Endotheliopathy in Acute COVID-19 and Long COVID.

The pulmonary endothelium is a highly regulated organ that performs a wide range of functions under physiological and pathological conditions. Since endothelial dysfunction has been demonstrated to play a direct role in sepsis and acute respiratory distress syndrome, its role in COVID-19 has also been extensively investigated. Indeed, apart from the COVID-19-associated coagulopathy biomarkers, new biomarkers were recognised early during the pandemic, including markers of endothelial cell activation or injury. We systematically searched the literature up to 10 March 2023 for studies examining the association between acute and long COVID-19 severity and outcomes and endothelial biomarkers.

COMPARATIVE EVALUATION AND PROGNOSTIC UTILITY OF NEURONAL INJURY BIOMARKERS IN COVID-19 PATIENTS: A PROSPECTIVE STUDY.

ABSTRACT: Background : COVID-19 disease severity markers include mostly molecules related to not only tissue perfusion, inflammation, and thrombosis, but also biomarkers of neural injury. Clinical and basic research has demonstrated that SARS-COV-2 affects the central nervous system. The aims of the present study were to investigate the role of neural injury biomarkers and to compare them with inflammatory markers in their predictive ability of mortality. Methods : We conducted a prospective observational study in critically ill patients with COVID-19 and in a cohort of patients with moderate/severe disease. S100b, neuron-specific enolase (NSE), and inflammatory markers, including soluble urokinase plasminogen activator receptor (suPAR), were measured on intensive care unit or ward admission, respectively. Statistical comparisons between patient groups were performed for all biomarkers under investigation. Correlations between different biomarkers were tested with Spearman correlation coefficient. Receiver operating characteristic curves were plotted using mortality as the classification variable and the biomarker levels on admission as the prognostic variables. Results : A total of 70 patients with COVID-19 were included in the final analysis. Of all studied biomarkers, s100b had the best predictive ability for death in the intensive care unit, with an area under the curve of 0.73 (0.61-0.83), P = 0.0003. S100b levels correlated with NSE, interleukin (IL)-8, and IL-10 (0.27 < rs < 0.37, P < 0.05), and tended to correlate with suPAR ( rs = 0.26, P = 0.05), but not with the vasopressor dose ( P = 0.62). Conclusion : Among the investigated biomarkers, s100b demonstrated the best predictive ability for death in COVID-19 patients. The overall biomarker profile of the patients implies direct involvement of the nervous system by the novel coronavirus.

Comparison of the Mortality Prediction Value of Soluble Urokinase Plasminogen Activator Receptor (suPAR) in COVID-19 and Sepsis.

In the last years, biomarkers of infection, such as the soluble urokinase plasminogen activator receptor (suPAR), have been extensively studied as potential diagnostic and prognostic biomarkers in the intensive care unit (ICU). In this study, we investigated whether this biomarker can be used in COVID-19 and non-COVID-19 septic patients for mortality prediction. Serum suPAR levels were measured in 79 non-COVID-19 critically ill patients upon sepsis (within 6 h), and on admission in 95 COVID-19 patients (66 critical and 29 moderate/severe). The non-COVID-19 septic patients were matched for age, sex, and disease severity, while the site of infection was the respiratory system. On admission, COVID-19 patients presented with higher suPAR levels, compared to non-COVID-19 septic patients (p < 0.01). More importantly, suPAR measured upon sepsis could not differentiate survivors from non-survivors (p > 0.05), as opposed to suPAR measured on admission in COVID-19 survivors and non-survivors (p < 0.0001). By the generated ROC curve, the prognostic value of suPAR in COVID-19 was 0.81, at a cut-off value of 6.3 ng/mL (p < 0.0001). suPAR measured early (within 24 h) after hospital admission seems like a specific and sensitive mortality risk predictor in COVID-19 patients. On the contrary, suPAR measured at sepsis diagnosis in non-COVID-19 critically ill patients, does not seem to be a prognostic factor of mortality.

Lactate and Lactate-to-Pyruvate Ratio in Critically Ill COVID-19 Patients: A Pilot Study.

A limited number of coronavirus disease-19 (COVID-19) cases may require treatment in an intensive care unit (ICU). Arterial blood lactate levels are routinely measured in the ICU to estimate disease severity, predict poor outcomes, and monitor therapeutic handlings. A number of studies have suggested that, simultaneously with lactate, pyruvate should also be measured, providing augmented prognostic ability, and a better understanding of the underlying metabolic alterations in ICU patients. Hence, the aim of the present study was to elucidate the relationship between lactate levels and the lactate-to-pyruvate (LP) ratio with the clinical outcome in mechanically ventilated COVID-19 patients. Lactate and pyruvate were serially measured during the first 24 h of ICU stay. A group of ICU non-COVID-19 patients was used as a comparison group. The majority of COVID-19 patients (82.5%) had normal lactate levels and a normal LP ratio on ICU admission (normal metabolic pattern). A small, yet significant, percentage of patients had either elevated lactate levels or a high LP ratio (abnormal metabolic pattern); these patients exhibited a significantly higher risk of ICU mortality compared to the patients with a normal metabolic pattern (72.7% vs. 34.6%, p = 0.04). In our critically ill COVID-19 patients, elevated lactate levels or high LP ratios on admission to the ICU could be associated with poor clinical outcome.

Endothelial, Immunothrombotic, and Inflammatory Biomarkers in the Risk of Mortality in Critically Ill COVID-19 Patients: The Role of Dexamethasone.

Endothelial dysfunction, coagulation and inflammation biomarkers are increasingly emerging as prognostic markers of poor outcomes and mortality in severe and critical COVID-19. However, the effect of dexamethasone has not been investigated on these biomarkers. Hence, we studied potential prognostic biomarkers of mortality in critically ill COVID-19 patients who had either received or not dexamethasone. Biomarker serum levels were measured on intensive care unit (ICU) admission (within 24 h) in 37 dexamethasone-free and 29 COVID-19 patients who had received the first dose (6 mg) of dexamethasone. Receiver operating characteristic (ROC) curves were generated to assess their value in ICU mortality prediction, while Kaplan-Meier analysis was used to explore associations between biomarkers and survival. In the dexamethasone-free COVID-19 ICU patients, non-survivors had considerably higher levels of various endothelial, immunothrombotic and inflammatory biomarkers. In the cohort who had received one dexamethasone dose, non-survivors had higher ICU admission levels of only soluble (s) vascular cell adhesion molecule-1 (VCAM-1), soluble urokinase-type plasminogen activator receptor (suPAR) and presepsin. As determined from the generated ROC curves, sVCAM-1, suPAR and presepsin could still be reliable prognostic ICU mortality biomarkers, following dexamethasone administration (0.7 < AUC < 0.9). Moreover, the Kaplan-Meier survival analysis showed that patients with higher than the median values for sVCAM-1 or suPAR exhibited a greater mortality risk than patients with lower values (Log-Rank test, p < 0.01). In our single-center study, sVCAM-1, suPAR and presepsin appear to be valuable prognostic biomarkers in assessing ICU mortality risk in COVID-19 patients, even following dexamethasone administration.

Increased Glucocorticoid Receptor Alpha Expression and Signaling in Critically Ill Coronavirus Disease 2019 Patients.

OBJECTIVES: Critical illness is characterized by increased serum cortisol concentrations and bioavailability resulting from the activation of the hypothalamic-pituitary-adrenal axis, which constitutes an essential part of the stress response. The actions of glucocorticoids are mediated by a ubiquitous intracellular receptor protein, the glucocorticoid receptor. So far, data on coronavirus disease 2019 and glucocorticoid receptor alpha expression are lacking. DESIGN: Prospective observational study. SETTING: One academic multidisciplinary ICU. SUBJECTS: Twenty-six adult coronavirus disease 2019 patients; 33 adult noncoronavirus disease 2019 patients, matched for age, sex, and disease severity, constituted the control group. All patients were steroid-free. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Glucocorticoid receptor alpha, glucocorticoid-inducible leucine zipper expression, and serum cortisol were measured on ICU admission. In coronavirus disease 2019 patients, glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper messenger RNA expression were upregulated (4.7-fold, p < 0.01 and 14-fold, p < 0.0001, respectively), and cortisol was higher (20.3 vs 14.3 µg/dL, p < 0.01) compared with the control group. CONCLUSIONS: ICU coronavirus disease 2019 patients showed upregulated glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper expression, along with cortisol levels, compared with ICU noncoronavirus disease 2019 patients. Thus, on ICU admission, critical coronavirus disease 2019 appears to be associated with hypercortisolemia, and increased synthesis of glucocorticoid receptor alpha and induced proteins.

Low Admission Immunoglobulin G Levels Predict Poor Outcome in Patients with Mild-to-Critical COVID-19: A Prospective, Single-Center Study.

INTRODUCTION: Immunoglobulins (Igs) comprise a critical part of the immune response. Little information exists on Ig serum levels in COVID-19 patients. We, therefore, investigated whether hospital admission Igs in patients with mild-to-critical disease are associated with clinical outcome. MATERIALS AND METHODS: This prospective, observational, single-center, cross-sectional study included 126 consecutive non-critically ill and critically ill and COVID-19 patients, in whom IgG, IgM, and IgA were measured on hospital admission. RESULTS: The cohort was divided in survivors and non-survivors, based on in-hospital mortality. Median IgG levels of survivors were significantly higher than non-survivors (p < 0.01). The cohort was subsequently divided in IgG deficient (< 690 mg/dl) and sufficient (≥ 690 mg/dl) patients. IgG-deficient patients had a higher mortality rate (p < 0.01). The multivariate logistic regression model showed that subnormal IgG was significantly associated with increased mortality risk (p < 0.01). CONCLUSION: In our COVID-19 cohort, admission subnormal IgG levels might be independently associated with reduced survival.

Evaluating the Role of the Interleukin-23/17 Axis in Critically Ill COVID-19 Patients.

Studies have hypothesized a potential role of the interleukin (IL)-23/17 axis in coronavirus disease 2019 (COVID-19). However, to date, levels of IL-23 and 17 have not been compared between critically ill COVID-19 patients and critically ill non-COVID-19 patients. IL-23 and 17 were measured on admission to the intensive care unit (ICU) in critically ill COVID-19 (N = 38) and critically ill non-COVID-19 (N = 34) patients with an equal critical illness severity. Critically ill non-COVID-19 patients did not have sepsis or septic shock on ICU admission. None of the enrolled patients had previously received corticosteroids. In our study, circulating IL-17 levels were higher in the COVID-19 patients. More specifically, critically ill COVID-19 patients had levels of 0.78 (0.05-1.8) pg/mL compared to 0.11 (0.05-0.9) pg/mL in the critically ill non-COVID-19 patients (p = 0.04). In contrast, IL-23 levels were comparable between groups. A group of patients hospitalized in the specialized COVID-19 clinic (N = 16) was also used to evaluate IL-17 and IL-23 levels with respect to COVID-19 severity. Non-critically ill COVID-19 patients had undetectable levels of both cytokines. Our results support the notion of inhibiting IL-17 in critical COVID-19 infection.

Soluble Angiotensin Converting Enzyme 2 (ACE2) Is Upregulated and Soluble Endothelial Nitric Oxide Synthase (eNOS) Is Downregulated in COVID-19-induced Acute Respiratory Distress Syndrome (ARDS).

A damaged endothelium is an underlying condition of the many complications of COVID-19 patients. The increased mortality risk associated with diseases that have underlying endothelial dysfunction, such as acute respiratory distress syndrome (ARDS), suggests that endothelial (e) nitric oxide synthase (NOS)-derived nitric oxide could be an important defense mechanism. Additionally, intravenous recombinant angiotensin converting enzyme 2 (ACE2) was recently reported as an effective therapy in severe COVID-19, by blocking viral entry, and thus reducing lung injury. Very few studies exist on the prognostic value of endothelium-related protective molecules in severe COVID-19 disease. To this end, serum levels of eNOS, inducible (i) NOS, adrenomedullin (ADM), soluble (s) ACE2 levels, and serum (s) ACE activity were measured on hospital admission in 89 COVID-19 patients, hospitalized either in a ward or ICU, of whom 68 had ARDS, while 21 did not. In our cohort, the COVID-19-ARDS patients had considerably lower eNOS levels compared to the COVID-19 non-ARDS patients. On the other hand, sACE2 was significantly higher in the ARDS patients. iNOS, ADM and sACE activity did not differ. Our results might support the notion of two distinct defense mechanisms in COVID-19-derived ARDS; eNOS-derived nitric oxide could be one of them, while the dramatic rise in sACE2 may also represent an endogenous mechanism involved in severe COVID-19 complications, such as ARDS. These results could provide insight to therapeutical applications in COVID-19.

Could Soluble Endothelial Protein C Receptor Levels Recognize SARS-CoV2-Positive Patients Requiring Hospitalization?

INTRODUCTION: The endothelial protein C receptor (EPCR) is a protein that regulates the protein C anticoagulant and anti-inflammatory pathways. A soluble form of EPCR (sEPCR) circulates in plasma and inhibits activated protein C (APC) activities. The clinical impact of sEPCR and its involvement in COVID-19 has not been explored. In this study, we investigated whether sEPCR levels were related to COVID-19 patients' requirement for hospitalization. METHODS: Plasma sEPCR levels were measured on hospital admission in 84 COVID-19 patients, and in 11 non-hospitalized SARS-CoV2-positive patients approximately 6 days after reported manifestation of their symptoms. Multiple logistic regression analysis was performed to identify potential risk factors for hospitalization and receiver operating characteristic (ROC) curves were generated to assess their value. RESULTS: In our cohort, hospitalized patients had considerably higher sEPCR levels upon admission compared with outpatients [107.5 (76.7-156.3) vs. 44.6 (12.1-84.4) ng/mL; P < 0.0001)]. The ROC curve using hospitalization as the classification variable and sEPCR levels as the prognostic variable generated an area under the curve at 0.845 (95% CI = 0.710-0.981, P < 0.001). Additionally, we investigated the predictive value of sEPCR combined with BMI, age, or D-dimers. CONCLUSIONS: In our cohort, sEPCR levels in COVID-19 patients upon hospital admission appear considerably elevated compared with outpatients; this could lead to impaired APC activities and might contribute to the pro-coagulant phenotype reported in such patients. sEPCR measurement might be useful as a point-of-care test in SARS-CoV2-positive patients.

Selection of the Appropriate Control Group Is Essential in Evaluating the Cytokine Storm in COVID-19.

BACKGROUND/AIM: Lately, studies have reported contradicting results on the cytokine storm seen in critically-ill COVID-19 patients. Depending on the control group used, cytokines have been found to be higher, similar or even lower in COVID-19 compared to critical illnesses associated with elevated cytokine concentrations. However, most of these studies do not take into account critical illness severity. Hence, we decided to compare cytokine levels in critically-ill COVID-19 patients and critically-ill patients of a general intensive care unit (ICU), who did not have sepsis or septic shock, but had an equal disease severity. PATIENTS AND METHODS: Interleukin (IL)-6, IL-8, IL-10 and tumour necrosis factor-α (TNF-α) were measured on ICU admission in mechanically ventilated, COVID-19 (N=36) and non-COVID-19 (N=30) patients, who had not received dexamethasone, and had equal critical illness severity. Non-COVID-19 patients did not have sepsis or septic shock. RESULTS: In our case control study, circulating IL-6 and IL-10 were lower, while TNF-α and IL-8 levels were higher in critically-ill COVID-19 patients, compared to critically-ill non-COVID-19 patients. CONCLUSION: It is difficult to infer whether the cytokine storm seen in COVID-19 differs from other critical conditions. It is important to recognize that the conclusions of related studies may depend on control group selection.

ICU Admission Levels of Endothelial Biomarkers as Predictors of Mortality in Critically Ill COVID-19 Patients.

Endotheliopathy is suggested to be an important feature of COVID-19 in hospitalized patients. To determine whether endotheliopathy is involved in COVID-19-associated mortality, markers of endothelial damage were assessed in critically ill COVID-19 patients upon intensive care unit (ICU) admission. Thirty-eight critically ill COVID-19 patients were included in this observational study, 10 of whom died in the ICU. Endothelial biomarkers, including soluble (s)E-selectin, sP-selectin, angiopoietin 1 and 2 (Ang-1 and Ang-2, respectively), soluble intercellular adhesion molecule 1 (sICAM-1), vascular endothelial growth factor (VEGF), soluble vascular endothelial (VE)-cadherin, and von Willebrand factor (vWf), were measured upon ICU admission. The ICU cohort was subsequently divided into survivors and non-survivors; Kaplan-Meier analysis was used to explore associations between biomarkers and survival, while receiver operating characteristic (ROC) curves were generated to determine their potential prognostic value. sE-selectin, sP-selectin, Ang-2, and sICAM-1 were significantly elevated in ICU non-survivors compared to survivors, and also associated with a higher mortality probability in the Kaplan-Meier analysis. The prognostic values of sE-selectin, Ang-2, and sICAM-1 from the generated ROC curves were greater than 0.85. Hence, we conclude that in our cohort, ICU non-survivors had higher levels of specific endothelial markers compared to survivors. Elevated levels of these markers upon ICU admission could possibly predict mortality in COVID-19.

Lactate Kinetics Reflect Organ Dysfunction and Are Associated with Adverse Outcomes in Intensive Care Unit Patients with COVID-19 Pneumonia: Preliminary Results from a GREEK Single-Centre Study.

Coronavirus disease-19 (COVID-19) continues to be a health threat worldwide. Increased blood lactate is common in intensive care unit (ICU) patients; however, its association with outcomes in ICU COVID-19 patients remains currently unexplored. In this retrospective, observational study we assessed whether lactate is associated with outcomes in COVID-19 patients. Blood lactate was measured on ICU admission and thereafter daily up to day 14 in 45 patients with confirmed COVID-19 pneumonia. Acute physiology and chronic health evaluation (APACHE II) was calculated on ICU admission, and sequential organ failure assessment (SOFA) score was assessed on admission and every second day. The cohort was divided into survivors and non-survivors based on 28-day ICU mortality (24.4%). Cox regression analysis revealed that maximum lactate on admission was independently related to 28-day ICU mortality with time in the presence of APACHE II (RR = 2.45, p = 0.008). Lactate's area under the curve for detecting 28-day ICU mortality was 0.77 (p = 0.008). Mixed model analysis showed that mean daily lactate levels were higher in non-survivors (p < 0.0001); the model applied on SOFA scores showed a similar time pattern. Thus, initial blood lactate was an independent outcome predictor in COVID-19 ICU patients. The time course of lactate mirrors organ dysfunction and is associated with poor clinical outcomes.