Inflammation and vascular remodeling in COVID-19 hearts.

A wide range of cardiac symptoms have been observed in COVID-19 patients, often significantly influencing the clinical outcome. While the pathophysiology of pulmonary COVID-19 manifestation has been substantially unraveled, the underlying pathomechanisms of cardiac involvement in COVID-19 are largely unknown. In this multicentre study, we performed a comprehensive analysis of heart samples from 24 autopsies with confirmed SARS-CoV-2 infection and compared them to samples of age-matched Influenza H1N1 A (n = 16), lymphocytic non-influenza myocarditis cases (n = 8), and non-inflamed heart tissue (n = 9). We employed conventional histopathology, multiplexed immunohistochemistry (MPX), microvascular corrosion casting, scanning electron microscopy, X-ray phase-contrast tomography using synchrotron radiation, and direct multiplexed measurements of gene expression, to assess morphological and molecular changes holistically. Based on histopathology, none of the COVID-19 samples fulfilled the established diagnostic criteria of viral myocarditis. However, quantification via MPX showed a significant increase in perivascular CD11b/TIE2 + -macrophages in COVID-19 over time, which was not observed in influenza or non-SARS-CoV-2 viral myocarditis patients. Ultrastructurally, a significant increase in intussusceptive angiogenesis as well as multifocal thrombi, inapparent in conventional morphological analysis, could be demonstrated. In line with this, on a molecular level, COVID-19 hearts displayed a distinct expression pattern of genes primarily coding for factors involved in angiogenesis and epithelial-mesenchymal transition (EMT), changes not seen in any of the other patient groups. We conclude that cardiac involvement in COVID-19 is an angiocentric macrophage-driven inflammatory process, distinct from classical anti-viral inflammatory responses, and substantially underappreciated by conventional histopathologic analysis. For the first time, we have observed intussusceptive angiogenesis in cardiac tissue, which we previously identified as the linchpin of vascular remodeling in COVID-19 pneumonia, as a pathognomic sign in affected hearts. Moreover, we identified CD11b + /TIE2 + macrophages as the drivers of intussusceptive angiogenesis and set forward a putative model for the molecular regulation of vascular alterations.

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Dissecting CD8+ T cell pathology of severe SARS-CoV-2 infection by single-cell immunoprofiling.

Introduction: SARS-CoV-2 infection results in varying disease severity, ranging from asymptomatic infection to severe illness. A detailed understanding of the immune response to SARS-CoV-2 is critical to unravel the causative factors underlying differences in disease severity and to develop optimal vaccines against new SARS-CoV-2 variants. Methods: We combined single-cell RNA and T cell receptor sequencing with CITE-seq antibodies to characterize the CD8+ T cell response to SARS-CoV-2 infection at high resolution and compared responses between mild and severe COVID-19. Results: We observed increased CD8+ T cell exhaustion in severe SARS-CoV-2 infection and identified a population of NK-like, terminally differentiated CD8+ effector T cells characterized by expression of FCGR3A (encoding CD16). Further characterization of NK-like CD8+ T cells revealed heterogeneity among CD16+ NK-like CD8+ T cells and profound differences in cytotoxicity, exhaustion, and NK-like differentiation between mild and severe disease conditions. Discussion: We propose a model in which differences in the surrounding inflammatory milieu lead to crucial differences in NK-like differentiation of CD8+ effector T cells, ultimately resulting in the appearance of NK-like CD8+ T cell populations of different functionality and pathogenicity. Our in-depth characterization of the CD8+ T cell-mediated response to SARS-CoV-2 infection provides a basis for further investigation of the importance of NK-like CD8+ T cells in COVID-19 severity.

Cardiopulmonary work up of patients with and without fatigue 6 months after COVID-19.

The pathogenesis of long-Covid symptoms remains incompletely understood. Therefore, we aimed to determine cardiopulmonary limitations 6 months after surviving COVID-19 using pulmonary function tests, echocardiographic studies to the point of analysis of global-longitudinal-strain (GLS), which describes the cycling myocardium deformation and provides better data on left ventricular (LV) dysfunction than LV ejection fraction (LVEF), and validated questionnaires. Overall, 60 consecutive hospitalized patients were included (61 ± 2 years, 40% treated in the ICU). At follow-up (194 ± 3 days after discharge), fatigue was the most prevalent symptom (28%). Patients with fatigue were more symptomatic overall and characterized by worse quality of life (QoL) scores compared to patients without fatigue (all p < 0.05), mainly due to limited mobility and high symptom burden. While PFT variables and LVEF were normal in the vast majority of patients (LVEF = 52% (45-52%)), GLS was significantly reduced (- 15% (- 18 to - 14%)). However, GLS values were not different between patients with and without fatigue. In conclusion, fatigue was the most prevalent long-Covid symptom in our cohort, which was associated with worse QoL mainly due to limited mobility and the high burden of concomitant symptoms. Patients showed a subtle myocardial dysfunction 6 months after surviving COVID-19, but this did not relate to the presence of fatigue.

Re-examining the widespread policy of stopping sodium-glucose cotransporter-2 inhibitors during acute illness: A perspective based on the updated evidence.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to control not only blood glucose but to improve cardiovascular and kidney outcomes. Diabetic ketoacidosis (DKA) is an uncommon but serious complication of type 2 diabetes, which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials in people with type 2 diabetes using SGLT2 inhibitors has been low, although the relative risk is higher in those assigned to SGLT2 inhibitors compared with placebo. In those without diabetes but prescribed SGLT2 inhibitors for heart failure or chronic kidney disease, the risk of DKA is similar to placebo. Over the course of the COVID-19 pandemic, cases of DKA have also been reported in cases of COVID-19 hospitalizations. Consensus guidelines have recommended that SGLT2 inhibitors should be avoided in cases of serious illness and suggest they are not recommended for routine in-hospital use. However, recent data suggest potential beneficial effects of SGLT2 inhibitors in the setting of acute illness with COVID-19 with no increase in adverse events and low rates of DKA, which were non-severe. Given the low rates of DKA in cardiovascular outcome trials and in hospitalized patients with type 2 diabetes, the potential for SGLT2 inhibitors not being re-initiated following discharge and their cardiovascular and kidney benefits, we believe the practice of routine 'sick day' guidance should be re-examined based on current evidence with a call for further research in this area. Furthermore, high-quality trials of initiation of SGLT2 inhibitors in people admitted to hospital with cardiovascular disease or kidney disease, and trials of continuation of SGLT2 inhibitors in people, with careful monitoring of DKA should be conducted. These should be further supplemented with large observational studies.

Empagliflozin reduces markers of acute kidney injury in patients with acute decompensated heart failure.

AIMS: In this prospective, placebo-controlled, double-blind, exploratory study, we examined early and more delayed effects of empagliflozin treatment on haemodynamic parameters (primary endpoint: cardiac output) and kidney function including parameters of acute kidney injury (AKI) in patients with acute decompensated heart failure (HF). METHODS AND RESULTS: Patients with acute decompensated HF with or without diabetes were randomized to empagliflozin 10 mg or placebo for 30 days. Haemodynamic, laboratory, and urinary parameters were assessed after 6 h, 1 day, 3 days, 7 days, and 30 days of treatment. Median time between hospital admission and randomization was 72 h. Baseline characteristics were not different in the empagliflozin (n = 10) and placebo (n = 9) groups. Empagliflozin led to a significant increase in urinary glucose excretion throughout the study (baseline: 37 ± 15 mg/24 h; Day 1: 14 565 ± 8663 mg/24 h; P = 0.001). Empagliflozin did not affect the primary endpoint of cardiac index or on systemic vascular resistance index at any time point. However, empagliflozin significantly reduced parameters of AKI (urinary TIMP-2 and IGFBP7 by NephroCheck® as indicators of tubular kidney damage), which became significant after 3 days of treatment [placebo: 1.1 ± 1.1 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.02] and remained significant at the 7 day time point [placebo: 2.5 ± 3.8 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.003]. CONCLUSIONS: In this study, empagliflozin treatment did not affect haemodynamic parameters but significantly reduced markers of tubular injury in patients with acute decompensated HF.

Diaphragm dysfunction as a potential determinant of dyspnea on exertion in patients 1 year after COVID-19-related ARDS.

Some COVID-19 patients experience dyspnea without objective impairment of pulmonary or cardiac function. This study determined diaphragm function and its central voluntary activation as a potential correlate with exertional dyspnea after COVID-19 acute respiratory distress syndrome (ARDS) in ten patients and matched controls. One year post discharge, both pulmonary function tests and echocardiography were normal. However, six patients with persisting dyspnea on exertion showed impaired volitional diaphragm function and control based on ultrasound, magnetic stimulation and balloon catheter-based recordings. Diaphragm dysfunction with impaired voluntary activation can be present 1 year after severe COVID-19 ARDS and may relate to exertional dyspnea.This prospective case-control study was registered under the trial registration number NCT04854863 April, 22 2021.

Glycaemic variability is associated with all-cause mortality in COVID-19 patients with ARDS, a retrospective subcohort study.

There is high mortality among intensive care unit (ICU) patients with acute respiratory distress syndrome (ARDS) caused by coronavirus disease (COVID-19). Important factors for COVID-19 mortality are diabetes status and elevated fasting plasma glucose (FPG). However, the effect of glycaemic variability on survival has not been explored in patients with COVID-19 and ARDS. This single-centre cohort study compared several metrics of glycaemic variability for goodness-of-fit in patients requiring mechanical ventilation due to COVID-19 ARDS in the ICU at University Hospital Aachen, Germany. 106 patients had moderate to severe ARDS (P/F ratio median [IQR]: 112 [87-148] mmHg). Continuous HRs showed a proportional increase in mortality risk with daily glycaemic variability (DGV). Multivariable unadjusted and adjusted Cox-models showed a statistically significant difference in mortality for DGV (HR: 1.02, (P) < 0.001, LR(P) < 0.001; HR: 1.016, (P) = 0.001, LR(P) < 0.001, respectively). Kaplan-Meier estimators yielded a shorter median survival (25 vs. 87 days) and a higher likelihood of death (75% vs. 31%) in patients with DGV ≥ 25.5 mg/dl (P < 0.0001). High glycaemic variability during ICU admission is associated with significant increase in all-cause mortality for patients admitted with COVID-19 ARDS to the ICU. This effect persisted even after adjustment for clinically predetermined confounders, including diabetes, median procalcitonin and FPG.

Efficacy and Safety of ELOM-080 as Add-On Therapy in COVID-19 Patients with Acute Respiratory Insufficiency: Exploratory Data from the Prospective Placebo-Controlled COVARI Trial.

INTRODUCTION: Enhancement of mucociliary clearance (MCC) might be a potential target in treating COVID-19. The phytomedicine ELOM-080 is an MCC enhancer that is used to treat inflammatory respiratory diseases. PATIENTS/METHODS: This randomised, double-blind exploratory study (EudraCT number 2020-003779-17) evaluated 14 days' add-on therapy with ELOM-080 versus placebo in patients with COVID-19 hospitalised with acute respiratory insufficiency. RESULTS: The trial was terminated early after enrolment of 47 patients as a result of poor recruitment. Twelve patients discontinued prematurely, leaving 35 in the per-protocol set (PPS). Treatment with ELOM-080 had no significant effect on overall clinical status versus placebo (p = 0.49). However, compared with the placebo group, patients treated with ELOM-080 had less dyspnoea in the second week of hospitalisation (p = 0.0035), required less supplemental oxygen (p = 0.0229), and were more often without dyspnoea when climbing stairs at home (p < 0.0001). CONCLUSION: These exploratory data suggest the potential for ELOM-080 to improve respiratory status during and after hospitalisation in patients with COVID-19.

Report from the CVOT Summit 2021: new cardiovascular, renal, and glycemic outcomes.

The 7th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Renal, and Glycemic Outcomes, was held virtually on November 18-19, 2021. Pursuing the tradition of the previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed CVOTs. This year's focus was placed on the outcomes of EMPEROR-Preserved, FIGARO-DKD, AMPLITUDE-O, SURPASS 1-5, and STEP 1-5. Trial implications for diabetes and obesity management and the impact on new treatment algorithms were highlighted for endocrinologists, diabetologists, cardiologists, nephrologists, and general practitioners. Discussions evolved from outcome trials using SGLT2 inhibitors as therapy for heart failure, to CVOTs with nonsteroidal mineralocorticoid receptor antagonists and GLP-1 receptor agonists. Furthermore, trials for glycemic and overweight/obesity management, challenges in diabetes management in COVID-19, and novel guidelines and treatment strategies were discussed.Trial registration The 8th Cardiovascular Outcome Trial Summit will be held virtually on November 10-11, 2022 ( http://www.cvot.org ).

COVID-19 and Cardiovascular Comorbidities.

The emergence of a new coronavirus - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - has resulted in a global pandemic. The associated coronavirus disease 2019 (COVID-19) has resulted in a high number of death worldwide. Observational studies and case reports have provided insights that older age and the presence of chronic diseases is frequently associated with a higher COVID-19 severity. These individuals also seem to have a higher risk of mortality due to COVID-19. In this review we provide insights into the impact chronic diseases associated with the cardiovascular system, such as obesity, diabetes mellitus, hypertension and cardiovascular disease might have on SARS-CoV-2 infection and COVID-19. Additionally we review recommendations and guidance's of international scientific associations and discuss which key learnings might be of importance for the future.

Extracorporeal membrane oxygenation in patients with COVID-19: 1-year experience.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) in patients with coronavirus disease 2019 (COVID-19) showed reasonable outcomes. However, recent studies indicated a negative trend and analysis is needed. METHODS: Baseline characteristics, laboratory parameters, and outcomes of ECMO-supported patients with COVID-19 were analyzed in a retrospective single-center study. We included hospital admissions until February 28, 2021; patients were followed until discharge/death. Eventually, we compared data between patients hospitalized before and after September 1, 2020. RESULTS: Median age of patients treated with ECMO (n=39) was 56 years; most patients were males (n=28, 72%). Median mechanical ventilation time (prior to ECMO) was 6 days, while the median ECMO duration was 19 days. Overall survival rate was 41%. In the sub-analysis, survival until discharge in the first and second epidemic waves was 53% (n=19) and 30% (n=20), respectively (P=0.2). At baseline, compared with patients of the first wave, those of the second wave had higher median body mass index (28.2 vs. 31.1 kg/m2, respectively, P=0.02), bicarbonate (27 vs. 31.8 mmol/L, respectively, P=0.033), plasma free hemoglobin (36 vs. 58 mg/L, respectively, P=0.013), alanine aminotransferase (33 vs. 52 U/L, respectively, P=0.018), and pH (7.29 vs. 7.42, respectively, P=0.005), lower rate of pulmonary hypertension (32% vs. 0%, respectively, P=0.008), lower positive end-expiratory pressure (14 vs. 12 cmH2O, respectively, P=0.04), longer median ECMO duration (16 vs. 24.5 days, respectively, P=0.074), and more frequent major bleeding events (42% vs. 80%, respectively, P=0.022). CONCLUSIONS: ECMO-supported patients with COVID-19 had an overall survival rate of 41%. Similar to international registries, we observed less favorable outcomes during the second wave. Further research is needed to confirm this signal and find predictors for mortality.

Epigenetic Clocks Are Not Accelerated in COVID-19 Patients.

Age is a major risk factor for severe outcome of the 2019 coronavirus disease (COVID-19). In this study, we followed the hypothesis that particularly patients with accelerated epigenetic age are affected by severe outcomes of COVID-19. We investigated various DNA methylation datasets of blood samples with epigenetic aging signatures and performed targeted bisulfite amplicon sequencing. Overall, epigenetic clocks closely correlated with the chronological age of patients, either with or without acute respiratory distress syndrome. Furthermore, lymphocytes did not reveal significantly accelerated telomere attrition. Thus, these biomarkers cannot reliably predict higher risk for severe COVID-19 infection in elderly patients.

Broncho-alveolar lavage in patients with acute respiratory distress syndrome due to COVID-19.

As data about microbiological testing and the cellular composition of the broncho-alveolar lavage (BAL) fluid in patients ventilated due to coronavirus disease 2019 (COVID-19) are lacking, this was investigated in a retrospective analysis (n = 58). Co-infection with pathogens was detected in 31 patients, whereas the analysis of BAL cellularity showed an increased total cell count and an alveolitis dominated by neutrophils. None of the physicians performing bronchoscopies in COVID-19 patients had serological evidence of severe acute respiratory syndrome coronavirus 2 infection.

Outcomes of Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome in COVID-19 Patients: A Propensity-Matched Analysis.

It remains unclear to what extent the outcomes and complications of extracorporeal membrane oxygenation (ECMO) therapy in COVID-19 patients with acute respiratory distress syndrome (ARDS) differ from non-COVID-19 ARDS patients. In an observational, propensity-matched study, outcomes after ECMO support were compared between 19 COVID-19 patients suffering from ARDS (COVID group) and 34 matched non-COVID-19 ARDS patients (NCOVID group) from our historical cohort. A 1:2 propensity matching was performed based on respiratory ECMO survival prediction (RESP) score, age, gender, bilirubin, and creatinine levels. Patients' characteristics, laboratory parameters, adverse events, and 90-day survival were analyzed. Patients' characteristics in COVID and NCOVID groups were similar. Before ECMO initiation, fibrinogen levels were significantly higher in the COVID group (median: 493 vs. 364 mg/dL, p < 0.001). Median ECMO support duration was similar (16 vs. 13 days, p = 0.714, respectively). During ECMO therapy, patients in the COVID group developed significantly more thromboembolic events (TEE) than did those in the NCOVID group (42% vs. 12%, p = 0.031), which were mainly pulmonary artery embolism (PAE) (26% vs. 0%, p = 0.008). The rate of major bleeding events (42% vs. 62%, p = 0.263) was similar. Fibrinogen decreased significantly more in the COVID group than in the NCOVID group (p < 0.001), whereas D-dimer increased in the COVID group (p = 0.011). Additionally, 90-day mortality did not differ (47% vs. 74%; p = 0.064) between COVID and NCOVID groups. Compared with that in non-COVID-19 ARDS patients, ECMO support in COVID-19 patients was associated with comparable in-hospital mortality and similar bleeding rates but a higher incidence of TEE, especially PAE. In contrast, coagulation parameters differed between COVID and NCOVID patients.

Six Months Follow-Up of Patients with Invasive Mechanical Ventilation due to COVID-19 Related ARDS.

Although patients who recovered from acute coronavirus disease 2019 (COVID-19) may have prolonged disabilities, follow-up data of those who have survived COVID-19 related acute respiratory distress syndrome (ARDS) is still very scarce. Therefore, COVID-19-ARDS survivors requiring invasive mechanical ventilation (IMV) were followed six months after discharge. Pulmonary function tests (PFTs), 6-min walk test (6MWT) and echocardiography were performed. Quality of life (QoL), depression and anxiety were assessed using validated questionnaires. Patients were compared based on respiratory mechanics and CT-phenotype during intensive care unit (ICU) stay. Eighteen patients were included (61 ± 7 years; ICU-stay: 34 ± 16 days; IMV: 30 ± 15 days). At follow-up (197 ± 15 days after discharge), PFTs did not reveal significant limitations (VC: 92 ± 16%; FEV1: 92 ± 20%; DLco/VA: 81 ± 16%). Cardiac systolic function was normal in all patients, but 50% of them had diastolic dysfunction. 6MWT was under the lower limit of normal in only two patients. Eight patients (44%) reported tiredness, six (33%) suffered from fatigue and one patient (6%) had depression and anxiety. Surprisingly, patients with worse respiratory mechanics during IMV reported fewer symptoms and less exertional dyspnea at follow-up. In conclusion, patients with COVID-19-ARDS have the possibility to fully recover regarding pulmonary function and exercise capacity, which seems to be independent of disease severity during ICU stay.

ACE2 polymorphism and susceptibility for SARS-CoV-2 infection and severity of COVID-19.

OBJECTIVES: The RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Cell entry is mediated by the human angiotensin-converting enzyme II (ACE2). ACE2 and its close homolog angiotensin-converting enzyme I (ACE) are currently discussed candidate genes, in which single-nucleotide polymorphisms (SNPs) could alter binding or entry of SARS-CoV-2 and enhance tissue damage in the lung or other organs. This could increase the susceptibility for SARS-CoV-2 infection and the severity of COVID-19. PATIENTS AND METHODS: We performed genotyping of SNPs in the genes ACE2 and ACE in 297 SARS-CoV-2-positive and 253 SARS-CoV-2-negative tested patients. We analyzed the association of the SNPs with susceptibility for SARS-CoV-2 infection and the severity of COVID-19. RESULTS: SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics and clinical characteristics. For ACE2 rs2285666, the GG genotype or G-allele was significantly associated with an almost two-fold increased SARS-CoV-2 infection risk and a three-fold increased risk to develop serious disease or COVID-19 fatality. In contrast, the ACE polymorphism was not related to infection risk or severity of disease. In a multivariable analysis, the ACE2 rs2285666 G-allele remained as an independent risk factor for serious disease besides the known risk factors male gender and cardiovascular disease. CONCLUSIONS: In summary, our report appears to be the first showing that a common ACE2 polymorphism impacts the risk for SARS-CoV-2 infection and the course of COVID-19 independently from previously described risk factors.

Elevated serum SDMA and ADMA at hospital admission predict in-hospital mortality of COVID-19 patients.

COVID-19 is a disease with a variable clinical course ranging from mild symptoms to critical illness, organ failure, and death. Prospective biomarkers may help to predict the severity of an individual's clinical course and mortality risk. We analyzed asymmetric (ADMA) and symmetric dimethylarginine (SDMA) in blood samples from 31 patients hospitalized for COVID-19. We calculated associations of ADMA and SDMA with mortality and organ failure, and we developed a predictive algorithm based upon these biomarkers to predict mortality risk. Nine patients (29%) experienced in-hospital death. SDMA and ADMA serum concentrations were significantly higher at admission in COVID-19 patients who died than in survivors. Cut-offs of 0.90 µmol/L for SDMA (AUC, 0.904, p = 0.0005) and 0.66 µmol/L for ADMA (AUC, 0.874, p = 0.0013) were found in ROC analyses to best discriminate both subgroups of patients. Hazard ratio for in-hospital mortality was 12.2 (95% CI: 2.2-31.2) for SDMA and 6.3 (1.1-14.7) for ADMA above cut-off. Sequential analysis of both biomarkers allowed discriminating a high-risk group (87.5% mortality) from an intermediate-risk group (25% mortality) and a low-risk group (0% mortality). Elevated circulating concentrations of SDMA and ADMA may help to better identify COVID-19 patients with a high risk of in-hospital mortality.

Thromboembolic and Bleeding Events in COVID-19 Patients receiving Extracorporeal Membrane Oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a potential treatment option in critically ill COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) if mechanical ventilation (MV) is insufficient; however, thromboembolic and bleeding events (TEBE) during ECMO treatment still need to be investigated. METHODS: We conducted a retrospective, single-center study including COVID-19 patients treated with ECMO. Additionally, we performed a univariate analysis of 85 pre-ECMO variables to identify factors influencing incidences of thromboembolic events (TEE) and bleeding events (BE), respectively. RESULTS: Seventeen patients were included; the median age was 57 years (interquartile range [IQR]: 51.5-62), 11 patients were males (65%), median ECMO duration was 16 days (IQR: 10.5-22), and the overall survival was 53%. Twelve patients (71%) developed TEBE. We observed 7 patients (41%) who developed TEE and 10 patients (59%) with BE. Upper respiratory tract (URT) bleeding was the most frequent BE with eight cases (47%). Regarding TEE, pulmonary artery embolism (PAE) had the highest incidence with five cases (29%). The comparison of diverse pre-ECMO variables between patients with and without TEBE detected one statistically significant value. The platelet count was significantly lower in the BE group (n = 10) than in the non-BE group (n = 7) with 209 (IQR: 145-238) versus 452 G/L (IQR: 240-560), with p = 0.007. CONCLUSION: This study describes the incidences of TEE and BE in critically ill COVID-19 patients treated with ECMO. The most common adverse event during ECMO support was bleeding, which occurred at a comparable rate to non-COVID-19 patients treated with ECMO.

Time on previous renal replacement therapy is associated with worse outcomes of COVID-19 in a regional cohort of kidney transplant and dialysis patients.

ABSTRACT: Chronic renal replacement therapy by either a kidney transplant (KTX) or hemodialysis (HD) predisposes patients to an increased risk for adverse outcomes of COVID-19. However, details on this interaction remain incomplete. To provide further characterization, we undertook a retrospective observational cohort analysis of the majority of the hemodialysis and renal transplant population affected by the first regional outbreak of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) in Germany. In a region of 250,000 inhabitants we identified a total of 21 cases with SARS-CoV-2 among 100 KTX and 260 HD patients, that is, 7 KTX with COVID-19, 14 HD with COVID-19, and 3 HD with asymptomatic carrier status. As a first observation, KTX recipients exhibited trends for a higher mortality (43 vs 18%) and a higher proportion of acute respiratory distress syndrome (ARDS) (57 vs 27%) when compared to their HD counterparts. As a novel finding, development of ARDS was significantly associated with the time spent on previous renal replacement therapy (RRT), defined as the composite of dialysis time and time on the transplant (non-ARDS 4.3 vs ARDS 10.6 years, P = .016). Multivariate logistic regression analysis showed an OR of 1.7 per year of RRT. The association remained robust when analysis was confined to KTX patients (5.1 vs 13.2 years, P = .002) or when correlating the time spent on a renal transplant alone (P = .038). Similarly, longer RRT correlated with death vs survival (P = .0002). In conclusion our data suggest renal replacement vintage as a novel risk factor for COVID-19-associated ARDS and death. The findings should be validated by larger cohorts.