Micronutrient Status of Critically Ill Patients with COVID-19 Pneumonia.

Micronutrient deficiencies can develop in critically ill patients, arising from factors such as decreased intake, increased losses, drug interactions, and hypermetabolism. These deficiencies may compromise important immune functions, with potential implications for patient outcomes. Alternatively, micronutrient blood levels may become low due to inflammation-driven redistribution rather than consumption. This explorative pilot study investigates blood micronutrient concentrations during the first three weeks of ICU stay in critically ill COVID-19 patients and evaluates the impact of additional micronutrient administration. Moreover, associations between inflammation, disease severity, and micronutrient status were explored. We measured weekly concentrations of vitamins A, B6, D, and E; iron; zinc; copper; selenium; and CRP as a marker of inflammation state and the SOFA score indicating disease severity in 20 critically ill COVID-19 patients during three weeks of ICU stay. Half of the patients received additional (intravenous) micronutrient administration. Data were analyzed with linear mixed models and Pearson's correlation coefficient. High deficiency rates of vitamins A, B6, and D; zinc; and selenium (50-100%) were found at ICU admission, along with low iron status. After three weeks, vitamins B6 and D deficiencies persisted, and iron status remained low. Plasma levels of vitamins A and E, zinc, and selenium improved. No significant differences in micronutrient levels were found between patient groups. Negative correlations were identified between the CRP level and levels of vitamins A and E, iron, transferrin, zinc, and selenium. SOFA scores negatively correlated with vitamin D and selenium levels. Our findings reveal high micronutrient deficiency rates at ICU admission. Additional micronutrient administration did not enhance levels or expedite their increase. Spontaneous increases in vitamins A and E, zinc, and selenium levels were associated with inflammation resolution, suggesting that observed low levels may be attributed, at least in part, to redistribution rather than true deficiencies.

Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19. METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort. RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively). CONCLUSIONS: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.

Anti-C5a antibody vilobelimab treatment and the effect on biomarkers of inflammation and coagulation in patients with severe COVID-19: a substudy of the phase 2 PANAMO trial.

We recently reported in the phase 3 PANAMO trial that selectively blocking complement 5a (C5a) with vilobelimab led to improved survival in critically ill COVID-19 patients. C5a is an important contributor to the innate immune system and can also activate the coagulation system. High C5a levels have been reported in severely ill COVID-19 patients and correlate with disease severity and mortality. Previously, we assessed the potential benefit and safety of vilobelimab in severe COVID-19 patients. In the current substudy of the phase 2 PANAMO trial, we aim to explore the effects of vilobelimab on various biomarkers of inflammation and coagulation. Between March 31 and April 24, 2020, 17 patients with severe COVID-19 pneumonia were enrolled in an exploratory, open-label, randomised phase 2 trial. Blood markers of complement, endothelial activation, epithelial barrier disruption, inflammation, neutrophil activation, neutrophil extracellular trap (NET) formation and coagulopathy were measured using enzyme-linked immunosorbent assay (ELISA) or utilizing the Luminex platform. During the first 15 days after inclusion, change in biomarker concentrations between the two groups were modelled with linear mixed-effects models with spatial splines and compared. Eight patients were randomized to vilobelimab treatment plus best supportive care (BSC) and nine patients were randomized to BSC only. A significant decrease over time was seen in the vilobelimab plus BSC group for C5a compared to the BSC only group (p < 0.001). ADAMTS13 levels decreased over time in the BSC only group compared to the vilobelimab plus BSC group (p < 0.01) and interleukin-8 (IL-8) levels were statistically more suppressed in the vilobelimab plus BSC group compared to the BSC group (p = 0.03). Our preliminary results show that C5a inhibition decreases the inflammatory response and hypercoagulability, which likely explains the beneficial effect of vilobelimab in severe COVID-19 patients. Validation of these results in a larger sample size is warranted.

Shock-Driven Endotheliopathy in Trauma Patients Is Associated with Leucocyte Derived Extracellular Vesicles.

Endotheliopathy following trauma is associated with poor outcome, but the underlying mechanisms are unknown. This study hypothesized that an increased extracellular vesicle (EV) concentration is associated with endotheliopathy after trauma and that red blood cell (RBC) transfusion could further enhance endotheliopathy. In this post hoc sub study of a multicentre observational trial, 75 trauma patients were stratified into three groups based on injury severity score or shock. In patient plasma obtained at hospital admission and after transfusion of four RBC transfusions, markers for endotheliopathy were measured and EVs were labelled with anti CD41 (platelet EVs), anti CD235a (red blood cell EVs), anti CD45 (leucocyte EVs), anti CD144 (endothelial EVs) or anti CD62e (activated endothelial EVs) and EV concentrations were measured with flow cytometry. Statistical analysis was performed by a Kruskall Wallis test with Bonferroni correction or Wilcoxon rank test for paired data. In patients with shock, syndecan-1 and von Willebrand Factor (vWF) were increased compared to patients without shock. Additionally, patients with shock had increased red blood cell EV and leucocyte EV concentrations compared to patients without shock. Endotheliopathy markers correlated with leucocyte EVs (ρ = 0.263, p = 0.023), but not with EVs derived from other cells. Injury severity score had no relation with EV release. RBC transfusion increased circulating red blood cell EVs but did not impact endotheliopathy. In conclusion, shock is (weakly) associated with EVs from leucocytes, suggesting an immune driven pathway mediated (at least in part) by shock.

Rotational thromboelastometry in critically ill COVID-19 patients does not predict thrombosis.

Background: Critically ill COVID-19 patients are in a hypercoagulable state with increased risk of thrombotic complications. Rotational thromboelastometry (ROTEM) is a viscoelastic test with the potential to reflect COVID-19-associated hypercoagulability and may therefore be useful to predict thrombotic complications. Objective: To investigate the potential of ROTEM profiles to predict thrombotic complications in critically ill COVID-19 patients. Patients/Methods: Retrospective multicenter cohort study in 113 adult patients with confirmed COVID-19 infection admitted to the intensive care unit (ICU) of two large teaching hospitals in the United States and in the Netherlands. ROTEM profiles of the EXTEM, INTEM, and FIBTEM tracings were measured within 72 h of ICU admission. Thrombotic complications encompass both arterial and venous thromboembolic complications, diagnosed with electrocardiogram, ultrasound, or computed tomography. ROTEM profiles were compared between patients with and without thrombosis. Univariable logistic regression followed by receiver operating characteristic (ROC) curves analysis was performed to identify ROTEM parameters associated with thrombosis. Results and Conclusions: Of 113 patients, 27 (23.9%) developed a thrombotic event. In the univariable analysis, EXTEM clot amplitude at 10 min (CA10) and EXTEM maximum clot formation (MCF) were associated with thrombosis with a p < 0.2 (p = 0.07 and p = 0.05, respectively). In ROC curve analysis, EXTEM CA10 had an area under the curve (AUC) of 0.58 (95% CI 0.47-0.70) and EXTEM MCF had an AUC of 0.60 (95% CI 0.49-0.71). Thereby, ROTEM profiles at ICU admission did not have the potential to differentiate between patients with a high and low risk for thrombotic complications.

Coagulopathy Underlying Rotational Thromboelastometry Derangements in Trauma Patients: A Prospective Observational Multicenter Study.

BACKGROUND: Viscoelastic hemostatic assays such as rotational thromboelastometry (ROTEM) are used to guide treatment of trauma induced coagulopathy. The authors hypothesized that ROTEM derangements reflect specific coagulation factor deficiencies after trauma. METHODS: This was a secondary analysis of a prospective cohort study in six European trauma centers in patients presenting with full trauma team activation. Patients with dilutional coagulopathy and patients on anticoagulants were excluded. Blood was drawn on arrival for measurement of ROTEM, coagulation factor levels, and markers of fibrinolysis. ROTEM cutoff values to define hypocoagulability were as follows: EXTEM clotting time greater than 80 s, EXTEM clot amplitude at 5 min less than 40 mm, EXTEM lysis index at 30 min less than 85%, FIBTEM clot amplitude at 5 min less than 10 mm, and FIBTEM lysis index at 30 min less than 85%. Based on these values, patients were divided into seven deranged ROTEM profiles and compared to the reference group (ROTEM values within reference range). The primary endpoint was coagulation factors levels and fibrinolysis. RESULTS: Of 1,828 patients, 732 (40%) had ROTEM derangements, most often consisting of a combined decrease in EXTEM and FIBTEM clot amplitude at 5 min, that was present in 217 (11.9%) patients. While an isolated EXTEM clotting time greater than 80 s had no impact on mortality, all other ROTEM derangements were associated with increased mortality. Also, coagulation factor levels in this group were similar to those of patients with a normal ROTEM. Of coagulation factors, a decrease was most apparent for fibrinogen (with a nadir of 0.78 g/l) and for factor V levels (with a nadir of 22.8%). In addition, increased fibrinolysis can be present when the lysis index at 30 min is normal but EXTEM and FIBTEM clot amplitude at 5 min is decreased. CONCLUSIONS: Coagulation factor levels and mortality in the group with an isolated clotting time prolongation are similar to those of patients with a normal ROTEM. Other ROTEM derangements are associated with mortality and reflect a depletion of fibrinogen and factor V. Increased fibrinolysis can be present when the lysis index after 30 min is normal.

The relation between fibrinogen level, neutrophil activity and nucleosomes in the onset of disseminated intravascular coagulation in the critically ill.

BACKGROUND: Nucleosomes and neutrophil extracellular traps (NETs) are important in the pathophysiology of disseminated intravascular coagulation (DIC). Fibrinogen, as an acute phase reactant, may be protective by engaging neutrophils. We hypothesize that DIC can occur when NET formation becomes uncontrolled in relation to low fibrinogen levels. PATIENTS/METHOD: The ratio of both circulating nucleosomes and human neutrophil elastase alpha-1-antitrypsine complexes (HNE-a1ATc) to fibrinogen was correlated to thrombocytopenia, DIC and organ failure in 64 critically ill coagulopathic patients. RESULTS: A high nucleosome to fibrinogen ratio correlated with thrombocytopenia and organ failure (ρ -0.391, p 0.01 and ρ 0.556, p 0.01, respectively). A high HNE-a1ATc to fibrinogen ratio correlated with thrombocytopenia, DIC and organ failure (ρ -0.418, p 0.01, ρ 0.391, p 0.01 and ρ 0.477, p 0.01 respectively). CONCLUSION: These findings support the hypothesis that fibrinogen is protective against DIC by counterbalancing excessive neutrophil activation.

Biomarkers for the prediction of venous thromboembolism in critically ill COVID-19 patients.

BACKGROUND: Venous thromboembolism (VTE) is a frequent complication in critically ill patients with coronavirus disease 2019 (COVID-19) and is associated with mortality. Early diagnosis and treatment of VTE is warranted. OBJECTIVE: To develop a prediction model for VTE in critically ill COVID-19 patients. PATIENTS AND METHODS: In this retrospective cohort study, 127 adult patients with confirmed COVID-19 infection admitted to the intensive care unit of two teaching hospitals were included. VTE was diagnosed with either ultrasound or computed tomography scan. Univariate receiver operating characteristic (ROC) curves were constructed for Positive End Expiratory Pressure, PaO2/FiO2 ratio, platelet count, international normalized ratio, activated partial thromboplastin time as well as levels of fibrinogen, antithrombin, D-dimer and C-reactive protein (CRP). Multivariate analysis was done using binary linear regression. RESULTS: Variables associated with VTE in both univariate and multivariate analysis were D-dimer and CRP with an area under the curve (AUC) of 0.64, P = 0.023 and 0.75, P = 0.045, respectively. Variables indicating hypoxemia were not predictive. The ROC curve of D-dimer and CRP combined had an AUC of 0.83, P < 0.05. Categorized values of D-dimer and CRP were used to compute a mean absolute risk for the combination of these variables with a high positive predictive value. The predicted probability of VTE with a D-dimer > 15 in combination with a CRP > 280 was 98%. The negative predictive value of D-dimer was low. CONCLUSION: Elevated CRP and D-dimer have a high positive predictive value for VTE in critically ill COVID-19 patients. We developed a prediction table with these biomarkers that can aid clinicians in the timing of imaging in patients with suspected VTE.

Usefulness of mean corpuscular volume as a surrogate marker for monitoring thiopurine treatment in inflammatory bowel disease.

BACKGROUND: Thiopurines are commonly used drugs in inflammatory bowel disease. Intracellular levels of thiopurine metabolites [i.e. 6-thioguaninenucleotides (6-TGN)] are associated with efficacy and toxicity. Because 6-TGN measurement is not globally available, the mean corpuscular volume (MCV) has been proposed as a surrogate marker for monitoring thiopurine therapy. AIMS: To analyze the relationship between MCV and efficacy of thiopurines, defined as either response to therapy or 6-TGN levels. METHODS: A systematic search on PubMed was performed. RESULTS: Fifteen studies were included. In six studies, a positive association was found between ΔMCV and 6-TGN. In four studies, it was suggested that ΔMCV can be used to predict clinical remission. In five articles, no association was found. CONCLUSION: In the majority of articles, it was reported that ΔMCV is useful in guiding intracellular metabolite levels. However, there is insufficient evidence showing that ΔMCV can predict clinical remission.