EVIDENCE FROM FATAL COVID-19 FOR TARGETING THE BRADYKININ METABOLISM-A SINGLE-CENTER COHORT STUDY.

ABSTRACT: Background: Severe progression of COVID-19 to critical illness, with pulmonary failure, multiple organ failure, and death, is driven by systemic inflammatory responses with overproduction of inflammatory cytokines. In the past years, the potential role of bradykinin, leading to inappropriate immune responses in the pathogenesis of COVID-19, has been raised in a so-called bradykinin storm. However, clinical investigations of bradykinin, its metabolite des-Arg 9 -bradykinin, or substance P, are rare or completely lacking during intensive care of COVID-19 patients. A prospective prolonged cohort study was conducted, including 44 COVID-19 patients (09/2020-02/2021, prevalent wildtype SARS-CoV-2) from the intensive care unit. Plasma levels of bradykinin, des-Arg 9 -bradykinin, and substance P were measured daily by ELISA in survivors (n = 21) and nonsurvivors (n = 23) of COVID-19 from admission until discharge or death. Results: We found significantly higher plasma levels of des-Arg 9 -bradykinin in survivors and nonsurvivors of COVID-19 compared with healthy controls. In addition, plasma des-Arg 9 -bradykinin levels were higher ( P < 0.001, effect size = 0.79) in nonsurvivors compared with survivors of COVID-19 and correlated significantly with disease worsening, and clinical parameters of inflammation, like leukocyte count, IL-6 or lactate dehydrogenase, and outcome. Consequently, compared with healthy controls, bradykinin and substance P plasma levels were significantly reduced in survivors and nonsurvivors of COVID-19. Furthermore, plasma substance P levels were significantly reduced ( P < 0.001, effect size = 0.7) in nonsurvivors compared with survivors of COVID-19, whereas plasma bradykinin levels did not significantly differ between survivors and nonsurvivors of COVID-19. Conclusion: Our data demonstrates that des-Arg 9 -bradykinin is significantly elevated in COVID-19 intensive care unit patients and is associated with disease severity, clinical inflammatory parameters, and survival. These results indicate that des-Arg 9 -bradykinin, not bradykinin, is one of the pivotal peptides of concern for the lethal COVID-19 aggravation and outcome. Further investigations are necessary to evaluate whether des-Arg 9 -bradykinin exhibits potent blood biomarker properties in COVID-19 and offer new treatment approaches.

Predicting Survival for Veno-Arterial ECMO Using Conditional Inference Trees-A Multicenter Study.

BACKGROUND: Despite increasing use and understanding of the process, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy is still associated with considerable mortality. Personalized and quick survival predictions using machine learning methods can assist in clinical decision making before ECMO insertion. METHODS: This is a multicenter study to develop and validate an easy-to-use prognostic model to predict in-hospital mortality of VA-ECMO therapy, using unbiased recursive partitioning with conditional inference trees. We compared two sets with different numbers of variables (small and comprehensive), all of which were available just before ECMO initiation. The area under the curve (AUC), the cross-validated Brier score, and the error rate were applied to assess model performance. Data were collected retrospectively between 2007 and 2019. RESULTS: 837 patients were eligible for this study; 679 patients in the derivation cohort (median (IQR) age 60 (49 to 69) years; 187 (28%) female patients) and a total of 158 patients in two external validation cohorts (median (IQR) age 57 (49 to 65) and 70 (63 to 76) years). For the small data set, the model showed a cross-validated error rate of 35.79% and an AUC of 0.70 (95% confidence interval from 0.66 to 0.74). In the comprehensive data set, the error rate was the same with a value of 35.35%, with an AUC of 0.71 (95% confidence interval from 0.67 to 0.75). The mean Brier scores of the two models were 0.210 (small data set) and 0.211 (comprehensive data set). External validation showed an error rate of 43% and AUC of 0.60 (95% confidence interval from 0.52 to 0.69) using the small tree and an error rate of 35% with an AUC of 0.63 (95% confidence interval from 0.54 to 0.72) using the comprehensive tree. There were large differences between the two validation sets. CONCLUSIONS: Conditional inference trees are able to augment prognostic clinical decision making for patients undergoing ECMO treatment. They may provide a degree of accuracy in mortality prediction and prognostic stratification using readily available variables.

HIGH HEPARANASE LEVEL IN SURVIVORS OF COVID-19 - INDICATOR OF VASCULAR AND PULMONARY RECOVERY?

ABSTRACT: Background: Severe progression of coronavirus disease 2019 (COVID-19) causes respiratory failure and critical illness. Recently, COVID-19 has been associated with heparanase (HPSE)-induced endothelial barrier dysfunction and inflammation, so called endothelitis, and therapeutic treatment with heparin or low-molecular-weight heparin (LMWH) targeting HPSE has been postulated. Because, up to this date, clinicians are unable to measure the severity of endothelitis, which can lead to multiorgan failure and concomitant death, we investigated plasma levels of HPSE and heparin-binding protein (HBP) in COVID-19 intensive care patients to render a possible link between endothelitis and these plasma parameters. Therefore, a prospective prolonged cohort study was conducted, including 47 COVID-19 patients from the intensive care unit. Plasma levels of HPSE, and HBP were measured daily by enzyme-linked immunosorbent assay in survivors (n = 35) and nonsurvivors (n = 12) of COVID-19 from admission until discharge or death. All patients were either treated with heparin or LMWH, aiming for an activated partial thromboplastin time of ≥60 seconds or an anti-Xa level of >0.8 IU/mL using enoxaparin, depending on the clinical status of the patient (patients with extracorporeal membrane oxygenation or >0.1 µg/kg/min noradrenaline received heparin, all others enoxaparin). Results: We found significantly higher plasma levels of HPSE and HBP in survivors and nonsurvivors of COVID-19, compared with healthy controls. Still, interestingly, plasma HPSE levels were significantly higher ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. In contrast, plasma HBP levels were significantly reduced ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. Furthermore, when patients received heparin, they had significantly lower HPSE ( P = 2.22 e - 16) and significantly higher HBP ( P = 0.00013) plasma levels as when they received LMWH. Conclusion: Our results demonstrated that patients, who recover from COVID-19-induced vascular and pulmonary damage and were discharged from the intensive care unit, have significantly higher plasma HPSE level than patients who succumb to COVID-19. Therefore, HPSE is not suitable as marker for disease severity in COVID-19 but maybe as marker for patient's recovery. In addition, patients receiving therapeutic heparin treatment displayed significantly lower heparanse plasma level than upon therapeutic treatment with LMWH.

Intravenous IgM-enriched immunoglobulins in critical COVID-19: a multicentre propensity-weighted cohort study.

BACKGROUND: A profound inflammation-mediated lung injury with long-term acute respiratory distress and high mortality is one of the major complications of critical COVID-19. Immunoglobulin M (IgM)-enriched immunoglobulins seem especially capable of mitigating the inflicted inflammatory harm. However, the efficacy of intravenous IgM-enriched preparations in critically ill patients with COVID-19 is largely unclear. METHODS: In this retrospective multicentric cohort study, 316 patients with laboratory-confirmed critical COVID-19 were treated in ten German and Austrian ICUs between May 2020 and April 2021. The primary outcome was 30-day mortality. Analysis was performed by Cox regression models. Covariate adjustment was performed by propensity score weighting using machine learning-based SuperLearner to overcome the selection bias due to missing randomization. In addition, a subgroup analysis focusing on different treatment regimens and patient characteristics was performed. RESULTS: Of the 316 ICU patients, 146 received IgM-enriched immunoglobulins and 170 cases did not, which served as controls. There was no survival difference between the two groups in terms of mortality at 30 days in the overall cohort (HRadj: 0.83; 95% CI: 0.55 to 1.25; p = 0.374). An improved 30-day survival in patients without mechanical ventilation at the time of the immunoglobulin treatment did not reach statistical significance (HRadj: 0.23; 95% CI: 0.05 to 1.08; p = 0.063). Also, no statistically significant difference was observed in the subgroup when a daily dose of ≥ 15 g and a duration of ≥ 3 days of IgM-enriched immunoglobulins were applied (HRadj: 0.65; 95% CI: 0.41 to 1.03; p = 0.068). CONCLUSIONS: Although we cannot prove a statistically reliable effect of intravenous IgM-enriched immunoglobulins, the confidence intervals may suggest a clinically relevant effect in certain subgroups. Here, an early administration (i.e. in critically ill but not yet mechanically ventilated COVID-19 patients) and a dose of ≥ 15 g for at least 3 days may confer beneficial effects without concerning safety issues. However, these findings need to be validated in upcoming randomized clinical trials. Trial registration DRKS00025794 , German Clinical Trials Register, https://www.drks.de . Registered 6 July 2021.

Low-Avidity CD4+ T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19.

CD4+ T cells reactive against SARS-CoV-2 can be found in unexposed individuals, and these are suggested to arise in response to common cold coronavirus (CCCoV) infection. Here, we utilized SARS-CoV-2-reactive CD4+ T cell enrichment to examine the antigen avidity and clonality of these cells, as well as the relative contribution of CCCoV cross-reactivity. SARS-CoV-2-reactive CD4+ memory T cells were present in virtually all unexposed individuals examined, displaying low functional avidity and multiple, highly variable cross-reactivities that were not restricted to CCCoVs. SARS-CoV-2-reactive CD4+ T cells from COVID-19 patients lacked cross-reactivity to CCCoVs, irrespective of strong memory T cell responses against CCCoV in all donors analyzed. In severe but not mild COVID-19, SARS-CoV-2-specific T cells displayed low functional avidity and clonality, despite increased frequencies. Our findings identify low-avidity CD4+ T cell responses as a hallmark of severe COVID-19 and argue against a protective role for CCCoV-reactive T cells in SARS-CoV-2 infection.

Lung Ultrasound Findings in Patients with COVID-19.

The current SARS-CoV-2 outbreak leads to a growing need of point-of-care thoracic imaging that is compatible with isolation settings and infection prevention precautions. We retrospectively reviewed 17 COVID-19 patients who received point-of-care lung ultrasound imaging in our isolation unit. Lung ultrasound was able to detect interstitial lung disease effectively; severe cases showed bilaterally distributed B-Lines with or without consolidations; one case showed bilateral pleural plaques. Corresponding to CT scans, interstitial involvement is accurately depicted as B-Lines on lung ultrasound. Lung ultrasound might be suitable for detecting interstitial involvement in a bedside setting under high security isolation precautions.

In-line filtration of intravenous infusion may reduce organ dysfunction of adult critical patients.

BACKGROUND: The potential harmful effects of particle-contaminated infusions for critically ill adult patients are yet unclear. So far, only significant improved outcome in critically ill children and new-borns was demonstrated when using in-line filters, but for adult patients, evidence is still missing. METHODS: This single-centre, retrospective controlled cohort study assessed the effect of in-line filtration of intravenous fluids with finer 0.2 or 1.2 µm vs 5.0 µm filters in critically ill adult patients. From a total of n = 3215 adult patients, n = 3012 patients were selected by propensity score matching (adjusting for sex, age, and surgery group) and assigned to either a fine filter cohort (with 0.2/1.2 µm filters, n = 1506, time period from February 2013 to January 2014) or a control filter cohort (with 5.0 µm filters, n = 1506, time period from April 2014 to March 2015). The cohorts were compared regarding the occurrence of severe vasoplegia, organ dysfunctions (lung, kidney, and brain), inflammation, in-hospital complications (myocardial infarction, ischemic stroke, pneumonia, and sepsis), in-hospital mortality, and length of ICU and hospital stay. RESULTS: Comparing fine filter vs control filter cohort, respiratory dysfunction (Horowitz index 206 (119-290) vs 191 (104.75-280); P = 0.04), pneumonia (11.4% vs 14.4%; P = 0.02), sepsis (9.6% vs 12.2%; P = 0.03), interleukin-6 (471.5 (258.8-1062.8) ng/l vs 540.5 (284.5-1147.5) ng/l; P = 0.01), and length of ICU (1.2 (0.6-4.9) vs 1.7 (0.8-6.9) days; P <  0.01) and hospital stay (14.0 (9.2-22.2) vs 14.8 (10.0-26.8) days; P = 0.01) were reduced. Rate of severe vasoplegia (21.0% vs 19.6%; P > 0.20) and acute kidney injury (11.8% vs 13.7%; P = 0.11) was not significantly different between the cohorts. CONCLUSIONS: In-line filtration with finer 0.2 and 1.2 µm filters may be associated with less organ dysfunction and less inflammation in critically ill adult patients. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (number: NCT02281604).

Red blood cell transfusion and its alternatives in oncologic surgery-A critical evaluation.

Although blood transfusions have been used for more than 100 years and their potential to save lives is indisputable, there is still limited data on medium- and long-term outcomes after hemotherapy. Until recently, red blood cell transfusions represented the most commonly employed treatment for cancer anemia. As transfusions have been related to worse patient outcome in oncologic surgery, preventive strategies and alternative treatment approaches in the perioperative setting are warranted. This review aims to evaluate the evidence concerning the impact of transfusion on the course of malignant diseases with a focus on oncologic surgery and to provide a bundle of measures to improve patient care. The perioperative period is pivotal in determining long-term cancer outcome. An increasingly recognized area for improvement during this highly sensitive period is the treatment of anemia for three main reasons: Firstly, anemia has been recognized as an independent predictor of poor prognosis in cancer patients. Secondly, anemia is largely undertreated. Thirdly and probably most importantly, anemia therapy relied and often still relies heavily on red blood cell (RBC) transfusions, which may be an often suboptimal stopgap treatment. Perioperative RBC transfusions should be kept to a minimum due to growing concerns regarding the associated risks, which this review tries to clarify by providing an update of recent literature. This review furthermore discusses treatments for anemia and provides best-practice approaches to improve perioperative management of oncology patients undergoing surgery.

Multimodal Patient Blood Management Program Based on a Three-pillar Strategy: A Systematic Review and Meta-analysis.

OBJECTIVES: To determine whether a multidisciplinary, multimodal Patient Blood Management (PBM) program for patients undergoing surgery is effective in reducing perioperative complication rate, and thereby is effective in improving clinical outcome. BACKGROUND: PBM is a medical concept with the focus on a comprehensive anemia management, to minimize iatrogenic (unnecessary) blood loss, and to harness and optimize patient-specific physiological tolerance of anemia. METHODS: A systematic review and meta-analysis was performed. Eligible studies had to address each of the 3 PBM pillars with at least 1 measure per pillar, for example, preoperative anemia management plus cell salvage plus rational transfusion strategy. The study protocol has been registered with PROSPERO (CRD42017079217). RESULTS: Seventeen studies comprising 235,779 surgical patients were included in this meta-analysis (100,886 pre-PBM group and 134,893 PBM group). Implementation of PBM significantly reduced transfusion rates by 39% [risk ratio (RR) 0.61, 95% confidence interval (CI) 0.55-0.68, P < 0.00001], 0.43 red blood cell units per patient (mean difference -0.43, 95% CI -0.54 to -0.31, P < 0.00001), hospital length of stay (mean difference -0.45, 95% CI -0.65 to -0.25, P < 0,00001), total number of complications (RR 0.80, 95% CI 0.74-0.88, P <0.00001), and mortality rate (RR 0.89, 95% CI 0.80-0.98, P = 0.02). CONCLUSIONS: Overall, a comprehensive PBM program addressing all 3 PBM pillars is associated with reduced transfusion need of red blood cell units, lower complication and mortality rate, and thereby improving clinical outcome. Thus, this first meta-analysis investigating a multimodal approach should motivate all executives and health care providers to support further PBM activities.

Strategies to reduce blood product utilization in obstetric practice.

PURPOSE OF REVIEW: Patient blood management (PBM) aims to improve patient outcome and safety by reducing the number of unnecessary RBC transfusions and vitalizing patient-specific anemia reserves. Although PBM is increasingly recognized as best clinical practice in elective surgery, implementation of PBM is restrained in the setting of obstetrics. This review summarizes recent findings to reduce blood product utilization in obstetric practice. RECENT FINDINGS: PBM-related evidence-based benefits should be urgently adopted in the field of obstetric medicine. Intravenous iron can be considered a safe, effective strategy to replenish iron stores and to correct both pregnancy-related and hemorrhage-related iron deficiency anemia. In addition to surgical techniques and the use of uterotonics, recent findings support early administration of tranexamic acid, fibrinogen and a coagulation factor concentrate-based, viscoelastically guided practice in case of peripartum hemorrhage to manage coagulopathy. In patients with cesarean section, autologous red cell blood salvage may reduce blood product utilization, although its use in this setting is controversial. SUMMARY: Implementation of PBM in obstetric practice offers large potential to reduce blood loss and transfusion requirements of allogeneic blood products, even though large clinical trials are lacking in this specific field. Intravenous iron supplementation may be suggested to increase peripartum hemoglobin levels. Additionally, tranexamic acid and point-of-care-guided supplementation of coagulation factors are potent methods to reduce unnecessary blood loss and blood transfusions in obstetrics.

Pparγ Expression in T Cells as a Prognostic Marker of Sepsis.

Translating murine data to the human situation, we proposed that the level of peroxisome proliferator-activated receptor γ (PPARγ) expression in T cells from septic patients correlates with clinical outcome. In this preliminary report, we analyzed PPARγ mRNA expression in CD3 T cells derived from blood of a very small number of septic patients (n = 18) on various days up to 2 weeks after the initial diagnosis. CD3 T cell count was determined by flow cytometry. T cells from n = 11 healthy donors were included as controls. Maximal PPARγ mRNA expression was observed on the day of sepsis diagnosis (day 0; 5,896 ±â€Š1,523 copies PPARγ mRNA/25 ng mRNA, P < 0.05 vs. controls). In contrast, the number of CD3 T cells was significantly decreased in septic patients compared with healthy controls (296 ±â€Š31 vs. 1,803 ±â€Š134 T cells/µL blood, P < 0.001). Setting two arbitrary limits: patients with a PPARγ expression in T cells higher than 7,000 copies/25 ng mRNA, of whom five of six patients died during the ICU stay, and patients with a T cell count below 100 T cells/µL blood, of whom five of eight patients died, we identified a correlation between sepsis survival and low T cell number, paired with high T cell-specific PPARγ expression. Among all 18 sepsis patients, four fulfilled the criteria for both arbitrary settings and all four of these patients subsequently died. We suggest that both high PPARγ expression in T cells and low absolute T cell number in blood of septic patients may have the potential as a new prognostic marker for a poor sepsis outcome.

PPARγ stabilizes HO-1 mRNA in monocytes/macrophages which affects IFN-ß expression.

NADPH oxidase activation in either RAW264.7 cells or peritoneal macrophages (PM) derived from PPARγ wild-type mice increased reactive oxygen species (ROS) formation, caused PPARγ activation, heme oxygenase-1 (HO-1) induction, and concomitant IFN-ß expression. In macrophages transduced with a dominant negative (d/n) mutant of PPARγ (RAW264.7 AF2) as well as PPARγ negative PM derived from Mac-PPARγ-KO mice, NADPH oxidase-dependent IFN-ß expression was attenuated. As the underlying mechanism, we noted decreased HO-1 mRNA stability in RAW264.7 AF2 cells as well as PPARγ negative PM, compared to either parent RAW264.7 cells or wild-type PM. Assuming mRNA stabilization of HO-1 by PPARγ we transfected macrophages with a HO-1 3'-UTR reporter construct. The PPARγ agonist rosiglitazone significantly up-regulated luciferase expression in RAW264.7 cells, while it remained unaltered in RAW264.7 AF2 macrophages. Deletion of each of two AU-rich elements in the 3'-UTR HO-1 decreased luciferase activity in RAW264.7 cells. Using LPS as a NADPH oxidase activator, PM from Mac-PPARγ-KO mice showed a decreased HO-1 mRNA half-life in vitro and in vivo compared to PPARγ wild-type mice. These data identified a so far unappreciated role of PPARγ in stabilizing HO-1 mRNA, thus, contributing to the expression of the HO-1 target gene IFN-ß.