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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.

Purpose To investigate antimicrobial use and primary and nosocomial infections in hospitalized COVID-19 patients to provide data for guidance of antimicrobial therapy. Methods Prospective observational cohort study conducted at Charité–Universitätsmedizin Berlin, including patients hospitalized with SARS-CoV-2-infection between March and November 2020. Results 309 patients were included, 231 directly admitted and 78 transferred from other centres. Antimicrobial therapy was initiated in 62/231 (26.8%) of directly admitted and in 44/78 (56.4%) of transferred patients. The rate of microbiologically confirmed primary co-infections was 4.8% (11/231). Although elevated in most COVID-19 patients, C-reactive protein and procalcitonin levels were higher in patients with primary co-infections than in those without (median CRP 110 mg/l, IQR 51–222 vs. 36, IQR 11–101, respectively; p Conclusions Primary co-infections are rare, yet antimicrobial use was frequent, mostly based on clinical worsening and elevated inflammation markers without clear evidence for co-infection. More reliable diagnostic prospects may help to reduce overtreatment. Rates of nosocomial infections are substantial in severely ill patients on organ support and associated with worse patient outcome.

With the increasing number of highly infectious disease incidents, outbreaks, and pandemics in our society (e.g., Ebola virus disease, Lassa fever, coronavirus diseases), the need for consensus and best practices on highly infectious decedent management is critical. In January 2020, a workshop of subject matter experts from across the world convened to discuss highly infectious live patient transport and highly infectious decedent management best practices. This commentary focuses on the highly infectious decedent management component of the workshop. The absence of guidance or disparate guidance on highly infectious decedent management can increase occupational safety and health risks for death care sector workers. To address this issue, the authorship presents these consensus recommendations on best practices in highly infectious decedent management, including discussion of what is considered a highly infectious decedent; scalability and storage for casualty events; integration of key stakeholders; infection control and facility considerations; transport; care and autopsy; psychological, ethical, and cultural considerations as well as multi-national care perspectives. These consensus recommendations are not intended to be exhaustive but rather to underscore this overlooked area and serve as a starting point for much-needed conversations.

Cardiopulmonary Exercise Testing (CPET) provides a comprehensive assessment of pulmonary, cardiovascular and musculosceletal function. Reduced CPET performance could be an indicator for chronic morbidity after COVID-19.Patients ≥18 years with confirmed PCR positive SARS-CoV-2 infection were offered to participate in a prospective observational study of clinical course and outcomes of COVID-19. 54 patients completed CPET, questionnaires on respiratory quality of life and performed pulmonary function tests 12 months after SARS-CoV-2 infection.At 12 months after SARS-CoV-2 infection, 46.3% of participants had a peak performance and 33.3% a peak oxygen uptake of80% of the predicted values, respectively. Further impairments were observed in diffusion capacity and ventilatory efficiency. Functional limitations were particularly pronounced in patients after invasive mechanical ventilation and extracorporeal membrane oxygenation treatment. Ventilatory capacity was reduced80% of predicted values in 55.6% of participants, independent from initial clinical severity. Patient reported dyspnea and respiratory quality of life after COVID-19 correlated with CPET performance and parameters of gas exchange. Risk factors for reduced CPET performance 12 months after COVID-19 were prior intensive care treatment (OR 5.58, p = 0.004), SGRQ outcome25 points (OR 3.48, p = 0.03) and reduced DFunctional limitations causing chronic morbidity in COVID-19 survivors persist over 12 months after SARS-CoV-2 infection. These limitations were particularly seen in parameters of overall performance and gas exchange resulting from muscular deconditioning and lung parenchymal changes. Patient reported reduced respiratory quality of life was a risk factor for adverse CPET performance.

Purpose Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. Methods A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. Results Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10–1.37, p p p Conclusions Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19.

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease., Graphical abstract, Demichev, Tober-Lau et al., present a time-resolved molecular map of the COVID-19, measuring plasma proteomes of patients with COVID-19 along with an extensive panel of clinical diagnostic parameters at 687-time points. They describe the specificity and dynamics, as well as the predictive and prognostic power of the molecular signatures in COVID-19.

Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Comprehensively capturing the host physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index and APACHE II score were poor predictors of survival. Plasma proteomics instead identified 14 proteins that showed concentration trajectories different between survivors and non-survivors. A proteomic predictor trained on single samples obtained at the first time point at maximum treatment level (i.e. WHO grade 7) and weeks before the outcome, achieved accurate classification of survivors in an exploratory (AUROC 0.81) as well as in the independent validation cohort (AUROC of 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that predictors derived from plasma protein levels have the potential to substantially outperform current prognostic markers in intensive care.Trial registrationGerman Clinical Trials Register DRKS00021688

SummarySevere COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathogenesis, and it remains unclear if T cells also contribute to disease pathology. Here, we combined single-cell transcriptomics and proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated, CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Age-dependent generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. The proportion of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a correlated with clinical outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.

ZusammenfassungEin 35-jähriger Patient stellte sich mit Fieber, Dyspnoe und Petechien in der Notaufnahme einer Universitätsklinik vor. Im Röntgen-Thorax zeigten sich bipulmonale Infiltrate. 5 Tage zuvor hatte sich der Patient Silikonöl als kosmetischen Laieneingriff subkutan in den Penis injizieren lassen. Bei zunehmender respiratorischer Verschlechterung musste der Patient analgosediert und intubiert werden. Im CT des Thorax und in der Bronchoskopie zeigte sich eine diffuse alveoläre Hämorrhagie. Die Diagnose einer Pneumonitis mit einem schweren akuten respiratorischen Versagen aufgrund eines Silikon-Embolisations-Syndroms wurde gestellt. Neben Bauchlagerung und Lungen-protektiver Beatmung wurde mit einer Kortison-Stoß-Therapie behandelt. Nach 19 intensivstationären Behandlungstagen konnte der Patient auf die Normalstation verlegt werden. In der ambulanten Nachsorge zeigte sich eine altersentsprechende Lungenfunktion. Fazit Bei Fieber, Atemnot und alveolärer Hämorrhagie sollte im Zusammenhang mit kosmetischen Eingriffen differenzialdiagnostisch an eine Silikon-Pneumonitis gedacht werden. Unter Hochdosis-Kortison-Therapie und Lungen-protektiver Beatmung kann ein schweres respiratorisches Lungenversagen bis zur vollständigen Ausheilung erfolgreich therapiert werden.

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathogenesis, and it remains unclear if T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and proteomics with mechanistic studies assessing pathogenic T cell functions and inducing signals. We identified activated, CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Age-dependent generation of C3a in severe COVID-19 induced activated CD16 + cytotoxic T cells. The proportion of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a correlated with clinical outcome, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19. Funding: This work was supported by the German Research Foundation (DFG): SA1383/3-1 to B.S.; SFB-TR84 114933180 to L.E.S., S.B., P.G., S.H. and W.M.K. INST 37/1049-1, INST 216/981- 1, INST 257/605-1, INST 269/768-1, INST 217/988-1, INST 217/577-1, and EXC2151- 390873048 to J.L.S.; GRK 2168 – 272482170, ERA CVD (00160389 to J.L.S.; SFB 1454 – 432325352 to A.C.A. and J.L.S.; SFB TR57 and SPP1937 to J.N.; GRK2157 to A.-E.S.; and ME 3644/5-1 to H.E.M.; RTG2424 to N.B.; SFB-TRR219 322900939, BO3755/13-1 Project- ID 454024652 to P.B.; the Berlin University Alliance (BUA) (PreEP-Corona grant to L.E.S. and V.M.C.); the Berlin Institute of Health (BIH) (to L.E.S., V.M.C.,B.S. and W.M.K.); Helmholtz- Gemeinschaft Deutscher Forschungszentren, Germany (sparse2big to J.L.S.), EU projects SYSCID (733100 to J.L.S.); European Research Council Horizon 2020 (grant agreement No 101001791 to P.B.); the DZIF, Germany (TTU 04.816 and 04.817 to J.N.); the Hector Foundation (M89 to J.N.); the EU projects ONE STUDY (260687), BIO-DrIM (305147) and INsTRuCT (860003) to B.S.); German Registry of COVID-19 Autopsies through Federal Ministry of Health (ZMVI1-2520COR201 to P.B.); Federal Ministry of Education and Research (DEFEAT PANDEMICs, 01KX2021 and STOP-FSGS-01GM1901A to P.B.); the Berlin Senate to German Rheumatism Research Centre (DRFZ); the Berlin Brandenburg School for regenerative Therapies (BSRT) to C.B.; the German Federal Ministry of Education and Research (BMBF) projects RECAST (01KI20337) to B.S., V.M.C., L.E.S and M.R.; VARIPath (01KI2021) to V.M.C.; NUM COVIM (01KX2021) to L.E.S., V.M.C., F.K., J.L.S., J.N. and B.S.; RAPID to and S.H.,; SYMPATH to N.S. and W.M.K.; PROVID to S.H. and W.M.K.; ZissTrans (02NUK047E) to N.B; National Research Node ‘Mass spectrometry in Systems Medicine (MSCoresys) (031L0220A) to M.R. and N.B.; Diet–Body–Brain (DietBB) (01EA1809A) to J.L.S.; the UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC), the Francis Crick Institute through the Cancer Research UK (FC001134), the UK Medical Research Council (FC001134), the Wellcome Trust (FC001134 and IA 200829/Z/16/Z) to M.R.; a Charite 3R project (to B.S., S.H., W.M.K.); and an intramural grant from the Department of Genomics & Immunoregulation at the LIMES Institute to A.C.A. We are grateful to the patients and donors volunteering to participate in this study making this research possible in the first place and wish for a speedy and full recovery. Conflict of Interest: V.M.C. is named together with Euroimmun GmbH on a patent application filed recently regarding SARS-CoV-2 diagnostics via antibody testing. A.R.S. and H.E.M. are listed as inventors on a patent application by the DRFZ Berlin in the field of mass cytometry. Ethical Approval: The study was approved by the Institutional Review board of Charite (EA2/066/20).

BackgroundAdequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories.MethodsA cohort of 168 hospitalized adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care center was analyzed.ResultsForty-four percent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95%CI 1.10-1.37, pConclusionOur results indicate a short duration of symptoms before admission as a risk factor for severe disease and different viral load kinetics in severely affected patients.

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. There is an urgent need for predictive markers that can guide clinical decision-making, inform about the effect of experimental therapies, and point to novel therapeutic targets. Here, we characterize the time-dependent progression of COVID-19 through different stages of the disease, by measuring 86 accredited diagnostic parameters and plasma proteomes at 687 sampling points, in a cohort of 139 patients during hospitalization. We report that the time-resolved patient molecular phenotypes reflect an initial spike in the systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution and immunomodulation. Further, we show that the early host response is predictive for the disease trajectory and gives rise to proteomic and diagnostic marker signatures that classify the need for supplemental oxygen therapy and mechanical ventilation, and that predict the time to recovery of mildly ill patients. In severely ill patients, the molecular phenotype of the early host response predicts survival, in two independent cohorts and weeks before outcome. We also identify age-specific molecular response to COVID-19, which involves increased inflammation and lipoprotein dysregulation in older patients. Our study provides a deep and time resolved molecular characterization of COVID-19 disease progression, and reports biomarkers for risk-adapted treatment strategies and molecular disease monitoring. Our study demonstrates accurate prognosis of COVID-19 outcome from proteomic signatures recorded weeks earlier.

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)

‘Severe Acute Respiratory Syndrome - Coronavirus-2’ (SARS-CoV-2) infection causes Coronavirus Disease 2019 (COVID-19), a mild to moderate respiratory tract infection in the majority of patients. A subset of patients, however, progresses to severe disease and respiratory failure with acute respiratory distress syndrome (ARDS). Severe COVID-19 has been associated with increased neutrophil counts and dysregulated immune responses. The mechanisms of protective immunity in mild forms and the pathogenesis of dysregulated inflammation in severe courses of COVID-19 remain largely unclear. Here, we combined two single-cell RNA-sequencing technologies and single-cell proteomics in whole blood and peripheral blood mononuclear cells (PBMC) to determine changes in immune cell composition and activation in two independent dual-center patient cohorts (n=46+n=54 COVID-19 samples), each with mild and severe cases of COVID-19. We observed a specific increase of HLA-DRhiCD11chiinflammatory monocytes that displayed a strong interferon (IFN)-stimulated gene signature in patients with mild COVID-19, which was absent in severe disease. Instead, we found evidence of emergency myelopoiesis, marked by the occurrence of immunosuppressive pre-neutrophils and immature neutrophils and populations of dysfunctional and suppressive mature neutrophils, as well as suppressive HLA-DRtomonocytes in severe COVID-19. Our study provides detailed insights into systemic immune response to SARS-CoV-2 infection and it reveals profound alterations in the peripheral myeloid cell compartment associated with severe courses of COVID-19.

PurposeSevere 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, in order to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions.MethodsPa-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, 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.ResultsOutcome 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.ConclusionWe 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.

Background: In face of the global spread of Corona Virus Disease (COVID)-19, best practice for mechanical ventilation in COVID-19 associated Acute Respiratory

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. Electronic supplementary material The online version of this article (10.1007/s10096-020-04017-0) contains supplementary material, which is available to authorized users.

Summary Coronavirus Disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progresses 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, remains 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 vs. severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi 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-DRlo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and it reveals profound alterations in the myeloid cell compartment associated with severe COVID-19., Highlights ● SARS-CoV-2 infection induces profound alterations of the myeloid compartment ● Mild COVID-19 is marked by inflammatory HLA-DRhiCD11chi CD14+ monocytes ● Dysfunctional HLA-DRloCD163hi and HLA-DRloS100Ahi CD14+ monocytes in severe COVID-19 ● Emergency myelopoiesis with immature and dysfunctional neutrophils in severe COVID-19

Objectives Dexamethasone has become the standard of care for severe coronavirus disease 2019 (COVID-19), but its virological impact is poorly understood. The objectives of this work were to characterize the kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) concentration in the upper respiratory tract (URT) and the antibody response in patients with (D+) and without (D–) dexamethasone treatment. Methods Data and biosamples from hospitalized patients with severe COVID-19, enrolled between 4th March and 11th December 2020 in a prospective observational study, were analysed. SARS-CoV-2 virus concentration in serial URT samples was measured using RT-PCR. SARS-CoV-2-specific immunoglobulins A and G (IgA and IgG) were measured in serum samples using S1-ELISA. Results We compared 101 immunocompetent patients who received dexamethasone (according to the inclusion criteria and dosage determined in the RECOVERY trial) to 93 immunocompetent patients with comparable disease severity from the first months of the pandemic, who had not been treated with dexamethasone or other glucocorticoids. We found no inter-group differences in virus concentration kinetics, duration of presence of viral loads >106 viral copies/mL (D+ median 17 days (IQR 13–24), D– 19 days (IQR 13–29)), or time from symptom onset until seroconversion (IgA: D+ median 11.5 days (IQR 11–12), D– 14 days (IQR 11.5–15.75); IgG: D+ 13 days (IQR 12–14.5), D– 12 days (IQR 11–15)). Conclusion Dexamethasone does not appear to lead to a change in virus clearance or a delay in antibody response in immunocompetent patients hospitalized with severe COVID-19.

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).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.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; p0.001) and 7.44 (7.27-7.56; p0.001), 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 %).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.

49 patients (22 women, 27 men, mean age 43.7 [21-65] years) with Hodgkin's disease were examined by Doppler echocardiography a median of 5.37 (2-10) years after the end of chemotherapy (given according to the COPP/ABVD scheme, with or without mediastinal irradiation) for possible chronic changes in myocardium, pericardium or cardiac valves, as well as for any haemodynamic sequelae. Maximal and integrated early (E, Ei) and late (A, Ai) diastolic flow velocities and their ratio (E/A, Ei/Ai) were measured by pulsed Doppler over the mitral and tricuspid valves. Although on two-dimensional echo 21 patients (42.9%) were found to have valvar thickening, 19 (38.8%) pericardial thickening and 9 (18.4%) a reduced fibre shortening fraction, the Doppler indices were statistically not significantly different from those in 25 controls with normal hearts. These echocardiographic data of functional and morphological parameters indicate that there was no effect on various measurements of diastolic function after chemotherapy with or without mediastinal radiation. In successfully treated patients with Hodgkin's disease the described changes are of minor significance.

Objectives Antibiotic resistance has risen dramatically over the past years. For individual patients, adequate initial antibiotic therapy is essential for clinical outcome. Computer-assisted decision support systems (CDSSs) are advocated to support implementation of rational anti-infective treatment strategies based on guidelines. The aim of this study was to evaluate long-term effects after implementation of a CDSS. Design This prospective ‘before/after’ cohort study was conducted over four observation periods within 5 years. One preinterventional period (pre) was compared with three postinterventional periods: directly after intensive implementation efforts (post1), 2 years (post2) and 3 years (post3) after implementation. Setting Five anaesthesiological-managed intensive care units (ICU) (one cardiosurgical, one neurosurgical, two interdisciplinary and one intermediate care) at a university hospital. Participants Adult patients with an ICU stay of >48 h were included in the analysis. 1316 patients were included in the analysis for a total of 12 965 ICU days. Intervention Implementation of a CDSS. Outcome measures The primary end point was percentage of days with guideline adherence during ICU treatment. Secondary end points were antibiotic-free days and all-cause mortality compared for patients with low versus high guideline adherence. Main results Adherence to guidelines increased from 61% prior to implementation to 92% in post1, decreased in post2 to 76% and remained significantly higher compared with baseline in post3, with 71% (p=0.178). Additionally, antibiotic-free days increased over study periods. At all time periods, mortality for patients with low guideline adherence was higher with 12.3% versus 8% (p=0.014) and an adjusted OR of 1.56 (95% CI 1.05 to 2.31). Conclusions Implementation of computerised regional adapted guidelines for antibiotic therapy is paralleled with improved adherence. Even without further measures, adherence stayed high for a longer period and was paralleled by reduced antibiotic exposure. Improved guideline adherence was associated with reduced ICU mortality. Trial registration number ISRCTN54598675.

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.

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. 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 Charite – 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

The net effects of acute changes in pre- and afterload on left ventricular filling, were examined by altering loading conditions in normal subjects. The specific purpose of this study was to investigate whether Doppler-derived transmitral flow patterns are able to differentiate the type of loading conditions. In 24 normal subjects (13 females, 11 males, mean age 44.1 +/- 11.5 years), the following Doppler variables were determined at baseline, after rapid volume infusion (preload increase), after nitroglycerin administration (preload decrease), during isometric exercise (afterload increase), and after application of a converting enzyme inhibitor (afterload decrease): the peak and integrated early (E, Ei) and late (A, Ai) diastolic flow velocities, their ratios (E/A, Ei/Ai), the percentage of atrial contribution (ACON), and the acceleration and deceleration times (Ac, Dc) of early filling. Reduced preload and increased afterload led to similar filling patterns characterized by a significant E and Ei decrease (p0.05, compared to baseline) accompanied by an A and Ai increase with a resultant reduction of E/A and Ei/Ai. Both changes increased the atrial contribution to filling and reduced Ac and Dc. Increased preload only significantly increased E and Ei, while reduced afterload did not induce any significant changes. Different loading conditions alter Doppler-derived diastolic filling patterns. However, the transmitral flow profile is not specific enough to distinguish the manner in which loading conditions have been altered.

The impact of valvular, myocardial and pericardial abnormalities on cardiac haemodynamics in patients treated for Hodgkin's disease with COPP/ABVD with and without mediastinal irradiation was determined in 49 patients 2-10 years after induction therapy. Diagnostic procedures to evaluate cardiac function consisted of history, physical examination, exercise bicycle stress test, M-mode two-dimensional and pulsed Doppler echocardiography. No patient reported symptoms related to cardiomyopathy, and only one of the 49 had evidence of coronary heart disease. Pericardial thickening was seen on echocardiograms in 19/49 patients (38.8%), valvular thickening in 21/49 (42.9%), and reduced fractional shortening in 9/49 (18.4%). The Doppler-derived mean E and A (+/- SD) of transmitral flow were 0.75 +/- 0.14 m/s and 0.56 +/- 0.09 m/s, respectively, in patients receiving chemotherapy and 0.81 +/- 0.19 m/s and 0.63 +/- 0.20 m/s in those with additional mediastinal irradiation. There was no statistically significant difference between mean E and A in transmitral flow in patients treated for Hodgkin's disease and control subjects. Furthermore, the transtricuspid and hepatic vein flow velocities did not differ significantly. Although the present study demonstrates high frequencies of pericardial and valvular thickening in patients treated for Hodgkin's disease with the COPP/ABVD regimen with or without mediastinal irradiation, it showed no impact on cardiac flow velocities. The abnormalities might thus be of minor clinical relevance in these patients.

There is still controversy as to the manner in which Doppler-derived transmitral filling patterns change because of myocardial ischemia. To evaluate the effects of exercise-induced ischemia on Doppler-derived filling patterns, 28 patients were examined at rest and during three stages of supine bicycle exercise (0.5, 1.0, and 1.5 W/kg). The peak early (E) and integrated early (Ei) and peak late (A) and integrated late (Ai) diastolic flow velocities, as well as their ratios (E/A, Ei/Ai), were compared between patients with exercise-induced ischemia but no wall-motion abnormalities at rest (ischemia group, n = 13) and those with akinetic scars from previous infarction but no exercise ischemia (scar group, n = 15). Normal subjects with no evidence of heart disease served as a control group (n = 11). At maximal workload the ischemia group showed a significantly lower peak flow velocity at atrial contraction than the control and scar group (0.74 +/- 0.18 vs 1.08 +/- 0.25 and 0.89 +/- 0.19 m/sec, respectively; p0.05) and also a significantly lower flow velocity integral at atrial contraction (8.24 +/- 2.2 vs 12.81 +/- 4.8 and 11.32 +/- 3.6 cm, respectively; p0.05). Therefore, the atrial contribution to filling was diminished during ischemia (36.2% +/- 9.2% vs 47.3% +/- 6.4% and 48.4% +/- 13.8%, respectively; p0.05). By maintaining the early filling rate during ischemia, the reduced atrial contribution resulted in a significantly higher E/A ratio (1.48 +/- 0.31 vs 1.05 +/- 0.15 and 1.16 +/- 0.44, respectively) and Ei/Ai ratio (2.0 +/- 1.06 vs 1.09 +/- 0.26 and 1.24 +/- 0.79, respectively). The assessment of Doppler-derived transmitral filling during exercise-induced ischemia shows mainly early diastolic filling, which is in contrast to the profile of impaired relaxation usually associated with ischemia. Evidence of exercise-induced ischemia leading to greater increases in left atrial pressure suggests that transmitral filling patterns are more closely related to hemodynamic status than to diastolic function.

Dependence of left heart opacification on ventricular function was evaluated for the new transpulmonary echo enhancing agent (SH U 508-A). The contrast agent was injected intravenously in 5 patients with normal cardiac function (ejection fraction [EF] greater than 60% and echocardiographic left ventricular end-diastolic diameter [LVED] less than 56 mm) and in five patients with pathological ventricular function (EF less than 40%, LVED greater than 65 mm). A concentration of 400 mg/mL with dosages of 5, 9, and 16 mL was used in all patients. The visually assessed signal enhancement as well as the videodensitometrically determined peak intensity and duration of signal enhancement did not differ significantly between the two patient groups, while the transit times were markedly prolonged in patients with impaired ventricular function. No significant alteration was found for systemic blood pressure and heart rate. Side effects were transitory and dose related. The noninvasive nature of the procedure and the absence of hemodynamic effects make repeated studies of left ventricular performance with SH U 508-A in patients with varied hemodynamic status possible.

COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS., SARS-CoV-2 infection, but not influenza A, triggers immunological and pathological changes in the lung that are hallmarks of pulmonary fibrosis. A subset of CD163+ macrophages are found to drive this fibroproliferative acute respiratory distress.