Inhaled prostacyclin therapy in the acute respiratory distress syndrome: a randomized controlled multicenter trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS. METHODS: We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride (Placebo). The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events. RESULTS: Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n = 73) or sodium chloride (n = 77). Data from 144 patients were analyzed. The baseline PaO2/FiO2 ratio did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than Placebo (p = 0.17). Secondary analysis showed that the oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p = 0.04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. CONCLUSIONS: The primary result of our study was negative. Our data suggest that inhaled prostacyclin might be beneficial treatment in patients with COVID-19 induced ARDS. TRIAL REGISTRATION: The study was approved by the Institutional Review Board of the Research Ethics Committee of the University of Tübingen (899/2018AMG1) and the corresponding ethical review boards of all participating centers. The trial was also approved by the Federal Institute for Drugs and Medical Devices (BfArM, EudraCT No. 2016003168-37) and registered at clinicaltrials.gov (NCT03111212) on April 6th 2017.

Membrane oxygenator longevity was higher in argatroban-treated patients undergoing vvECMO.

BACKGROUND: In severe acute respiratory distress syndrome (ARDS), venovenous extracorporeal membrane oxygenation (vvECMO) can be a lifesaver. However, anticoagulation therapy is mandatory because the nonendothelial extracorporeal surface increases the risk of thromboembolic problems. Heparin is still the most common anticoagulant, but argatroban could be an alternative. This work investigates whether argatroban offers a therapeutic advantage over heparin during vvECMO. METHODS: We performed a retrospective cohort study of patients who underwent vvECMO for severe ARDS and received heparin or argatroban as anticoagulation therapy. Demographic variables, intensive care unit (ICU) treatment and outcome parameters were evaluated. The primary outcome parameter was the operating time of the membrane oxygenator normalized to the duration of vvECMO treatment. Secondary outcome parameters were transfusion requirements normalized to the duration of vvECMO therapy. RESULTS: Fifty seven patients from January 2019 to February 2021 underwent vvECMO and were included in this study. Thirty three patients received heparin and 24 patients argatroban as anticoagulatory therapy. The groups did not differ in demographics, ICU scoring systems, or comorbidities. Platelet counts and partial prothrombin time did not differ between the two groups during the first 6 days of vvECMO. The argatroban group had lower requirements for red blood cells, platelets and fresh frozen plasma. The mean runtime of the individual membrane oxygenator increased from 12.3 days (heparin group) to 16.6 days in the argatroban group. CONCLUSIONS: Our findings suggest that argatroban can be considered as anticoagulant during vvECMO.

COVID-19 does not influence functional status after ARDS therapy.

RATIONALE: Health-related quality of life after surviving acute respiratory distress syndrome has come into focus in recent years, especially during the coronavirus disease 2019 pandemic. OBJECTIVES: A total of 144 patients with acute respiratory distress syndrome caused by COVID-19 or of other origin were recruited in a randomized multicenter trial. METHODS: Clinical data during intensive care treatment and data up to 180 days after study inclusion were collected. Changes in the Sequential Organ Failure Assessment score were used to quantify disease severity. Disability was assessed using the Barthel index on days 1, 28, 90, and 180. MEASUREMENTS: Mortality rate and morbidity after 180 days were compared between patients with and without COVID-19. Independent risk factors associated with high disability were identified using a binary logistic regression. MAIN RESULTS: The SOFA score at day 5 was an independent risk factor for high disability in both groups, and score dynamic within the first 5 days significantly impacted disability in the non-COVID group. Mortality after 180 days and impairment measured by the Barthel index did not differ between patients with and without COVID-19. CONCLUSIONS: Resolution of organ dysfunction within the first 5 days significantly impacts long-term morbidity. Acute respiratory distress syndrome caused by COVID-19 was not associated with increased mortality or morbidity.

Antibody binding and ACE2 binding inhibition is significantly reduced for both the BA1 and BA2 omicron variants.

BACKGROUND: The rapid emergence of the omicron variant and its large number of mutations led to its classification as a variant of concern (VOC) by the WHO. Subsequently, omicron evolved into distinct sublineages (e.g. BA1 and BA2), which currently represent the majority of global infections. Initial studies of the neutralizing response towards BA1 in convalescent and vaccinated individuals showed a substantial reduction. METHODS: We assessed antibody (IgG) binding, ACE2 (Angiotensin-Converting Enzyme 2) binding inhibition, and IgG binding dynamics for the omicron BA1 and BA2 variants compared to a panel of VOC/VOIs, in a large cohort (n = 352) of convalescent, vaccinated, and infected and subsequently vaccinated individuals. RESULTS: While omicron was capable efficiently binding to ACE2, antibodies elicited by infection or immunization showed reduced binding capacities and ACE2 binding inhibition compared to WT. Whereas BA1 exhibited less IgG binding compared to BA2, BA2 showed reduced inhibition of ACE2 binding. Among vaccinated samples, antibody binding to omicron only improved after administration of a third dose. CONCLUSION: omicron BA1 and BA2 can still efficiently bind to ACE2, while vaccine/infection-derived antibodies can bind omicron. The extent of the mutations within both variants prevent a strong inhibitory binding response. As a result, both omicron variants are able to evade control by pre-existing antibodies.

COVID-19 patient serum less potently inhibits ACE2-RBD binding for various SARS-CoV-2 RBD mutants.

As global vaccination campaigns against SARS-CoV-2 proceed, there is particular interest in the longevity of immune protection, especially with regard to increasingly infectious virus variants. Neutralizing antibodies (Nabs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are promising correlates of protective immunity and have been successfully used for prevention and therapy. As SARS-CoV-2 variants of concern (VOCs) are known to affect binding to the ACE2 receptor and by extension neutralizing activity, we developed a bead-based multiplex ACE2-RBD inhibition assay (RBDCoV-ACE2) as a highly scalable, time-, cost-, and material-saving alternative to infectious live-virus neutralization tests. By mimicking the interaction between ACE2 and the RBD, this serological multiplex assay allows the simultaneous analysis of ACE2 binding inhibition to the RBDs of all SARS-CoV-2 VOCs and variants of interest (VOIs) in a single well. Following validation against a classical virus neutralization test and comparison of performance against a commercially available assay, we analyzed 266 serum samples from 168 COVID-19 patients of varying severity. ACE2 binding inhibition was reduced for ten out of eleven variants examined compared to wild-type, especially for those displaying the E484K mutation such as VOCs beta and gamma. ACE2 binding inhibition, while highly individualistic, positively correlated with IgG levels. ACE2 binding inhibition also correlated with disease severity up to WHO grade 7, after which it reduced.

Mechanical circulatory support for cardiovascular complications in a young COVID-19 patient

BACKGROUND: The current coronavirus (COVID-19) pandemic is associated with severe pulmonary and cardiovascular complications. CASE PRESENTATION: This report describes a young patient with COVID-19 without any comorbidity presenting with severe cardiovascular complications, manifesting with pulmonary embolism, embolic stroke, and right heart failure. CONCLUSION: Management with short-term mechanical circulatory support, including different cannulation strategies, resulted in a successful outcome despite his critical cardiovascular status.

[SARS-CoV-2 Infections and Clinical Consequences in a Cohort of Solid Organ Transplant Recipients during the first Wave in Germany - a Single Centre Survey and a Case Report]. / SARS-CoV-2-Infektionen und klinische Konsequenzen bei organtransplantierten Patienten im Rahmen der ersten Ansteckungswelle in Deutschland - eine monozentrische Umfrage und ein Fallbericht.

BACKGROUND: The SARS-CoV-2 pandemic has caused an unprecedented global health crisis, with exceptionally high mortality rates in high-risk groups of affected patients. It is alarming that a steadily increasing number of clinical reports on outcomes of COVID-19 in solid organ transplant (SOT) recipients suggests a detrimental impact linked to high overall mortality. However, systematic data on SARS-CoV-2 infections in SOT recipients in Germany are still scarce. MATERIAL AND METHODS: We conducted a survey on SARS-CoV-2 infection status among 387 SOT recipients treated at our centre during the past 5 years - located in a severely affected region in Germany. The survey was sent out two months after the first SARS CoV-2 outbreak in our region had resulted in government-imposed lockdown measures. RESULTS: An incidence rate of 0.4% SARS-CoV-2-positive SOT recipients was determined in our cohort, in line with reported local infection rates in the general population at this time. However, the only SARS CoV-2 infection known to us within this group of patients led to severe morbidity - resulting in prolonged mechanical ventilation, hospitalisation > 60 days and finally in irreversible loss of graft function. CONCLUSION: Our data demonstrate that SOT recipients are at equal risk for SARS-CoV-2 infections when compared to the general population, while SARS-CoV-2 infections in SOT recipients seem to be associated with deleterious clinical consequences.

Machine learning identifies ICU outcome predictors in a multicenter COVID-19 cohort.

BACKGROUND: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. METHODS: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. RESULTS: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict "survival". Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients' age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. CONCLUSIONS: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration "ClinicalTrials" (clinicaltrials.gov) under NCT04455451.

SARS-CoV-2 in Solid Organ Transplant Recipients: A Structured Review of 2020.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is challenging health systems all over the world. Particularly high-risk groups show considerable mortality rates after infection. In 2020, a huge number of case reports, case series, and consecutively various systematic reviews have been published reporting on morbidity and mortality risk connected with SARS-CoV-2 in solid organ transplant (SOT) recipients. However, this vast array of publications resulted in an increasing complexity of the field, overwhelming even for the expert reader. METHODS: We performed a structured literature review comprising electronic databases, transplant journals, and literature from previous systematic reviews covering the entire year 2020. From 164 included articles, we identified 3451 cases of SARS-CoV-2-infected SOT recipients. RESULTS: Infections resulted in a hospitalization rate of 84% and 24% intensive care unit admissions in the included patients. Whereas 53.6% of patients were reported to have recovered, cross-sectional overall mortality reported after coronavirus disease 2019 (COVID-19) was at 21.1%. Synoptic data concerning immunosuppressive medication attested to the reduction or withdrawal of antimetabolites (81.9%) and calcineurin inhibitors (48.9%) as a frequent adjustment. In contrast, steroids were reported to be increased in 46.8% of SOT recipients. CONCLUSIONS: COVID-19 in SOT recipients is associated with high morbidity and mortality worldwide. Conforming with current guidelines, modifications of immunosuppressive therapies mostly comprised a reduction or withdrawal of antimetabolites and calcineurin inhibitors, while frequently maintaining or even increasing steroids. Here, we provide an accessible overview to the topic and synoptic estimates of expectable outcomes regarding in-hospital mortality of SOT recipients with COVID-19.

Mechanical circulatory support for cardiovascular complications in a young COVID-19 patient.

BACKGROUND: The current coronavirus (COVID-19) pandemic is associated with severe pulmonary and cardiovascular complications. CASE PRESENTATION: This report describes a young patient with COVID-19 without any comorbidity presenting with severe cardiovascular complications, manifesting with pulmonary embolism, embolic stroke, and right heart failure. CONCLUSION: Management with short-term mechanical circulatory support, including different cannulation strategies, resulted in a successful outcome despite his critical cardiovascular status.