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Against the background of the pandemic caused by infection with the SARS-CoV-2 virus, the German Respiratory Society has appointed experts to develop therapy strategies for COVID-19 patients with acute respiratory failure (ARF). Here we present key position statements including observations about the pathophysiology of (ARF). In terms of the pathophysiology of pulmonary infection with SARS-CoV-2, COVID-19 can be divided into 3 phases. Pulmonary damage in advanced COVID-19 often differs from the known changes in acute respiratory distress syndrome (ARDS). Two types (type L and type H) are differentiated, corresponding to early- and late-stage lung damage. This differentiation should be taken into consideration in the respiratory support of ARF. The assessment of the extent of ARF should be based on arterial or capillary blood gas analysis under room air conditions, and it needs to include the calculation of oxygen supply (measured from the variables of oxygen saturation, hemoglobin level, the corrected values of Hüfner’s factor, and cardiac output). Aerosols can cause transmission of infectious, virus-laden particles. Open systems or vented systems can increase the release of respirable particles. Procedures in which the invasive ventilation system must be opened and endotracheal intubation carried out are associated with an increased risk of infection. Personal protective equipment (PPE) should have top priority because fear of contagion should not be a primary reason for intubation. Based on the current knowledge, inhalation therapy, nasal high-flow therapy (NHF), continuous positive airway pressure (CPAP), or noninvasive ventilation (NIV) can be performed without an increased risk of infection to staff if PPE is provided. A significant proportion of patients with ARF present with relevant hypoxemia, which often cannot be fully corrected, even with a high inspired oxygen fraction (FiO 2 ) under NHF. In this situation, the oxygen therapy can be escalated to CPAP or NIV when the criteria for endotracheal intubation are not met. In ARF, NIV should be carried out in an intensive care unit or a comparable setting by experienced staff. Under CPAP/NIV, a patient can deteriorate rapidly. For this reason, continuous monitoring and readiness for intubation are to be ensured at all times. If the ARF progresses under CPAP/NIV, intubation should be implemented without delay in patients who do not have a “do not intubate” order.

Purpose This study aimed to concisely describe the current standards of care, major recent advances, common beliefs that have been contradicted by recent trials, areas of uncertainty, and clinical studies that need to be performed over the next decade and their expected outcomes with regard to extracorporeal membrane oxygenation (ECMO). Methods Narrative review based on a systematic analysis of the medical literature, national and international guidelines, and expert opinion. Results The use of venovenous ECMO (VV-ECMO) is increasing in the most severe forms of acute lung injury. In patients with cardiogenic shock, short-term veno-arterial ECMO (VA-ECMO) provides both pulmonary and circulatory support. Technological improvements and recently published studies suggest that ECMO is able to improve patients’ outcomes. There are, however, many uncertainties regarding the real benefits of this technique both in hemodynamic and respiratory failure, the territorial organization to deliver ECMO, the indications and the use of concomitant treatments. Conclusions Although there have been considerable advances regarding the use of ECMO in critically ill patients, the risk/benefit ratio remains underinvestigated. ECMO indications, organization of ECMO delivery, and use of adjuvant therapeutics need also to be explored. Ongoing and future studies may be able to resolve these issues.

The plasticizer di(2-ethylhexyl)phthalate (DEHP) is often used for PVC medical devices, that are also largely used for intensive care medical treatments, like extracorporeal membrane oxygenation (ECMO) therapy. Due to the toxicological potential of DEHP, the inner exposure of patients with this plasticizer is a strong matter of concern as many studies have shown a high leaching potential of DEHP into blood. In this study, the inner DEHP exposure of patients undergoing ECMO treatment was investigated. The determined DEHP blood levels of ECMO patients and the patients of the control group ranged from 31.5 to 1009 μg/L (median 156.0 μg/L) and from 19.4 to 75.3 μg/L (median 36.4 μg/L), respectively. MEHP blood levels were determined to range from < LOD to 475 μg/L (median 15.9 μg/L) in ECMO patients and from < LOD to 9.9 μg/L (median 3.7 μg/L) in the control group patients, respectively. Increased DEHP exposure was associated with the number of cannulas and membranes of the ECMO setting, whereas residual diuresis decreased the exposure. Due to the suspected toxicological potential of DEHP, its use in medical devices should be further investigated, in particular for ICU patients with long-term exposure to PVC, like in ECMO therapy.

Glycyrrhizin, an active component of liquorice root extract, exhibits antiviral and immunomodulatory properties by direct inhibition of the pro-inflammatory alarmin HMGB1 (High-mobility group box 1). The aim of this study was to explore the role of liquorice intake on the viral entry receptor ACE2 (angiotensin-converting enzyme 2) and the immunoregulatory HMGB1 in healthy individuals and to explore HMGB1 expression in coronavirus disease 2019 (COVID-19) or non-COVID-19 in ARDS (acute respiratory distress syndrome patients). This study enrolled 43 individuals, including hospitalised patients with i) acute respiratory distress syndrome (ARDS) due to COVID-19 (n = 7) or other underlying causes (n = 12), ii) mild COVID-19 (n = 4) and iii) healthy volunteers (n = 20). Healthy individuals took 50 g of liquorice (containing 3% liquorice root extract) daily for 7 days, while blood samples were collected at baseline and on day 3 and 7. Changes in ACE2 and HMGB1 levels were determined by Western blot analysis and enzyme-linked immunosorbent assay, respectively. Additionally, HMGB1 levels were measured in hospitalised COVID-19 patients with mild disease or COVID-19 associated acute respiratory distress syndrome (ARDS) and compared with a non-COVID-19-ARDS group. Liquorice intake significantly reduced after 7 days both cellular membranous ACE2 expression (-51% compared to baseline levels, p = 0.008) and plasma HMGB1 levels (-17% compared to baseline levels, p<0.001) in healthy individuals. Half of the individuals had a reduction in ACE2 levels of at least 30%. HMGB1 levels in patients with mild COVID-19 and ARDS patients with and without COVID-19 were significantly higher compared with those of healthy individuals (+317%, p = 0.002), but they were not different between COVID-19 and non-COVID-19 ARDS. Liquorice intake modulates ACE2 and HMGB1 levels in healthy individuals. HMGB1 is enhanced in mild COVID-19 and in ARDS with and without COVID-19, warranting evaluation of HMGB1 as a potential treatment target and glycyrrhizin, which is an active component of liquorice root extract, as a potential treatment in COVID-19 and non-COVID-19 respiratory disease.

Background Mechanical thrombectomy has been shown to reduce thrombus burden and pulmonary artery pressure (PAP) and to improve right ventricular (RV) function in patients with high-risk or intermediate-high-risk pulmonary embolism (PE). As hemodynamic data after mechanical thrombectomy for PE are scarce, we aimed to assess the hemodynamic effects of mechanical thrombectomy in acute PE with right heart overload. Methods In this prospective, open-label study, patients with acute symptomatic, computed tomography-documented PE with signs of right heart overload underwent mechanical thrombectomy using the FlowTriever System. Right heart catheterization was performed immediately before and after thrombectomy and after three months. Transthoracic echocardiography was performed before thrombectomy, discharge, and at three months. This analysis was done after 20 patients completed three months of follow-up. Results Twenty-nine patients (34% female) underwent mechanical thrombectomy, of which 20 completed three months follow-up with right heart catheterization. Most patients were at high (17%) or intermediate-high (76%) risk and had bilateral PE (79%). Before thrombectomy, systolic PAP (sPAP) was severely elevated (mean 51.3 ± 11.6 mmHg). Mean sPAP dropped by -15.0 mmHg (95% confidence interval [CI]: -18.9 to -11.0; p < 0.001) immediately after the procedure and continued to decrease from post-thrombectomy to three months (-6.4 mmHg, 95% CI: -10-0 to -2.9; p = 0.002). RV/left ventricular (LV) ratio immediately reduced within two days by -0.37 (95% CI: -0.47 to -0.27; p < 0.001). The proportion of patients with a tricuspid annular plane systolic excursion (TAPSE)/sPAP ratio < 0.31 mm/mmHg decreased from 28% at baseline to 0% before discharge and at three months (p = 0.007). There were no procedure-related major adverse events. Conclusions Mechanical thrombectomy for acute PE was safe and immediately reduced PAP and improved right heart function. The reduction in PAP was maintained at three months follow-up.

As a consequence of the continued Covid-19 lockdown in Germany, in-hospital teaching for medical students was impossible. While lectures and other theoretical training were relatively easily converted into online sessions using platforms such as Moodle, Zoom and Microsoft Teams, this was not the case for practical skills and clinical interventions, such as bronchoscopy or colonoscopy. This study describes a workaround that was implemented at the Saarland University Hospital utilizing virtual reality equipment to convey the impressions of shadowing clinical procedures to the students without physical presence. To achieve this, 3D 180° videos of key clinical interventions of various internal medicine specialities were recorded, cut, and censored. The videos were uploaded to the e-learning YouTube channel of our institution and shared with the students via the private share function. The students could choose whether to use a VR-viewer to watch the videos immersively or to watch them without a viewer on a screen non-immersively. At the end of the course after 1 week, the students completed a questionnaire anonymously focusing on learning-success regarding the presented topics, a self-assessment, and an evaluation of the course. A total of 27 students watched the videos with a VR-Viewer and 74 watched non-immersively. Although the VR-viewer group self-assessed their expertise higher, there was no significant difference between the two groups in the learning-success test score. However, students in the VR-viewer group rated the learning atmosphere, comprehensibility, and overall recommendation of the course significantly higher. They also agreed significantly more to the statement, that they gained a better conception of the presented procedures, and that virtual reality might be an appropriate tool for online teaching. Video-assisted teaching facilitates learning and might be a valuable add-on to conventional teaching. Abbreviations: Covid-19: severe acute respiratory syndrome coronavirus 2; 3D: three-dimensional; 2D: Two-dimensional; VR: virtual reality

Objectives The implementation of the Lung Allocation Score (LAS) in the Eurotransplant international collaborative framework decreased waiting list mortality, but organ shortage remains a significant problem. Transplantation of two single lungs from one donor into two recipients (lung twinning) may decrease waiting list mortality. We sought to analyze if this strategy can lead to an acceptable intermediate-term outcome. Methods Since the LAS-implementation we performed 32 paired single-lung transplantations from 16 postmortal donors. Data and outcome were analyzed retrospectively comparing recipients receiving the first lung (first twins) with recipients receiving the second lung (second twins), left versus right transplantation and restrictive versus obstructive disease. Results Survival at one year was 81% and 54% at five years. Veno-venous ECMO had been successfully used as bridge-to-transplant in three patients with ECMO-explantation immediately after surgery. Bronchial anastomotic complications were not observed in any patient. First twins and second twins exhibited similar survival ( p  = 0.82) despite higher LAS in first twins (median 45 versus 34, p  < 0.001) and longer cold ischemic time in second twins (280 ± 83 vs. 478 ± 125 min, p  < 0.001). Survival of left and right transplantation was similar ( p  = 0.45) with similar best post-transplant FEV1 (68 ± 15% versus 62 ± 14%, p  = 0.26). Survival was similar in restrictive and obstructive disease ( p  = 0.28) with better post-transplant FEV1 (70 ± 15% versus 57 ± 11%, p  = 0.02) in restrictive disease. Conclusions Performing two single-lung transplantations from one donor can be performed safely with encouraging intermediate-term outcome and good functional capacity. Lung twinning maximizes the donor pool and may help to overcome severe organ shortage. Clinical trials This research is not a clinical trial. Thus no registration details will be provided.

BACKGROUNDPatients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) differ in the severity of disease. We hypothesized that characteristics of SARS-CoV-2-specific immunity correlate with disease severity.METHODSIn this study, SARS-CoV-2-specific T cells and antibodies were characterized in uninfected controls and patients with different coronavirus disease 2019 (COVID-19) disease severity. SARS-CoV-2-specific T cells were flow cytometrically quantified after stimulation with SARS-CoV-2 peptide pools and analyzed for expression of cytokines (IFN-γ, IL-2, and TNF-α) and markers for activation, proliferation, and functional anergy. SARS-CoV-2-specific IgG and IgA antibodies were quantified using ELISA. Moreover, global characteristics of lymphocyte subpopulations were compared between patient groups and uninfected controls.RESULTSDespite severe lymphopenia affecting all major lymphocyte subpopulations, patients with severe disease mounted significantly higher levels of SARS-CoV-2-specific T cells as compared with convalescent individuals. SARS-CoV-2-specific CD4+ T cells dominated over CD8+ T cells and closely correlated with the number of plasmablasts and SARS-CoV-2-specific IgA and IgG levels. Unlike in convalescent patients, SARS-CoV-2-specific T cells in patients with severe disease showed marked alterations in phenotypical and functional properties, which also extended to CD4+ and CD8+ T cells in general.CONCLUSIONGiven the strong induction of specific immunity to control viral replication in patients with severe disease, the functionally altered characteristics may result from the need for contraction of specific and general immunity to counteract excessive immunopathology in the lung.FUNDINGThe study was supported by institutional funds to MS and in part by grants of Saarland University, the State of Saarland, and the Rolf M. Schwiete Stiftung.

At the participating centers, all patients with reverse transcriptase polymerase chain reaction (rtPCR) positive testing for SARS-CoV-2, who received V-V ECMO from March 12 to June 5, 2020 (i.e., during the first wave of the pandemic), were included. [...]even though 90-day-survival of patients aged ≥ 71 years was significantly lower than for patients < 71 years, not all treatments in this elderly population ended fatal. [...]age limits should be viewed with caution and decisions for or against the use of ECMO for patients above 70 years of age should be performed on an individual case-by-case level. [...]our data may support the use of V-V ECMO in severe COVID-19 ARDS, also after prolonged periods of mechanical ventilation in selected patients. Collaborating authors (COVEC-study group): Jeff DellaVolpe, Methodist Hospital, San Antonio, Texas, USA; Dominik Scharpf, SLK-Hospital Heilbronn, Germany; Matthias Ulmer, RKH Hospital Ludwigsburg, Germany; Maximilian Halbe, Heart Center, University Hospital Zurich, Switzerland; Alexander Vogt, Department of Medicine III, University Clinic Halle (Saale), Germany; Raj Ramanan, University of Pittsburgh Medical Center (UPMC), Pennsylvania, USA; David Boldt, UCLA Healthcare System, Los Angeles, USA; Stephanie-Susanne Stecher, Medical Department II, LMU Hospital Munich, Germany; Andrea Montisci, Istituto Clinico Sant’Ambrogio, University of Milan, Italy; Tobias Spangenberg, Department of Cardiology, Angiology and Intensive Care, Marien Hospital Hamburg, Germany; Olivier Marggraf, Asklepios Clinic North, Hamburg, Germany; Chandra Kunavarapu, Methodist Hospital, San Antonio, Texas, USA; Lorenzo Peluso, Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium; Sebastian Muenz, SLK-Hospital Heilbronn, Germany; Monica Buerle, RKH Hospital Ludwigsburg, Germany; Naveen G. Nagaraj, Heart Center, University Hospital Zurich, Switzerland; Sebastian Nuding, Department of Medicine III, University Clinic Halle (Saale), Germany; Catalin Toma, University of Pittsburgh Medical Center (UPMC), Pennsylvania, USA; Vadim Gudzenko, UCLA Healthcare System, Los Angeles, USA; Hans Joachim Stemmler, Medical Department III, LMU Hospital Munich, Germany; Federico Pappalardo, Department of Anesthesia and Intensive Care, IRCCS ISMETT, UPMC Italy, Palermo, Italy; Georg Trummer, Department of Cardiovascular Surgery, Heart Center, University of Freiburg, Germany; Christoph Benk, Department of Cardiovascular Surgery, Heart Center, University of Freiburg, Germany; Guido Michels, Department of Acute and Emergency Care, St. Antonius Hospital Eschweiler, Eschweiler, Germany; Christoph Bode, Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center, Faculty of Medicine, University of Freiburg, Germany, Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany; Daniel Duerschmied, Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center, Faculty of Medicine, University of Freiburg, Germany, Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany; Constantin von zur Muehlen, Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center, Faculty of Medicine, University of Freiburg, Germany, Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany; Klaus Kaier, Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany, Institute of Medical Biometry and Statistics, Faculty of Medicine, University of Freiburg, Germany, Daniel Brodie, Columbia University College of Physicians & Surgeons/New York-Presbyterian Hospital, New York, USA, Center for Acute Respiratory Failure, Columbia University Medical Center, New York, USA; Tobias Wengenmayer, Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center, Faculty of Medicine, University of Freiburg, Germany, Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany.

The IL-17 family of cytokines consists of at least six members (IL-17A to -F). IL-17 directly activates epithelial cells leading to the expression of inflammatory mediators and antimicrobial factors. Recent studies showed that IL-17C is expressed by epithelial cells. It was the purpose of this study to examine the expression of IL-17 family members in respiratory epithelial cells during bacterial infection. We show that common bacterial pathogens, such as Pseudomonas aeruginosa and Haemophilus influenzae, and ligands of Toll-like receptors 3 and 5 (flagellin, polyI:C) induced the expression and release of IL-17C in cultured human bronchial epithelial cells (HBECs). The expression of IL-17A, -B, -D, or -E was not induced by bacterial stimuli in HBECs. IL-17C enhanced inflammatory responses of respiratory epithelial cells infected with P. aeruginosa. Furthermore, we demonstrate that cigarette smoke suppressed the expression of IL-17C in HBECs in response to bacterial infection and in vivo in the upper airways of mice colonized with H. influenzae. IL-17C could also be detected in bronchial tissue of subjects with infection-related lung diseases. These data show that IL-17C is involved in the innate immune response of respiratory epithelial cells and is suppressed by cigarette smoke.