Transcriptional responses of PBMC in psychosocially stressed animals indicate an alerting of the immune system in female but not castrated male pigs

Background[br/] Brain and immune system are linked in a bi-directional manner. To date, it remained largely unknown why immune components become suppressed, enhanced, or remain unaffected in relation to psychosocial stress. Therefore, we mixed unfamiliar pigs with different levels of aggressiveness. We separated castrated male and female pigs into psychosocially high- and low- stressed animals by skin lesions, plasma cortisol level, and creatine kinase activity obtained from agonistic behaviour associated with regrouping. Peripheral blood mononuclear cells (PBMC) were collected post-mortem and differential gene expression was assessed using the Affymetrix platform (n = 16).[br/] [br/] Results[br/] Relevant stress-dependent alterations were found only between female samples, but not between castrated male samples. Molecular routes related to TREM 1 signalling, dendritic cell maturation, IL-6 signalling, Toll-like receptor signalling, and IL-8 signalling were increased in high stressed females compared to low stressed females. This indicates a launch of immune effector molecules as a direct response. According to the shifts of transcripts encoding cell surface receptors (e.g. CD14, TLR2, TLR4, TREM1) the study highlights processes acting on pattern recognition, inflammation, and cell-cell communication.[br/] [br/] Conclusions[br/] The transcriptional response partly affected the degree of ‘stress responsiveness’, indicating that the high stressed females altered their signal transduction due to potential infections and injuries while fighting

Microvascular dysfunction in COVID-19: the MYSTIC study

Rationale Pre-clinical and autopsy studies have fueled the hypothesis that a dysregulated vascular endothelium might play a central role in the pathogenesis of ARDS and multi-organ failure in COVID-19. Objectives To comprehensively characterize and quantify microvascular alterations in patients with COVID-19. Methods Hospitalized adult patients with moderate-to-severe or critical COVID-19 (n = 23) were enrolled non-consecutively in this prospective, observational, cross-sectional, multi-center study. Fifteen healthy volunteers served as controls. All participants underwent intravital microscopy by sidestream dark field imaging to quantify vascular density, red blood cell velocity (V-RBC), and glycocalyx dimensions (perfused boundary region, PBR) in sublingual microvessels. Circulating levels of endothelial and glycocalyx-associated markers were measured by multiplex proximity extension assay and enzyme-linked immunosorbent assay. Measurements and main results COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries (diameter 4-6 mu m), and also significant reductions ofV(RBC). Especially, patients on mechanical ventilation showed severe glycocalyx damage as indicated by higher PBR values (i.e., thinner glycocalyx) and increased blood levels of shed glycocalyx constituents. Several markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19. PBR (AUC 0.75,p = 0.01), ADAMTS13 (von Willebrand factor-cleaving protease; AUC 0.74,p = 0.02), and vascular endothelial growth factor A (VEGF-A; AUC 0.73,p = 0.04) showed the best discriminatory ability to predict 60-day in-hospital mortality. Conclusions Our data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19

Microvascular and proteomic signatures overlap in COVID-19 and bacterial sepsis: the MICROCODE study

Aims Although coronavirus disease 2019 (COVID-19) and bacterial sepsis are distinct conditions, both are known to trigger endothelial dysfunction with corresponding microcirculatory impairment. The purpose of this study was to compare microvascular injury patterns and proteomic signatures in COVID-19 and bacterial sepsis patients.Methods and results This multi-center, observational study included 22 hospitalized adult COVID-19 patients, 43 hospitalized bacterial sepsis patients, and 10 healthy controls from 4 hospitals. Microcirculation and glycocalyx dimensions were quantified via intravital sublingual microscopy. Plasma proteins were measured using targeted proteomics (Olink). Coregulation and cluster analysis of plasma proteins was performed using a training-set and confirmed in a test-set. An independent external cohort of 219 COVID-19 patients was used for validation and outcome analysis. Microcirculation and plasma proteome analysis found substantial overlap between COVID-19 and bacterial sepsis. Severity, but not disease entity explained most data variation. Unsupervised correlation analysis identified two main coregulated plasma protein signatures in both diseases that strictly counteract each other. They were associated with microvascular dysfunction and several established markers of clinical severity. The signatures were used to derive new composite biomarkers of microvascular injury that allow to predict 28-day mortality or/and intubation (area under the curve 0.90, p < 0.0001) in COVID-19.Conclusion Our data imply a common biological host response of microvascular injury in both bacterial sepsis and COVID-19. A distinct plasma signature correlates with endothelial health and improved outcomes, while a counteracting response is associated with glycocalyx breakdown and high mortality. Microvascular health biomarkers are powerful predictors of clinical outcomes.[GRAPHICS]

Microvascular and proteomic signatures overlap in COVID-19 and bacterial sepsis: the MICROCODE study

AIMS: Although coronavirus disease 2019 (COVID-19) and bacterial sepsis are distinct conditions, both are known to trigger endothelial dysfunction with corresponding microcirculatory impairment. The purpose of this study was to compare microvascular injury patterns and proteomic signatures in COVID-19 and bacterial sepsis patients. METHODS AND RESULTS: This multi-center, observational study included 22 hospitalized adult COVID-19 patients, 43 hospitalized bacterial sepsis patients, and 10 healthy controls from 4 hospitals. Microcirculation and glycocalyx dimensions were quantified via intravital sublingual microscopy. Plasma proteins were measured using targeted proteomics (Olink). Coregulation and cluster analysis of plasma proteins was performed using a training-set and confirmed in a test-set. An independent external cohort of 219 COVID-19 patients was used for validation and outcome analysis. Microcirculation and plasma proteome analysis found substantial overlap between COVID-19 and bacterial sepsis. Severity, but not disease entity explained most data variation. Unsupervised correlation analysis identified two main coregulated plasma protein signatures in both diseases that strictly counteract each other. They were associated with microvascular dysfunction and several established markers of clinical severity. The signatures were used to derive new composite biomarkers of microvascular injury that allow to predict 28-day mortality or/and intubation (area under the curve 0.90, p < 0.0001) in COVID-19. CONCLUSION: Our data imply a common biological host response of microvascular injury in both bacterial sepsis and COVID-19. A distinct plasma signature correlates with endothelial health and improved outcomes, while a counteracting response is associated with glycocalyx breakdown and high mortality. Microvascular health biomarkers are powerful predictors of clinical outcomes. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10456-022-09843-8

Selective ABO immunoadsorption in hematopoietic stem cell transplantation with major ABO incompatibility

Objective ABO mismatch between donor and recipient occurs in 40% of allogeneic hematopoietic stem cell transplantations (HCT). Different strategies have been described to reduce isohemagglutinins (IHA) before HCT. We describe the effect of selective ABO immunoadsorption (ABO IA) on erythrocyte transfusion rate and the development of post-transplant pure red cell aplasia (ptPRCA). Methods 63 patients with major ABO incompatibility were retrospectively analyzed. Nine patients with major ABO incompatibility and high-IHA titer were treated by ABO IA before HCT. We analyzed the need for transfusion and the occurrence of ptPRCA. We compared the outcome with patients treated by other methods to reduce IHA. Results In all nine patients treated by ABO IA, IHA decreased in a median four times. PtPRCA occurred in one patient. The median number of transfusions was 8 (range: 0-36) between d0 and d100. In 25 patients with high-IHA titer without treatment or treated by other methods to reduce IHA, the need for transfusions was comparable. No difference in the incidence of ptPRCA was observed. Conclusions Selective ABO IA is a feasible, safe, and effective method to reduce IHA before HCT in major ABO incompatibility. No effect on transfusion rate or ptPRCA compared to other strategies could be observed

Effects of preoperative plasma exchange therapy with albumin replacement fluid on blood coagulation in patients undergoing ABO-incompatible living-donor kidney transplantation using rotational thromboelastometry

Abstract Background ABO-incompatible living-donor kidney transplantation (LDKT) requires immunotherapy and plasma exchange therapy (PEX). PEX with albumin replacement fluid reportedly decreases fibrinogen levels. However, no reports have described the effects of PEX with albumin replacement fluid on blood coagulation parameters and blood loss during the perioperative period. Therefore, we investigated the effects of preoperative PEX on blood coagulation parameters and blood loss during the perioperative period in patients undergoing ABO-incompatible LDKT as measured by rotational thromboelastometry (ROTEM®). Methods Twenty-eight patients undergoing LDKT were divided into the PEX group (ABO incompatible with PEX, n = 13) and non-PEX group (ABO compatible without PEX, n = 15). ROTEM® parameters, standard laboratory test parameters, bleeding volume, and transfusion volume were compared between PEX and non-PEX group. MCEplatelet, which represents platelet contribution to clot strength and where “MCE” stands for maximum clot elasticity, was calculated from the difference in MCE between EXTEM and FIBTEM. Results The bleeding volume during surgery and the intensive care unit (ICU) stay was significantly higher in the PEX than non-PEX group (p < 0.01). Maximum clot firmness (MCF) of EXTEM (MCFEXTEM), MCFFIBTEM, and MCEplatelet was significantly lower in the PEX than non-PEX group (p < 0.01). In the PEX group, the bleeding volume during surgery was very strongly correlated with the baseline MCFEXTEM and MCEplatelet, and the bleeding volume during the ICU stay was strongly correlated with the postoperative MCFEXTEM and MCEplatelet. Conclusions These results suggest that the increased blood loss in the PEX group during surgery and the ICU stay was associated with decreased platelet contribution to clot strength as measured by ROTEM®. Trial registration UMIN-Clinical Trial Registry UMIN000018355. Registered 21 July 2015