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This case reports on a patient with antineutrophil cytoplasmatic antibody–associated vasculitis and severe pulmonary and cutaneous involvement who received conventional therapy that failed and who was rescued by daratumumab therapy.

Coronavirus disease 2019 (COVID-19) has drastically increased the number of patients requiring extracorporeal life support. We investigate the efficacy and safety of low-dose recombinant tissue-type plasminogen activator (rtPA) injection into exhausted oxygenators to delay exchange in critically ill COVID-19 patients on veno-venous extracorporeal membrane oxygenation (V-V ECMO). Small doses of rtPA were injected directly into the draining section of a V-V ECMO circuit. We compared transmembrane pressure gradient, pump head efficiency, membrane arterial partial oxygen pressure, and membrane arterial partial carbon dioxide pressure before and after the procedure. Bleeding was compared with a matched control group of 20 COVID-19 patients on V-V ECMO receiving standard anticoagulation. Four patients received 16 oxygenator instillations with rtPA at 5, 10, or 20 mg per dose. Administration of rtPA significantly reduced transmembrane pressure gradient (Δ pm = 54.8 ± 18.1 mmHg before vs . 38.3 ± 13.3 mmHg after, p0.001) in a dose-dependent manner (Pearson's R -0.63, p = 0.023), allowing to delay oxygenator exchange, thus reducing the overall number of consumed oxygenators. rtPA increased blood flow efficiency η (1.20 ± 0.28 ml/revolution before vs . 1.24 ± 0.27 ml/r, p = 0.002). Lysis did not affect membrane blood gases or systemic coagulation. Minor bleeding occurred in 2 of 4 patients (50%) receiving oxygenator lysis as well as 19 of 20 control patients (95%). Lysis of ECMO oxygenators effectively delays oxygenator exchange, if exchange is indicated by an increase in transmembrane pressure gradient. Application of lysis did not result in higher bleeding incidences compared with anticoagulated patients on V-V ECMO for COVID-19.

Background COVID-19 comprises several severity stages ranging from oligosymptomatic disease to multi-organ failure and fatal outcomes. The mechanisms why COVID-19 is a mild disease in some patients and progresses to a severe multi-organ and often fatal disease with respiratory failure are not known. Biomarkers that predict the course of disease are urgently needed. The aim of this study was to evaluate a large spectrum of established laboratory measurements. Patients and Methods Patients from the prospective PULMPOHOM and CORSAAR studies were recruited and comprised 35 patients with COVID-19, 23 with conventional pneumonia, and 28 control patients undergoing elective non-pulmonary surgery. Venous blood was used to measure the serum concentrations of 79 proteins by Luminex multiplex immunoassay technology. Distribution of biomarkers between groups and association with disease severity and outcomes were analyzed. Results The biomarker profiles between the three groups differed significantly with elevation of specific proteins specific for the respective conditions. Several biomarkers correlated significantly with disease severity and death. Uniform manifold approximation and projection (UMAP) analysis revealed a significant separation of the three disease groups and separated between survivors and deceased patients. Different models were developed to predict mortality based on the baseline measurements of several protein markers. A score combining IL-1ra, IL-8, IL-10, MCP-1, SCF and CA-9 was associated with significantly higher mortality (AUC 0.929). Discussion Several newly identified blood markers were significantly increased in patients with severe COVID-19 (AAT, EN-RAGE, myoglobin, SAP, TIMP-1, vWF, decorin) or in patients that died (IL-1ra, IL-8, IL-10, MCP-1, SCF, CA-9). The use of established assay technologies allows for rapid translation into clinical practice., Graphical Abstract

Critically ill patients in need of specialized diagnostic or therapeutic procedures, but are being cared for in a hospital without such equipment, have to be transferred to appropriate centers without discontinuation of current critical care (interhospital critical care transfer). These transfers are resource intensive, challenging, and require high logistical effort, which must be managed by a specialized and highly trained team, predeployment planning and efficient crew-resource management strategies. If planned adequately, interhospital critical care transfers can be performed safely without frequent adverse events. Beside routine interhospital critical care transfers, there are special missions (e.g., for patients in quarantine or supported by extracorporeal organ support) that might require adaption of the team composition or standard equipment. This article describes interhospital critical care transport missions including their different phases and special circumstances.Kritisch kranke Patienten, die spezialisierte diagnostische oder therapeutische Verfahren benötigen, jedoch in einem Krankenhaus ohne diesbezügliche Ausstattung versorgt werden, müssen unter Fortführung intensivmedizinischer Maßnahmen zu geeigneten Zentren transportiert werden. Solche Transporte sind herausfordernde Einsätze mit hohem Ressourcenbedarf und logistischem Aufwand, die durch ein spezialisiertes Team bewältigt werden müssen. Hierzu ist neben einem effizienten Crew Resource Management eine gute Planung des Einsatzes notwendig. Bei adäquater Vorbereitung sind solche Einsätze für den Patienten sicher und komplikationsarm durchführbar. Neben Routineintensivtransporten gibt es Sondereinsätze (z. B. isolationspflichtiger Patienten oder Patienten mit extrakorporaler Organunterstützung), die eine Anpassung des Teams oder des vorgehaltenen Materials erfordern. Dieser Beitrag beschreibt die Grundlagen des interhospitalen Intensivtransportes, seine Phasen und Sonderfälle.

OBJECTIVES Patients with chronic obstructive pulmonary disease and lung emphysema may benefit from surgical or endoscopic lung volume reduction (ELVR). Previously reported outcomes of nitinol coil-based ELVR techniques have been ambiguous. The analysis was done to analyse outcomes of ELVR with nitinol coils in patients with severe pulmonary emphysema. METHODS From September 2013 to November 2014, our centre performed a total of 41 coil implantations on 29 patients with severe emphysema. Coils were bronchoscopically placed during general anaesthesia. Twelve out of 29 patients received staged contralateral treatments up to 112 days later to avoid bilateral pneumothorax. Lung function and 6-min walking distance were assessed 1 week prior, 1 week after as well as 6–12 months after the procedure. Patients were followed up to 48 months after ELVR and overall mortality was compared to a historic cohort. RESULTS While coil-based ELVR led to significant short-term improvement of vital capacity (VC, +0.14 ± 0.39 l, P = 0.032) and hyperinflation (Δ residual volume/total lung capacity −2.32% ± 6.24%, P = 0.022), no significant changes were observed in 6-min walking distance or forced expiratory volume in 1 s. Benefits were short-lived, with only 15.4% and 14.3% of patients showing sustained improvements in forced expiratory volume in 1 s or residual volume after 6 months. Adverse events included haemoptysis (40%) and pneumothorax (3.4%), major complications occurred in 6.9% of cases. Overall survival without lung transplant was 63.8% after 48 months following ELVR, differing insignificantly from what BODE indices of patients would have predicted as median 4-year survival (57%) at the time of ELVR treatment. CONCLUSIONS ELVR with coils can achieve small and short-lived benefits in lung function at the cost of major complications in a highly morbid cohort. Treatment failed to improve 4-year overall survival. ELVR coils are not worthwhile the risk for most patients with severe emphysema.

In late 2020, during the second wave of COVID-19 in Germany, we started using the MobyBox, which is a novel fully pneumatically driven ECMO device, on a regular basis to meet the increasing demand for ECMO therapy. In this case series, we performed a retrospective chart review of seven patients with severe COVID-19-related acute respiratory distress syndrome (ARDS) requiring veno-venous (vv)-ECMO support with the MobyBox. During ECMO treatments we have observed no disadvantages in comparison to conventional ECMO systems. There were no system failures or adverse events directly attributable to the MobyBox system. Our data support that providing vv-ECMO with the MobyBox device is safe and feasible. Furthermore, our findings suggest that the MobyBox device might represent an advantage in terms of biocompatibility. Therefore, more data on this issue is needed to better understand how the pneumatically driven pump affects cellular blood components.

Hyperinflammation is frequently observed in patients with severe COVID-19. Inadequate and defective IFN type I responses against SARS-CoV-2, associated with autoantibodies in a proportion of patients, lead to severe courses of disease. In addition, hyperactive responses of the humoral immune system have been described. In the current study we investigated a possible role of neutralizing autoantibodies against anti-inflammatory mediators. Plasma from adult patients with severe and critical COVID-19 was screened by ELISA for antibodies against PGRN, IL-1-Ra, IL-10, IL-18BP, IL-22BP, IL-36-Ra, CD40, IFN-α2, IFN-γ, IFN-ω and serpinB1. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations. In a discovery cohort with severe to critical COVID-19 high titers of PGRN-autoantibodies were detected in 11 of 30 (36.7%), and of IL-1-Ra-autoantibodies in 14 of 30 (46.7%) patients. In a validation cohort of 64 patients with critical COVID-19 high-titer PGRN-Abs were detected in 25 (39%) and IL-1-Ra-Abs in 32 of 64 patients (50%). PGRN-Abs and IL-1-Ra-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19, PGRN-Abs and IL-1-Ra-Abs were detected in low frequency (i.e. in < 5% of patients) and at low titers. Neither PGRN- nor IL-1-Ra-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2 or 188 unvaccinated healthy controls. PGRN-Abs were not cross-reactive against SARS-CoV-2 structural proteins nor against IL-1-Ra. Plasma levels of both free PGRN and free IL-1-Ra were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID-19 controls. In vitro PGRN-Abs from patients functionally reduced PGRN-dependent inhibition of TNF-α signaling, and IL-1-Ra-Abs from patients reduced IL-1-Ra- or anakinra-dependent inhibition of IL-1ß signaling. The pSer81 hyperphosphorylated PGRN isoform was exclusively detected in patients with high-titer PGRN-Abs; likewise, a hyperphosphorylated IL-1-Ra isoform was only found in patients with high-titer IL-1-Ra-Abs. Thr111 was identified as the hyperphophorylated amino acid of IL-1-Ra. In longitudinally collected samples hyperphosphorylated isoforms of both PGRN and IL-1-Ra emerged transiently, and preceded the appearance of autoantibodies. In hospitalized patients, the presence of IL-1-Ra-Abs or IL-1-Ra-Abs in combination with PGRN-Abs was associated with a higher morbidity and mortality.To conclude, neutralizing autoantibodies to IL-1-Ra and PGRN occur in a significant portion of patients with critical COVID-19, with a concomitant decrease in circulating free PGRN and IL-1-Ra, indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical hyperphosphorylated isoforms of both antigens, whose appearances precede autoantibody induction. Our data suggest that these immunogenic secondary modifications are induced by the SARS-CoV-2-infection itself or the inflammatory environment evoked by the infection and predispose for a critical course of COVID-19.

BackgroundDespite numerous advances in the identification of risk factors for the development of severe coronavirus disease 2019 (COVID-19), factors that promote recovery from COVID-19 remain unknown. Natural killer (NK) cells provide innate immune defense against viral infections and are known to be activated during moderate and severe COVID-19. Killer immunoglobulin-like receptors (KIR) mediate NK cell cytotoxicity through recognition of an altered MHC-I expression on infected target cells. However, the influence of KIR genotype on outcome of patients with COVID-19 has not been investigated so far. We retrospectively analyzed the outcome associations of NK cell count and KIR genotype of patients with COVID-19 related severe ARDS treated on our tertiary intensive care unit (ICU) between February and June 2020 and validated our findings in an independent validation cohort of patients with moderate COVID-19 admitted to our tertiary medical center.ResultsMedian age of all patients in the discovery cohort (n = 16) was 61 years (range 50–71 years). All patients received invasive mechanical ventilation; 11 patients (68%) required extracorporeal membrane oxygenation (ECMO). Patients who recovered from COVID-19 had significantly higher median NK cell counts during the whole observational period compared to patients who died (121 cells/µL, range 16–602 cells/µL vs 81 cells/µL, range 6–227 cells/µL,p-value = 0.01). KIR2DS5 positivity was significantly associated with shorter time to recovery (21.6 ± 2.8 days vs. 44.6 ± 2.2 days,p-value = 0.01). KIR2DS5 positivity was significantly associated with freedom from transfer to ICU (0% vs 9%,p-value = 0.04) in the validation cohort which consisted of 65 patients with moderate COVID-19.ConclusionNK cells and KIR genotype might have an impact on recovery from COVID-19.

Background: There is ongoing debate whether lung physiology of COVID-19 associated acute respiratory distress syndrome (ARDS) differs from ARDS of other origin.Objective: The aim of this study was to analyze and compare how critically ill patients with COVID-19 and Influenza A or B were ventilated in our tertiary care center with or without extracorporeal membrane oxygenation (ECMO). We ask if acute lung failure due to COVID-19 requires different intensive care management compared to conventional ARDS. Methods: 25 patients with COVID-19 associated ARDS were matched to a cohort of 25 Influenza patients treated in our center from 2011 to 2021. Subgroup analysis addressed whether patients on ECMO received different mechanical ventilation than patients without extracorporeal support.Results: Compared to Influenza-associated ARDS, COVID-19 patients had higher ventilatory system compliance (40.7 ml/mbar [31.8 – 46.7 ml/mbar] vs. 31.4 ml/mbar [13.7 – 42.8 ml/mbar], p = 0.198), higher ventilatory ratio (1.57 [1.31 – 1.84] vs. 0.91 [0.44 – 1.38], p = 0.006) and higher minute ventilation at the time of intubation (mean minute ventilation 10.7 l/min [7.2 – 12.2 l/min] for COVID-19 vs. 6.0 l/min [2.5 – 10.1 l/min] for Influenza, p = 0.013). There were no measurable differences in P/F ratio, positive end-expiratory pressure (PEEP) and driving pressures (ΔP). Respiratory system compliance deteriorated considerably in COVID-19 patients on ECMO during 2 weeks of mechanical ventilation (Crs, mean decrease over 2 weeks -23.87 ml/mbar ± 32.94 ml/mbar, p = 0.037), but not in ventilated Influenza patients on ECMO and less so in ventilated COVID-19 patients without ECMO. For COVID-19 patients, low driving pressures on ECMO were strongly correlated to a decline in compliance after 2 weeks (Pearson’s R 0.80, p = 0.058). Overall mortality was insignificantly lower for COVID-19 patients compared to Influenza patients (40% vs. 48%, p = 0.31). Outcome was insignificantly worse for patients requiring veno-venous ECMO in both groups (50% mortality for COVID-19 on ECMO vs. 27% without ECMO, p = 0.30 / 56% vs 34% mortality for Influenza A/B with and without ECMO, p = 0.31)Conclusion: The pathophysiology of early COVID-19-associated ARDS differs from Influenza-associated acute lung failure by sustained respiratory mechanics during the early phase of ventilation. We question whether intubated COVID-19 patients on ECMO benefit from extremely low driving pressures, as this appears to accelerate derecruitment and consecutive loss of ventilatory system compliance.

Extracorporeal membrane oxygenation (ECMO) is a means to support patients with acute respiratory failure. Initially, recommendations to treat severe cases of pandemic Coronavirus Disease 2019 (COVID-19) with ECMO have been restrained. In the meantime, ECMO has been shown to produce similar outcomes in patients with severe COVID-19 compared to existing data on ARDS mortality. Objective: We performed an international email survey to assess how ECMO providers worldwide have previously used ECMO during the treatment of critically ill patients with COVID-19.MethodsA questionnaire with 45 questions (covering e.g. indication, technical aspects, benefit and reasons for treatment discontinuation), mostly multiple-choice, was distributed by email to ECMO centers. The survey was approved by the European branch of the Extracorporeal Life Support Organization (ELSO). Results: 276 centers worldwide responded that they employed ECMO for very severe COVID-19 cases, mostly in veno-venous configuration (87%). The most common reason to establish ECMO was isolated hypoxemic respiratory failure (50%), followed by a combination of hypoxemia and hypercapnia (39%). Only a small fraction of patients required veno-arterial cannulation due to heart failure (3%). Time on ECMO varied between less than two and more than four weeks. The main reason to discontinue ECMO treatment prior to patient’s recovery was lack of clinical improvement (53%), followed by major bleeding, mostly intracranially (13%). Only 4% of respondents reported that triage situations, lack of staff or lack of oxygenators were responsible for discontinuation of ECMO support. Most ECMO physicians (66% ± 26%) agreed that patients with COVID-19 induced ARDS (CARDS) benefitted from ECMO. Overall mortality of COVID-19 patients on ECMO was estimated to be about 55%, scoring higher than what has previously been reported for Influenza patients on ECMO (29 – 36%). Conclusion: ECMO has been utilized successfully during the COVID-19 pandemic to stabilize CARDS patients in hypoxemic or hypercapnic lung failure. Age and multimorbidity limited the use of ECMO. Triage situations were rarely a concern. ECMO providers stated that patients with severe COVID-19 benefitted from ECMO. An increasing use in patients with respiratory failure in a future stage of the pandemic may be expected. Funding Statement: COVID-19 research was funded by the Federal state of Saarland, Saarland University and Dr. Rolf M. Schwiete Foundation. Declaration of Interests: Robert Bals declares funding from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, Novartis, CLS Behring, the German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), Sander-Stiftung, Schwiete-Stiftung, Krebshilfe and Mukoviszidose eV. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. All other authors: No potential conflicts of interest. Ethics Approval Statement: The ethical committee (Arztekammer des Saarlandes) waived the need for a formal approval since the questionnaire did not retrieve actual patient data.

Background In 2020, a novel coronavirus caused a global pandemic with a clinical picture termed COVID-19 accounting for numerous cases of ARDS. However, there are still other infectious causes of ARDS that should be considered, especially, as the majority of these pathogens are specifically treatable. Case Presentation We present the case of a 36-year-old gentleman who was admitted to the hospital with flu-like symptoms after completing a half-marathon one week before admission. As infection with SARS-CoV2 was suspected based on radiologic imaging, the hypoxemic patient was immediately transferred to the ICU, where he developed ARDS. Empiric antimicrobial chemotherapy was initiated, the patient deteriorated further, therapy was changed and the patient was transferred to a tertiary care ARDS center. As cold agglutinins were present, the hypothesis of an infection with SARS-CoV-2 was then questioned. Bronchoscopic sampling revealed Mycoplasma (M.) pneumoniae. When antimicrobial chemotherapy was adjusted, the patient recovered quickly. Conclusion Usually, M. pneumoniae causes mild disease. When antimicrobial chemotherapy was adjusted, the patient recovered quickly. The case underlines the importance of adhering to established treatment guidelines, scrutinizing treatment modalities and not forgetting other potential causes of severe pneumonia or ARDS.

Background: It has been suggested that COVID-19-associated severe respiratory failure (CARDS) might differ from usual acute respiratory distress syndrome (ARDS) due to failing auto-regulation of pulmonary vessels and higher shunt. We sought to investigate pulmonary hemodynamics and ventilation properties in patients with CARDS compared to patients with ARDS of pulmonary origin. Methods: Retrospective analysis of prospectively collected data of consecutive adults with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 patients treated on our ICU in 04/2020 and comparison of the data to matched controls with ARDS due to respiratory infections treated on our ICU from 01/2014 to 08/2019 and for whom pulmonary artery catheter data were available. Results: CARDS patients (n = 10) had similar ventilation characteristics as compared to ARDS (n = 10) patients. Still, mechanical power applied by ventilation was significantly higher in CARDS patients (23.4 ± 8.9 J/min) than in ARDS (15.9 ± 4.3 J/min; p0.05) and was in both groups correlated with hypoxemia. The arterio-venous pCO2 difference (DpCO2) was elevated (CARDS 5.5±2.8 mmHg vs. ARDS 4.7±1.1 mmHg; p>0.05) as was P(v-a)CO2/C(a-v)O2 ratio (CARDS mean 2.2±1.5 vs. ARDS 1.7±0.8; p>0.05). Conclusions: Respiratory failure in COVID-19 patients seems to differ only slightly from ARDS regarding ventilation characteristics and pulmonary hemodynamics. Differences are mainly due to increased CO2 production in CARDS patients. Our data indicate microcirculatory dysfunction. More data needs to be collected to assure these findings and gain more pathophysiological insights in COVID-19 and respiratory failure.

BackgroundPatients with chronic obstructive pulmonary disease (COPD) and lung emphysema may benefit from surgical or endoscopic lung volume reduction (ELVR). Previously reported outcomes of nitinol-coil-based endoscopic lung volume reduction techniques have been ambiguous.Objectives The analysis was done to analyze outcomes of ELVR with nitinol-coils in patients with severe pulmonary emphysema.MethodsFrom September 2013 to November 2014, our center performed a total of 41 coil implantations on 29 patients with severe emphysema. Coils were bronchoscopically placed during general anesthesia. 12 out of 29 patients received contralateral treatments 4-6 weeks later to avoid bilateral pneumothorax. Lung function and 6-minute walking distance were assessed one week prior, one week after as well as 6 to 12 months after the procedure. Patients were followed up to 48 months after ELVR and overall mortality was compared to a historic cohort.ResultsWhile coil-based ELVR led to significant short-term improvement of vital capacity (VC, + 0.14 l ± 0.39 l, p = 0.032) and hyperinflation (ΔRV / TLC -2.32% ± 6.24%, p = 0.022), no significant changes were observed in 6-minute walking distance (6-MWD) or forced expiratory volume in one second (FEV1). Benefits were short-lived, with only 15.4% and 14.3% of patients showing sustained improvements in FEV1 or residual volume (RV) after 6 months. Adverse events included hemoptysis (40 %) and pneumothorax (3.4 %), major complications occurred in 6.9% of cases. Overall survival without lung transplant was 63.8% after 48 months following ELVR, differing insignificantly from what BODE indices of patients would have predicted as median 4-year survival (57%) at the time of ELVR treatment.ConclusionEndoscopic lung volume reduction coils can achieve small and short-lived benefits in lung function at the cost of major complications in a highly morbid cohort. Treatment failed to improve 4-year overall survival. ELVR coils are not worthwhile the risk for most patients with severe emphysema.

Immune therapy of cancer is among the most promising recent advances in medicine. Whether the immune system can keep cancer in check depends on, among other factors, the efficiency of immune cells to recognize and eliminate cancer cells. We describe a time-resolved single-cell assay that reports the quality, quantity, and kinetics of target cell death induced by single primary human natural killer (NK) cells. The assay reveals that single NK cells induce cancer cell death by apoptosis and necrosis but also by mixed forms. Inhibition of either one of the two major cytotoxic pathways, perforin/granzyme release or FasL/FasR interaction, unmasked the parallel activity of the other one. Ca(2+) influx through Orai channels is important for tuning killer cell function. We found that the apoptosis/necrosis ratio of cancer cell death by NK cells is controlled by the magnitude of Ca(2+) entry and furthermore by the relative concentrations of perforin and granzyme B. The possibility to change the apoptosis/necrosis ratio employed by NK cells offers an intriguing possibility to modulate the immunogenicity of the tumor microenvironment.