.035). Basic characteristics were comparable, except an increased rate of soft tissue infections in LAG. Multivariate analysis revealed an odds ratio of 2.5-fold for LAG to develop AKI compared with HAG (95% confidence interval 1.195 to 5.124, P = 0.039).

Conclusion: Low adherence to SOPs for potentially nephrotoxic antibiotics was associated with a higher occurrence of AKI.

Trial Registration: Current Controlled Trials ISRCTN54598675. Registered 17 August 2007.
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June 2014

Influenza A (H1N1) vs non-H1N1 ARDS: analysis of clinical course.

J Crit Care 2014 Jun 30;29(3):340-6. Epub 2013 Dec 30.

Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany. Electronic address:

Purpose: The purpose of the study is to compare H1N1-induced acute respiratory distress syndrome (ARDS) with ARDS due to other causes of severe community-acquired pneumonia focusing on pulmonary function.

Materials And Methods: This is a retrospective data analysis of adult ARDS patients between January 2009 and December 2010 in an ARDS referral center. Patient characteristics, severity of illness scores, modalities, and duration of extracorporeal lung support were evaluated as well as intensive care unit stay and survival. Parameters of mechanical ventilation and pulmonary function were analyzed on day of admission and over the consecutive 10 days using a nonparametric analysis of longitudinal data in a 2-factorial design. In a logistic regression analysis, risk factors for extracorporeal lung support were investigated.

Results: Twenty-one patients with H1N1-ARDS and 41 with non-H1N1-ARDS were identified. Gas exchange was more severely impaired in patients with H1N1-ARDS over course of time. Extracorporeal membrane oxygenation was more frequently needed in H1N1-ARDS. Despite significantly prolonged weaning off extracorporeal lung support and intensive care unit stay in H1N1 patients, the proportion of survivors did not differ significantly. Only Sepsis-Related Organ Failure Assessment score could be identified as an independent predictor of extracorporeal lung support.

Conclusions: Clinical course of H1N1-ARDS is substantially different from non-H1N1-ARDS. Affected patients may require extensive therapy including extracorporeal lung support in ARDS referral centers.
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June 2014

Avoiding invasive mechanical ventilation by extracorporeal carbon dioxide removal in patients failing noninvasive ventilation.

Intensive Care Med 2012 Oct 27;38(10):1632-9. Epub 2012 Jul 27.

Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

Purpose: To evaluate whether extracorporeal carbon dioxide removal by means of a pumpless extracorporeal lung-assist (PECLA) device could be an effective and safe alternative to invasive mechanical ventilation in patients with chronic pulmonary disease and acute hypercapnic ventilatory failure not responding to noninvasive ventilation (NIV).

Methods: In this multicentre, retrospective study, 21 PECLA patients were compared with respect to survival and procedural outcomes to 21 matched controls with conventional invasive mechanical ventilation. Matching criteria were underlying diagnosis, age, Simplified Acute Physiology Score II and pH at ICU admission.

Results: Of the 21 patients treated with PECLA, 19 (90 %) did not require intubation. Median PaCO(2) levels and pH in arterial blood prior to PECLA were 84.0 mmHg (54.2-131.0) and 7.28 (7.10-7.41), respectively. Within 24 h, median PaCO(2) levels and pH had significantly improved to 52.1 (33.0-70.1; p < 0.001) and 7.44 (7.27-7.56; p < 0.001), respectively. Two major and seven minor bleeding complications related to the device occurred. Further complications were one pseudoaneurysm and one heparin-induced thrombocytopenia type 2. Compared to the matched control group, there was a trend toward a shorter hospital length of stay in the PECLA group (adjusted p = 0.056). There was no group difference in the 28-day (24 % vs. 19 %, adjusted p = 0.845) or 6-month mortality (33 % vs. 33 %).

Conclusions: In this study the use of extracorporeal carbon dioxide removal allowed avoiding intubation and invasive mechanical ventilation in the majority of patients with acute on chronic respiratory failure not responding to NIV. Compared to conventional invasive ventilation, short- and long-term survivals were similar.
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October 2012