COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 beta [IL-1beta] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy. Copyright © 2021, The Author(s), under exclusive licence to Springer Nature B.V.

Evaluation of extracellular vesicles as noninvasive early predictive markers for severe COVID-19

Background: There is an urgent need to identify novel biomarkers for early detection of severe cases of COVID-19. Extracellular Vesicles (EVs) contain cargoes derived from the cell of origin that include proteins, lipids, and nucleic acids and have been used as biomarkers in other diseases. Aim: To identify EVs-derived biomarkers in broncho-alveolar lavages (BAL) and plasma for the early detection of severe COVID-19. Methods: We included patients hospitalized without and with severe COVID-19 and non-hospitalized mild cases. EVs were isolated from BAL and plasma, and characterized by western blot, electron microscopy and mass spectrometry-based proteomics. EVs derived proteins in both BAL and plasma from severe cases but not from mild or controls will be selected to generate a mathematical model to distinguish severe from mild and non-COVID-19. An independent validation cohort will be used to evaluate sensitivity and specificity. Results: We isolated EVs from BAL and plasma of non-COVID-19 patients and optimized the protocol for mass spectrometry. The EVs isolated were expressing the common EVs markers such as CD63, stomatin and TSG101 and electron microscopy confirmed the enrichment of EVs after isolation. Proteomic analysis showed a great overlap in the EVs proteins detected between different patients. We found 80% of the proteins were EVs derived confirming the EVs isolation protocol. Conclusions: Isolated EVs from plasma and BAL showed characteristic markers, microscopy patterns and proteomic analysis compatible with EV origin. We are currently isolating EVs from COVID- 19 patients and would identified proteins that allow us to predict COVID-19 severity.

Recommendations for treatment of critically ill patients with COVID-19 : Version 3 S1 guideline.

Since December 2019 a novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has rapidly spread around the world resulting in an acute respiratory illness pandemic. The immense challenges for clinicians and hospitals as well as the strain on many healthcare systems has been unprecedented.The majority of patients present with mild symptoms of coronavirus disease 2019 (COVID-19); however, 5-8% become critically ill and require intensive care treatment. Acute hypoxemic respiratory failure with severe dyspnea and an increased respiratory rate (>30/min) usually leads to intensive care unit (ICU) admission. At this point bilateral pulmonary infiltrates are typically seen. Patients often develop a severe acute respiratory distress syndrome (ARDS).So far, remdesivir and dexamethasone have shown clinical effectiveness in severe COVID-19 in hospitalized patients. The main goal of supportive treatment is to ascertain adequate oxygenation. Invasive mechanical ventilation and repeated prone positioning are key elements in treating severely hypoxemic COVID-19 patients.Strict adherence to basic infection control measures (including hand hygiene) and correct use of personal protection equipment (PPE) are essential in the care of patients. Procedures that lead to formation of aerosols should be carried out with utmost precaution and preparation.

The diagnostic dilemma of covid-19 pneumonia in a kidney transplant patient-a case report

Introduction: On March 11, 2020, the WHO declared COVID-19 as global pandemic. Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a new strain of coronavirus. By 20May 2020 there have been nearly five million confirmed cases with COVID-19 and more than 320.000 deaths worldwide. There is still limited data about the course of the disease in transplant patients. Some reports suggest that immunosuppression can have a protective role in patients with COVID-19, however other reports suggest an increased mortality in transplant patients. The specificity and sensitivity of diagnostic tests for SARSCoV-2 in immunosuppressed patients are also unclear at this point. Methods: We present a case report of diagnostic difficulties of SARS-CoV-2 in a female AB0-incompatible kidney transplant patient with severe COVID-19 pneumonia requiring intubation and mechanical ventilation. Results: Albeit she presented with typical symptoms for at least two weeks, PCR of two nasopharyngeal swabs and one throat wash were negative. Ultimately, typical findings on CT scans and positive stool samples confirmed the diagnosis before bronchoscopy was done and BAL tested positive. Despite immunosuppressive therapy was reduced her condition worsened. Mechanical ventilation was necessary for 17 days, however she was able to recover and could be discharged. Kidney function remained stable without renal replacement therapy. Conclusion: Our findings suggest that-especially in areas or situations where bronchoscopy and CT scans might not be available-stool testing for SARSCoV-2 might be of additional value to identify, isolate and treat COVID-19 patients. Taken together, this case highlights the importance of different diagnostic approaches when dealing with transplant patients to reach a proper diagnosis of COVID-19. Invasive procedures bear the potential of worsening the clinical course. Non-invasive stool testing might be an interesting supplemental diagnostic method. Moreover, at this point there is only scarce information published in relation to the extent of COVID-19 in transplant patients. Our case shows that reduced immunosuppression and IVIg-therapy was sufficient for a complete recovery with functioning graft.

[Structure of hospital care for COVID-19 patients up to July 2020 in Germany]. / Stationäre und intensivmedizinische Versorgungsstrukturen von COVID-19-Patienten bis Juli 2020.

BACKGROUND: Hospitalized coronavirus disease 2019 (COVID-19) patients have a high morbidity and mortality and are often dependent on intensive care, especially mechanical ventilation. Little is as yet known about COVID-19 patient allocation. OBJECTIVES: Analysis of the structures of German hospital care for COVID-19 patients up to July 2020 in terms of number of beds and previous ventilation experience. DATA AND METHODS: For the analysis of the care structures, only completed COVID-19 cases in which the virus was detected by a PCR test were evaluated. Claims data from the German Local Health Care Funds (Allgemeine Ortskrankenkassen, AOK) were analysed. The sample includes 17,094 COVID-19 cases that were treated in 1082 hospitals. RESULTS: A total of 77% of all hospitals participated in the treatment COVID-19 patients and 48% of all hospitals provided intensive care for these patients. One half of the hospitals that treated COVID-19 cases cared for 88% of all cases. Although this suggests a centralization effect of COVID-19 cases in specific hospitals, the remaining 12% of the cases were distributed among many hospitals with often very small numbers of cases. Furthermore, 23% of the ventilated COVID-19 cases were treated in hospitals with below-average ventilation experience. CONCLUSIONS: In the context of increasing numbers of infections, it is both necessary to improve the allocation of hospitalized, and therefore potentially ventilated, COVID-19 cases by means of clearly defined and centrally controlled pyramid-type concepts and to continue to care for patients without COVID-19. For Germany, a comprehensive pyramid-type concept with a greater concentration in the best-qualified hospitals seems reasonable for the care of these patients with complex diseases.

[Nationwide exposure model for COVID-19 intensive care unit admission]. / Bundesweites Belastungsmodell für Intensivstationen durch COVID-19.

BACKGROUND: Forecasting models for intensive care occupancy of coronavirus disease 2019 (COVID-19) patients are important in the current pandemic for strategic planning of patient allocation and avoidance of regional overcrowding. They are often trained entirely on retrospective infection and occupancy data, which can cause forecast uncertainty to grow exponentially with the forecast horizon. METHODOLOGY: We propose an alternative modeling approach in which the model is created largely independent of the occupancy data being simulated. The distribution of bed occupancies for patient cohorts is calculated directly from occupancy data from "sentinel clinics". By coupling with infection scenarios, the prediction error is constrained by the error of the infection dynamics scenarios. The model allows systematic simulation of arbitrary infection scenarios, calculation of bed occupancy corridors, and sensitivity analyses with respect to protective measures. RESULTS: The model was based on hospital data and by adjusting only two parameters of data in the Aachen city region and Germany as a whole. Using the example of the simulation of the respective bed occupancy rates for Germany as a whole, the loading model for the calculation of occupancy corridors is demonstrated. The occupancy corridors form barriers for bed occupancy in the event that infection rates do not exceed specific thresholds. In addition, lockdown scenarios are simulated based on retrospective events. DISCUSSION: Our model demonstrates that a significant reduction in forecast uncertainty in occupancy forecasts is possible by selectively combining data from different sources. It allows arbitrary combination with infection dynamics models and scenarios, and thus can be used both for load forecasting and for sensitivity analyses for expected novel spreading and lockdown scenarios.

[S2k Guideline - Recommendations for Inpatient Therapy of Patients with COVID-19]. / S2k-Leitlinie ­ Empfehlungen zur stationären Therapie von Patienten mit COVID-19.

Since December 2019, the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome - Corona Virus-2) has been spreading rapidly in the sense of a global pandemic. This poses significant challenges for clinicians and hospitals and is placing unprecedented strain on the healthcare systems of many countries. The majority of patients with Coronavirus Disease 2019 (COVID-19) present with only mild symptoms such as cough and fever. However, about 6 % require hospitalization. Early clarification of whether inpatient and, if necessary, intensive care treatment is medically appropriate and desired by the patient is of particular importance in the pandemic. Acute hypoxemic respiratory insufficiency with dyspnea and high respiratory rate (> 30/min) usually leads to admission to the intensive care unit. Often, bilateral pulmonary infiltrates/consolidations or even pulmonary emboli are already found on imaging. As the disease progresses, some of these patients develop acute respiratory distress syndrome (ARDS). Mortality reduction of available drug therapy in severe COVID-19 disease has only been demonstrated for dexamethasone in randomized controlled trials. The main goal of supportive therapy is to ensure adequate oxygenation. In this regard, invasive ventilation and repeated prone positioning are important elements in the treatment of severely hypoxemic COVID-19 patients. Strict adherence to basic hygiene, including hand hygiene, and the correct wearing of adequate personal protective equipment are essential when handling patients. Medically necessary actions on patients that could result in aerosol formation should be performed with extreme care and preparation.