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Chrysi Keskinidou, Alice G Vassiliou, Ioanna Dimopoulou, Anastasia Kotanidou, Stylianos E Orfanos First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, “Evangelismos” Hospital, Athens, GreeceCorrespondence: Alice G Vassiliou; Stylianos E Orfanos, First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, “Evangelismos” Hospital, Athens, Greece, Tel +30 210 7235521, Fax +30 210 7239127, Email alvass75@gmail.com; stylianosorfanosuoa@gmail.comAbstract: Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury characterized by an acute inflammatory response in the lung parenchyma. Hence, it is considered as the most appropriate clinical syndrome to study pathogenic mechanisms of lung inflammation. ARDS is associated with increased morbidity and mortality in the intensive care unit (ICU), while no effective pharmacological treatment exists. It is very important therefore to fully characterize the underlying pathobiology and the related mechanisms, in order to develop novel therapeutic approaches. In vivo and in vitro models are important pre-clinical tools in biological and medical research in the mechanistic and pathological understanding of the majority of diseases. In this review, we will present data from selected experimental models of lung injury/acute lung inflammation, which have been based on clinical disorders that can lead to the development of ARDS and related inflammatory lung processes in humans, including ventilation-induced lung injury (VILI), sepsis, ischemia/reperfusion, smoke, acid aspiration, radiation, transfusion-related acute lung injury (TRALI), influenza, Streptococcus (S.) pneumoniae and coronaviruses infection. Data from the corresponding clinical conditions will also be presented. The mechanisms related to lung inflammation that will be covered are oxidative stress, neutrophil extracellular traps, mitogen-activated protein kinase (MAPK) pathways, surfactant, and water and ion channels. Finally, we will present a brief overview of emerging techniques in the field of omics research that have been applied to ARDS research, encompassing genomics, transcriptomics, proteomics, and metabolomics, which may recognize factors to help stratify ICU patients at risk, predict their prognosis, and possibly, serve as more specific therapeutic targets.Keywords: acute respiratory distress syndrome, lung inflammation, mechanisms, biomarkers, omics

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients ( p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49-1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93-1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52-1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78-1.34)] compared to the survivors [0.57 (0.48-0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis.

Objective: Critically ill patients, including those with brain injuries (BI), are frequently hospitalized in an intensive care unit (ICU). As with other critical states, an adequate stress response is essential for survival. Research on the hypothalamic-pituitary-adrenal gland (HPA) axis function in BI has primarily focused on assessing ACTH and cortisol levels. However, the immunological, metabolic, and hemodynamic effects of glucocorticoids (GCs) are mediated through the glucocorticoid receptor (GCR), a ubiquitously distributed intracellular receptor protein. Data on GCR-α expression and its signaling in acute BI injury are lacking., Methods: We designed a prospective observational study, carried out in one academic multi-disciplinary ICU. Forty-two critically ill patients with acute (BI)were included. These patients suffered from traumatic BI (N= 20), subarachnoid hemorrhage (N= 12), intracranial hemorrhage (N= 7), or ischemic stroke (N= 3). All patients were steroid-free. Twenty-four age and sex-matched healthy controls were used for comparison., Results: Expression of GCR-α and the glucocorticoid-inducible leucine zipper ( GILZ ), serum cortisol, interleukins (IL) 6, 8, 10 and TNF- α, and the BI biomarkers glial fibrillary acidic protein (GFAP) and total Tau were measured on ICU admission (within 48 hours) and 5-7 days from admission. Compared to healthy controls, in the critically ill patients with BI, GCR-α mRNA expression was significantly downregulated on admission, and after 5-7 days in the ICU (2.3-fold, p<0.05 and 2.6-fold, p<0.01, respectively). Even though GCR-α was downregulated, its downstream gene, GILZ , was expressed at the same levels as in normal controls on admission and was significantly upregulated 5-7 days following admission (2-fold, p<0.001). TNF-α levels were undetectable at both time-points. GCR-α expression levels inversely correlated with IL-6. The levels of cortisol and the BI biomarkers did not differ between the 2 time-points., Conclusions: We provide novel evidence on the downregulated expression and upregulated signaling of the ligand-binding and functionally active GCR-α isoform in the polymorphonuclear neutrophils (PMNs) of critically ill patients with BI. The increased GILZ expression indicates an increased GC sensitivity in the PMNs of BI critically ill patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lotsios, Vrettou, Poupouzas, Chalioti, Keskinidou, Pratikaki, Giannopoulou, Kotanidou, Vassiliadi, Dimopoulou and Vassiliou.)

Background: Smoking cessation is crucial for reducing complications of type 2 diabetes mellitus (T2DM), but associated weight gain can worsen glycemic control, discouraging quitting attempts. Varenicline, a partial agonist of α4β2 nicotinic receptors, aids smoking cessation. This study examines the effects of varenicline on body weight and metabolic parameters in patients with T2DM and prediabetes., Methods: Fifty-three patients were enrolled, of which 32 successfully quit smoking after a three-month course of varenicline and were examined after an additional month with no medication. Measurements taken at baseline, 2.5 months, and 4 months included body weight, blood pressure, resting metabolic rate (RMR), glycated hemoglobin (HbA1c), fasting glucose, blood lipids, C-reactive protein (CRP), appetite-related hormones, and physical activity., Results: Post-treatment, there were no significant changes in body weight, blood pressure, RMR, or glycemic control. Total (CHOL) and low-density lipoprotein (LDL-C) cholesterol decreased significantly at 4 months of the study (from 168 to 156 mg/dL, p = 0.013, and from 96 to 83 mg/dL, p = 0.013, respectively). Leptin levels increased (from 11 to 13.8 ng/dL, p = 0.004), as did glucagon-like peptide-1 (GLP-1) levels (from 39.6 to 45.8 pM, p = 0.016) at 4 months of follow-up. The percentage of participants who reported moderate-intensity activity increased from 28% to 56%, while those reporting high-intensity activity increased from 19% to 22%, respectively ( p = 0.039)., Conclusions: Our study showed that smoking cessation with varenicline in smokers with T2DM and prediabetes led to significant improvements in lipid profile, significant increase in plasma leptin and GLP-1 levels, and increased physical activity, without significant weight gain. Thus, smoking cessation without weight gain or deteriorated glycemic control is feasible for these smokers, with added benefits to lipid profiles, GLP-1 regulation, and physical activity.

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive increase in mean pulmonary arterial pressure. Mutations in the BMPR2 and AQP1 genes have been described in familial PAH. The bone morphogenetic proteins BMP9 and BMP10 bind with high affinity to BMPR2. Administration of BMP9 has been proposed as a potential therapeutic strategy against PAH, although recent conflicting evidence dispute the effect of such a practice. Considering the involvement of the above molecules in PAH onset, progression, and therapeutic value, we examined the effects of modulation of BMP9, BMPR2, and AQP1 on BMP9, BMP10, BMPR2, AQP1, and TGFB1 expression in human pulmonary microvascular endothelial cells in vitro. Our results demonstrated that silencing the BMPR2 gene resulted in increased expression of its two main ligands, namely BMP9 and BMP10. Exogenous administration of BMP9 caused the return of BMP10 to basal levels, while it restored the decreased AQP1 protein levels and the decreased TGFB1 mRNA and protein expression levels caused by BMPR2 silencing. Moreover, AQP1 gene silencing also resulted in increased expression of BMP9 and BMP10. Our results might possibly imply that the effect of exogenously administered BMP9 on molecules participating in the BMP signaling pathway could depend on the expression levels of BMPR2 . Taken together, these results may provide insight into the highly complex interactions of the BMP signaling pathway.

Background: Post-COVID-19 syndrome has affected millions of people, with rehabilitation being at the center of non-pharmacologic care. However, numerous published studies show conflicting results due to, among other factors, considerable variation in subject characteristics. Currently, the effects of age, sex, time of implementation, and prior disease severity on the outcomes of a supervised rehabilitation program after COVID-19 remain unknown., Methods: This was a non-randomized case-control study. Subjects with post-COVID-19 sequelae were enrolled. Among study participants, those who could attend an 8-week, supervised rehabilitation program composed the intervention group, whereas those who couldn't the control group. Measurements were collected at baseline and 8 weeks thereafter., Results: Study groups ( N = 119) had similar baseline measurements. Participation in rehabilitation ( n = 47) was associated with clinically important improvements in the 6-min walk test (6MWT) distance, adjusted (for potential confounders) odds ratio (AOR) 4.56 (95% CI 1.95-10.66); 1-min sit-to-stand test, AOR 4.64 (1.88-11.48); Short Physical Performance Battery, AOR 7.93 (2.82-22.26); health-related quality of life (HRQOL) 5-level EuroQol-5D (Visual Analog Scale), AOR 3.12 (1.37-7.08); Montreal Cognitive Assessment, AOR 6.25 (2.16-18.04); International Physical Activity Questionnaire, AOR 3.63 (1.53-8.59); Fatigue Severity Scale, AOR 4.07 (1.51-10.98); Chalder Fatigue Scale (bimodal score), AOR 3.33 (1.45-7.67); Modified Medical Research Council dyspnea scale (mMRC), AOR 4.43 (1.83-10.74); Post-COVID-19 Functional Scale (PCFS), AOR 3.46 (1.51-7.95); and COPD Assessment Test, AOR 7.40 (2.92-18.75). Time from disease onset was marginally associated only with 6MWT distance, AOR 0.99 (0.99-1.00). Prior hospitalization was associated with clinically important improvements in the mMRC dyspnea scale, AOR 3.50 (1.06-11.51); and PCFS, AOR 3.42 (1.16-10.06). Age, sex, and ICU admission were not associated with the results of any of the aforementioned tests/grading scales., Conclusions: In this non-randomized, case-control study, post-COVID-19 rehabilitation was associated with improvements in physical function, activity, HRQOL, respiratory symptoms, fatigue, and cognitive impairment. These associations were observed independently of timing of rehabilitation, age, sex, prior hospitalization, and ICU admission., (Copyright © 2024 by Daedalus Enterprises.)

Acute hypoxemic respiratory failure (AHRF) is defined as acute and progressive, and patients are at a greater risk of developing acute respiratory distress syndrome (ARDS). Until now, most studies have focused on prognostic and diagnostic biomarkers in ARDS. Since there is evidence supporting a connection between dysregulated coagulant and fibrinolytic pathways in ARDS progression, it is plausible that this dysregulation also exists in AHRF. The aim of this study was to explore whether levels of soluble endothelial protein C receptor (sEPCR) and plasminogen differentiate patients admitted to the emergency department (ED) with AHRF. sEPCR and plasminogen levels were measured in 130 AHRF patients upon ED presentation by ELISA. Our results demonstrated that patients presenting to the ED with AHRF had elevated levels of sEPCR and plasminogen. It seems that dysregulation of coagulation and fibrinolysis occur in the early stages of respiratory failure requiring hospitalisation. Further research is needed to fully comprehend the contribution of sEPCR and plasminogen in AHRF.

Background: this prospective observational study aims to assess serum levels of glial fibrillary acidic protein (GFAP), s100b, and total Tau in long-COVID patients, exploring correlations with symptoms, cognitive decline, mental health, and quality of life., Methods: Long-COVID patients visiting our outpatient clinic (February 2021-December 2022) were screened alongside age- and sex-matched controls. GFAP, s100b, and total Tau in serum were measured with ELISA. Cognitive function, depression, anxiety, post-traumatic stress disorder, and quality of life were evaluated using MoCA, HADS (depression and anxiety), IES-R, and SF-36, respectively., Results: Sixty-five long-COVID patients and 20 controls were included. GFAP levels were significantly higher in long-COVID patients ( p = 0.031), though not correlating with the presence of long-COVID symptoms. S100b and total Tau showed no significant differences between patients and controls. Nervous system-related symptoms were reported in 47% of patients. High rates of cognitive decline (65.9%), depression (32.2%), anxiety (47.5%), and post-traumatic stress disorder (44.1%) were observed. Over 80% of the study population scored below normative cutoffs for SF-36, indicating a significant impact on quality of life., Conclusions: in this long-COVID cohort with substantial psychological and cognitive symptoms, GFAP levels were elevated compared to controls, though not correlating with the presence of long-COVID symptoms.

Objective: To investigate hormonal status in patients with long-COVID and explore the interrelationship between hormone levels and long-COVID symptoms., Design: Prospective observational study., Participants: Patients who visited our long-COVID outpatients' clinic due to long-COVID symptoms from February 2021 to December 2022., Measurements: Total triiodothyronine, free thyroxine, thyrotropin, thyroglobulin, anti-thyroperoxidase, and antithyroglobulin autoantibodies were measured for thyroid assessment. Other hormones measured were growth hormone, insulin-like growth factor 1 (IGF-1), adrenocorticotropic hormone (ACTH), serum cortisol, dehydroepiandrosterone sulfate (DHEA-S), total testosterone, plasma insulin, and C-peptide. Blood glucose and glycosylated hemoglobin were also measured. To assess adrenal reserve, an ACTH stimulation test was performed. The fatigue assessment scale (FAS) was used to evaluate fatigue severity., Results: Eighty-four adult patients were included. Overall, 40.5% of the patients had at least one endocrine disorder. These included prediabetes (21.4%), low DHEA-S (21.4%), subclinical hypothyroidism (3.6%), non-specific thyroid function abnormality (7.1%), thyroid autoimmunity (7.1%), low testosterone in males (6.6%), and low IGF-1 (3.6%). All patients had normal adrenal reserve. Long-COVID-19 symptoms were present in all patients and the most commonly reported symptom was fatigue (89.3%). The FAS score was higher than normal (≥ 22) in 42.8% of patients. There were no associations between patients' symptoms and hormone levels. Diabetic patients reported confusion (p = 0.020) and hair loss (p = 0.040) more often than non-diabetics., Conclusions: The evaluation of endocrine function 3 months after a positive SARS-CoV2 test revealed only subclinical syndromes. The vast majority of patients reported mainly fatigue, among other symptoms, which were unrelated, however, to endocrine function., (© 2023. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Purpose: We aimed to identify whether hypothalamic-pituitary-adrenal (HPA) axis dysfunction is related to deterioration in a percentage of patients who progress to severe COVID-19., Methods: In this cohort observational study, we evaluated HPA axis activation by measuring cortisol, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate (DHEA-S) levels, whole blood expression levels of the key glucocorticoid receptor, GCR-α, and the glucocorticoid-induced leucine zipper (GILZ), and cytokines, as markers of the inflammatory phase, in 149 patients with respiratory infection admitted in the ward, without known adrenal disease and/or confounding medications (glucocorticoids). One hundred and four (104) patients were SARS-CoV-2 positive (C +) and controls consisted of 45 SARS-CoV-2-negative patients (NC)., Results: No differences in cortisol levels were observed between the C + and the NC patients. Cortisol levels correlated with ACTH (r = 0.284, p = 0.001) and IL-6 (r = 0.289, p = 0.04). In C + patients, cortisol levels mainly correlated with IL-6 levels (r = 0.28; p = 0.017). GCR-α expression was significantly higher in C + patients compared to NC. Patients with higher cortisol levels were more likely to progress to respiratory function deterioration or die. Both GCR-α and GILZ expression were significantly higher in C + non-survivors., Conclusion: Our findings indicate that cortisol serves as an indicator of disease severity. GILZ expression appears to be a more effective marker of mortality prediction in moderate COVID-19 cases. However, routine measurement of GILZ levels is currently unavailable. Elevated levels of cortisol may be indicative of patients with moderate COVID-19 who are at a higher risk of deterioration. This information can aid in identifying individuals who require early medical attention., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Sepsis is an inflammatory disorder caused by the host's dysfunctional response to infection. Septic patients present diverse clinical characteristics, and in the recent years, it has been the main cause of death in intensive care units (ICU). Aquaporins, membrane proteins with a role in water transportation, have been reported to participate in numerous biological processes. Their role in sepsis progression has been studied extensively. This review aims to examine recent literature on aquaporin expression and regulation in clinical sepsis, as well as established experimental models of sepsis. We will present how sepsis affects aquaporin expression at the molecular and protein level. Moreover, we will delve into the importance of aquaporin regulation at transcriptional, post-transcriptional, translational, and post-translational levels in sepsis by presenting data on aquaporin regulation by non-coding RNAs and selected chemical molecules. Finally, we will focus on the importance of aquaporin single-nucleotide polymorphisms in the setting of sepsis.

Severe COVID-19 is related to hyperinflammation and multiple organ injury, including respiratory failure, thus requiring intensive care unit (ICU) admission. Galectin-3, a carbohydrate-binding protein exhibiting pleiotropic effects, has been previously recognized to participate in inflammation, the immune response to infections and fibrosis. The aim of this study was to evaluate the relationship between galectin-3 and the clinical severity of COVID-19, as well as assess the prognostic accuracy of galectin-3 for the probability of ICU mortality. The study included 235 COVID-19 patients with active disease, treated in two different Greek hospitals in total. Our results showed that median galectin-3 serum levels on admission were significantly increased in critical COVID-19 patients (7.2 ng/mL), as compared to the median levels of patients with less severe disease (2.9 ng/mL, p = 0.003). Galectin-3 levels of the non-survivors hospitalized in the ICU were significantly higher than those of the survivors (median 9.1 ng/mL versus 5.8 ng/mL, p = 0.001). The prognostic accuracy of galectin-3 for the probability of ICU mortality was studied with a receiver operating characteristic (ROC) curve and a multivariate analysis further demonstrated that galectin-3 concentration at hospital admission could be assumed as an independent risk factor associated with ICU mortality. Our results were validated with galectin-3 measurements in a second patient cohort from a different Greek university hospital. Our results, apart from strongly confirming and advancing previous knowledge with two patient cohorts, explore the possibility of predicting ICU mortality, which could provide useful information to clinicians. Therefore, galectin-3 seems to establish its involvement in the prognosis of hospitalized COVID-19 patients, suggesting that it could serve as a promising biomarker in critical COVID-19.

Background: Novel molecular diagnostic methods are being evaluated in order to expedite pathogen identification in patients with bacteraemia., Aims: To evaluate the feasibility and diagnostic accuracy of the T2 magnetic resonance (T2MR) assays - T2 Bacteria (T2B) and T2 Resistance (T2R) - as point-of-care tests in the intensive care unit compared with blood-culture-based tests., Methods: Prospective cross-sectional study of consecutive patients with suspected bacteraemia. Diagnostic accuracy was evaluated using blood culture as the reference method., Findings: In total, 208 cases were included in the study. The mean time from sampling to report was lower for the T2MR assays compared with blood-culture-based methods (P<0.001). The rate of invalid reports was 6.73% for the T2B assay and 9.9% for the T2R assay. For the T2B assay, overall positive percentage agreement (PPA) was 84.6% [95% confidence interval (CI) 71.9-93.1%], negative percentage agreement (NPA) was 64.3% (95% CI 55.4-72.6%), positive predictive value (PPV) was 48.9% (95% CI 42.5-55.3%) and negative predictive value (NPV) was 91.2% (95% CI 84.4-95.2%). Cohen's kappa coefficient was 0.402. For the T2R assay, overall PPA was 80% (95% CI 51.9-95.7%), NPA was 69.2% (95% CI 54.9-81.3%), PPV was 42.9% (95% CI 31.7-54.8%) and NPV was 92.3% (95% CI 81.1-97.1%). Cohen's kappa coefficient was 0.376., Conclusion: T2MR assays have high NPV for rapid exclusion of bacteraemia, and could potentially assist with antimicrobial stewardship when applied as point-of-care diagnostic tests in the intensive care unit., (Copyright © 2023 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Since the beginning of the pandemic, both COVID-19-associated coagulopathy biomarkers and a plethora of endothelial biomarkers have been proposed and tested as prognostic tools of severity and mortality prediction. As the pandemic is gradually being controlled, attention is now focusing on the long-term sequelae of COVID-19. In the present study, we investigated the role of endothelial activation/dysfunction in long COVID syndrome. This observational study included 68 consecutive long COVID patients and a healthy age and sex-matched control group. In both groups, we measured 13 endothelial biomarkers. Moreover, in the long COVID patients, we evaluated fatigue and dyspnea severity, lung diffusion capacity (DLCO), and the 6-min walk (6MWT) test as measures of functional capacity. Our results showed that markers of endothelial activation/dysfunction were higher in long COVID patients, and that soluble intracellular adhesion molecule 1 (sICAM-1) and soluble vascular adhesion molecule 1 (sVCAM-1) negatively correlated with lung diffusion and functional capacity (sICAM-1 vs. DLCO, r = -0.306, p = 0.018; vs. 6MWT, r = -0.263, p = 0.044; and sVCAM-1 vs. DLCO, r= -0.346, p = 0.008; vs. 6MWT, r = -0.504, p < 0.0001). In conclusion, evaluating endothelial biomarkers alongside clinical tests might yield more specific insights into the pathophysiological mechanisms of long COVID manifestations.

Sepsis is associated with dysregulated cortisol secretion, leading to abnormal levels of cortisol in the blood. In the early stages of the condition, cortisol levels are typically elevated due to increased secretion from the adrenal glands. However, as the disease progresses, cortisol levels may decline due to impaired adrenal function, leading to relative adrenal insufficiency. The latter is thought to be caused by a combination of factors, including impaired adrenal function, decreased production of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by the hypothalamus and pituitary gland, and increased breakdown of cortisol. The dysregulation of cortisol secretion in sepsis is thought to contribute to the pathophysiology of the disease by impairing the body's ability to mount an appropriate inflammatory response. Given the dysregulation of cortisol secretion and corticosteroid receptors in sepsis, there has been considerable interest in the use of steroids as a treatment. However, clinical trials have yielded mixed results and corticosteroid use in sepsis remains controversial. In this review, we will discuss the changes in cortisol secretion and corticosteroid receptors in critically ill patients with sepsis/septic shock. We will also make special note of COVID-19 patients, who presented a recent challenge for ICU management, and explore the scope for corticosteroid administration in both COVID-19 and non-COVID-19 septic patients., Competing Interests: The authors report that they have no conflicts of interest.

Aging negatively affects the endothelium. Endocan (ESM-1), an endothelium-derived soluble proteoglycan, participates in fundamental biological processes of endothelial cells. We aimed to examine the role of endothelial dysfunction and age in poor outcomes in critical illness. ESM-1 levels were measured in the sera of mechanically ventilated critically ill patients, including COVID-19, non-septic, and septic patients. The 3 patient cohorts were divided based on age (≥65 and <65). Critically ill COVID-19 patients had statistically higher ESM-1 levels compared to critically ill septic and non-septic patients. Only in critically ill septic patients were ESM-1 levels higher in older compared to younger patients. Finally, the age-subgrouped patients were further subdivided based on intensive care unit (ICU) outcome. ESM-1 levels were similar in COVID-19 survivors and non-survivors, irrespective of age. Interestingly, only for the younger critically ill septic patients, non-survivors had higher ESM-1 levels compared to survivors. In the non-septic survivors and non-survivors, ESM-1 levels remained unaltered in the younger patients and tended to be higher in the elderly. Even though endocan has been recognized as an important prognostic biomarker in critically ill patients with sepsis, in our patient cohort, increased age, as well as the extent of endothelial dysfunction, seemed to affect its prognostic ability.

Hypoxia is characterized as one of the main consequences of sepsis, which is recognized as the leading cause of death in intensive care unit (ICU) patients. In this study, we aimed to examine whether the expression levels of genes regulated under hypoxia could be utilized as novel biomarkers for sepsis prognosis in ICU patients. Whole blood expression levels of hypoxia-inducible factor-1α ( HIF1A ), interferon-stimulated gene 15 ( ISG15 ), hexokinase 2 ( HK2 ), lactate dehydrogenase ( LDHA ), heme oxygenase-1 ( HMOX1 ), erythropoietin ( EPO ), and the vascular endothelial growth factor A ( VEGFA ) were measured on ICU admission in 46 critically ill, initially non-septic patients. The patients were subsequently divided into two groups, based on the development of sepsis and septic shock (n = 25) or lack thereof (n = 21). HMOX1 mRNA expression was increased in patients who developed sepsis/septic shock compared to the non-septic group ( p < 0.0001). The ROC curve, multivariate logistic regression, and Kaplan-Meier analysis demonstrated that HMOX1 expression could be utilized for sepsis and septic shock development probability. Overall, our results indicate that HMOX1 mRNA levels have the potential to be a valuable predictive factor for the prognosis of sepsis and septic shock in ICU patients.

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.

Objective: The mineralocorticoid receptor (MR) has two ligands, aldosterone and cortisol. Hydroxysteroid 11-beta dehydrogenase (HSD11B) isoenzymes regulate which ligand will bind to MR. In this study we aimed to evaluate the expression of the MR and the HSD11B isozymes in peripheral polymorphonuclear cells (PMNs) in critical illness for a 13-day period. Design: Prospective study Setting: One multi-disciplinary intensive care unit (ICU) Participants: Forty-two critically ill patients Methods: Messenger RNA (mRNA) expression of MR, HSD11B1 , and HSD11B2 , aldosterone levels, and plasma renin activity (PRA) were measured in 42 patients on ICU admission and on days 4, 8, and 13. Twenty-five age and sex-matched healthy subjects were used as controls. Results: Compared to healthy controls, MR expression in critically ill patients was lower during the entire study period. HSD11B1 expression was also lower, while HSD11B2 expression was higher. In patients, PRA, aldosterone, the aldosterone:renin ratio, and cortisol remained unaltered during the study period. Conclusion: Our results suggest that, in our cohort of critically ill patients, local endogenous cortisol availability is diminished, pointing towards glucocorticoid resistance. Aldosterone probably occupies the MR, raising the possibility that PMNs might be useful to study to gain insights into MR functionality during pathological states., Competing Interests: Disclosure: The authors have not reported any financial or personal conflicts of interest related to this research., (Copyright © 2023 Marshfield Clinic Health System.)

The SARS-CoV-2 infection was previously associated with the expression of the dopamine biosynthetic enzyme L-Dopa decarboxylase (DDC). Specifically, a negative correlation was detected between DDC mRNA and SARS-CoV-2 RNA levels in in vitro infected epithelial cells and the nasopharyngeal tissue of COVID-19 patients with mild/no symptoms. However, DDC, among other genes related to both DDC expression and SARS-CoV-2-infection ( ACE2 , dACE2 , EPO ), was upregulated in these patients, possibly attributed to an orchestrated host antiviral response. Herein, by comparing DDC expression in the nasopharyngeal swab samples of severe/critical to mild COVID-19 cases, we showed a 20 mean-fold reduction, highlighting the importance of the expression of this gene as a potential marker of COVID-19 severity. Moreover, we identified an association of SARS-CoV-2 infection with the expression of key catecholamine biosynthesis/metabolism-related genes, in whole blood samples from hospitalized patients and in cultured cells. Specifically, viral infection downregulated the biosynthetic part of the dopamine pathway (reduction in DDC expression up to 7.5 mean-fold), while enhanced the catabolizing part (increase in monoamine oxidases A and B expression up to 15 and 10 mean-fold, respectively) in vivo, irrespectively of the presence of comorbidities. In accordance, dopamine levels in the sera of severe cases were reduced (up to 3.8 mean-fold). Additionally, a moderate positive correlation between DDC and MAOA mRNA levels (r = 0.527, p < 00001) in the blood was identified upon SARS-CoV-2-infection. These observations were consistent to the gene expression data from SARS-CoV-2-infected Vero E6 and A549 epithelial cells. Furthermore, L-Dopa or dopamine treatment of infected cells attenuated the virus-derived cytopathic effect by 55% and 59%, respectively. The SARS-CoV-2 mediated suppression of dopamine biosynthesis in cell culture was, at least in part, attributed to hypoxia-like conditions triggered by viral infection. These findings suggest that L-Dopa/dopamine intake may have a preventive or therapeutic value for COVID-19 patients.

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by the Shock Society.)

Introduction: Post intensive care syndrome (PICS) affects an increasing number of critical illness survivors and their families, with serious physical and psychological sequelae. Since little is known about the burden of critical illness on ICU survivor families, we conducted a prospective observational study aiming to assess this, and investigate correlations of the patients' psychometric and health-related quality of life (HRQOL) scores with family burden., Materials and Methods: Twenty-nine patients were evaluated in the presence of a family member. Participants were assessed with the use of validated scales for anxiety, depression, post-traumatic stress disorder, cognitive decline, and the family burden scale (FBS)., Results: High burden was present in 27.6% of family members. Statistically significant correlations were observed between the FBS score and trait anxiety, depression, and the physical and psychological components of HRQOL., Conclusions: Our results suggest that family burden following critical illness is common, suggesting that its assessment should be incorporated in the evaluation of PICS-family in large observational studies., Competing Interests: Conflict of interest None to declare., (© 2022 Vassiliki Mantziou, Charikleia S. Vrettou, Alice G. Vassiliou, Stylianos E. Orfanos, Anastasia Kotanidou, Ioanna Dimopoulou, published by Sciendo.)

The unprecedented scale of the current SARS-CoV-2/COVID-19 pandemic has led to an extensive-yet fragmented-assessment of its endocrine repercussions; in many reports, the endocrine aspects of COVID-19 are lumped together in intensive care unit (ICU) patients and non-ICU patients. In this brief review, we aimed to present endocrine alterations in ICU-hospitalized patients with COVID-19. There are tangible endocrine disturbances that may provide fertile ground for COVID-19, such as preexisting diabetes. Other endocrine disturbances accompany the disease and more particularly its severe forms. Up to the time of writing, no isolated robust endocrine/hormonal biomarkers for the prognosis of COVID-19 have been presented. Among those which may be easily available are admission glycemia, thyroid hormones, and maybe (OH) 25 -vitamin D3. Their overlap among patients with severe and less severe forms of COVID-19 may be considerable, so their levels may be indicative only. We have shown that insulin-like growth factor 1 may have prognostic value, but this is not a routine measurement. Possibly, as our current knowledge is expanding, the inclusion of selected routine endocrine/hormonal measurements into artificial intelligence/machine learning models may provide further information.

Aquaporin-1 (AQP1), a water channel, and the hypoxia-inducible factor 1α (HIF1A) are implicated in acute lung injury responses, modulating among others pulmonary vascular leakage. We hypothesized that the AQP1 and HIF1A systems interact, affecting mRNA, protein levels and function of AQP1 in human pulmonary microvascular endothelial cells (HPMECs) exposed to lipopolysaccharide (LPS). Moreover, the role of AQP1 in apoptosis and wound healing progression was examined. Both AQP1 mRNA and protein expression levels were higher in HPMECs exposed to LPS compared to untreated HPMECs. However, in the LPS-exposed HIF1A -silenced cells, the mRNA and protein expression levels of AQP1 remained unaltered. In the permeability experiments, a statistically significant volume increase was observed at the 360 s time-point in the LPS-exposed HPMECs, while LPS-exposed HIF1A -silenced HPMECs did not exhibit cell swelling, implying a dysfunctional AQP1. AQP1 did not seem to affect cell apoptosis yet could interfere with endothelial migration and/or proliferation. Based on our results, it seems that HIF1A silencing negatively affects AQP1 mRNA and protein expression, as well as AQP1 function, in the setting of lung injury.

The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types through its at least six G-protein-coupled LPA receptors (LPARs). Here, we investigated a possible role of the ATX/LPA axis in sepsis in an animal model of endotoxemia as well as in septic patients. Mice with 50% reduced serum ATX levels showed improved survival upon lipopolysaccharide (LPS) stimulation compared to their littermate controls. Similarly, mice bearing the inducible inactivation of ATX and presenting with >70% decreased ATX levels were even more protected against LPS-induced endotoxemia; however, no significant effects were observed upon the chronic and systemic transgenic overexpression of ATX. Moreover, the genetic deletion of LPA receptors 1 and 2 did not significantly affect the severity of the modelled disease, suggesting that alternative receptors may mediate LPA effects upon sepsis. In translation, ATX levels were found to be elevated in the sera of critically ill patients with sepsis in comparison with their baseline levels upon ICU admission. Therefore, the results indicate a role for ATX in LPS-induced sepsis and suggest possible therapeutic benefits of pharmacologically targeting ATX in severe, systemic inflammatory disorders.

Heme-oxygenase (HO)-1 is a cytoprotective enzyme with strong antioxidant and anti-apoptotic properties and previous reports have also emphasized the antiviral properties of HO-1, either directly or via induction of interferons. To investigate the potential role of HO-1 in patients with coronavirus disease 2019 (COVID-19), the present study assessed changes in HO-1 expression in whole blood and tissue samples. Upregulation of HO-1 protein was observed in lung, liver, and skin tissue independently of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presence. A significant increase of blood HO-1 mRNA levels was observed in critically ill COVID-19 patients compared to those in severe COVID-19 patients and healthy controls. This increase was accompanied by significantly elevated levels of serum ferritin and bilirubin in critically ill compared to patients with severe disease. Further grouping of patients in survivors and non-survivors revealed a significant increase of blood HO-1 mRNA levels in the later. Receiver operating characteristic (ROC) analysis for prediction of ICU admission and mortality yielded an AUC of 0.705 ( p = 0.016) and 0.789 ( p = 0.007) respectively indicating that HO-1 increase is associated with poor COVID-19 progression and outcome. The increase in HO-1 expression observed in critically ill COVID-19 patients could serve as a mechanism to counteract increased heme levels driving coagulation and thrombosis or as an induced protective mechanism.

The COVID-19 pandemic transforms the healthcare delivery models and accelerates the implementation and the adoption of telemedicine solutions at all levels of the healthcare system. Telehealth services ensure the continuity of care and treatment of both inpatients and outpatients during this pandemic, while reducing the spread of the virus through hospitals. The aim of this paper is to present an intelligent remote monitoring system with innovative data analytics features for COVID-19 patients. The i-COVID platform provides remote COVID-19 patients monitoring. The presented solution is addressed to patients with mild COVID-19 symptoms, as well as it can be used for post intensive-care monitoring. The platform offers advanced analytic capabilities using Proactive AI, to detect health condition deterioration, and automatically trigger personalized support workflows. Remote monitoring of COVID-19 patients using bio-sensors, seems to be an effective tool against the COVID-19 pandemic, as reduces the number of visits to patient screening centres and hospital admissions.

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.

Background: Low testosterone (mainly total testosterone [TTe]) has been noted in patients with COVID-19. Calculated free testosterone (FTe) and bioavailable testosterone (BavTe) may reflect more accurately this hormone's levels. In this study, we sought to assess TTe, FTe as well as BavTe in male patients with COVID-19., Methods: Sera were collected upon admission from 65 men (10 in the intensive care units [ICU] and 55 in the wards) with polymerase chain reaction - proven COVID-19. A group of age-matched COVID-19-negative men (N.=29) hospitalized in general medical wards served as controls. Age, Body Mass Index (BMI) and 28-day mortality were noted. Measurements included TTe, sex-hormone binding globulin, albumin (the latter two for calculating FTe and BavTe) and laboratory markers of inflammation (white blood cell count [WBC], D-Dimers [D-D], lactate dehydrogenase [LDH], ferritin [Fer] and C-reactive protein [CRP])., Results: Profoundly low TTe, FTe and BavTe were noted in most patients, and were associated with disease severity/outcome (being the lowest in COVID-19 patients in the ICU and overall being lower in non-survivors; analysis of covariance P<0.05). Pearson's correlations for logTe, logFTe or logBavTe versus WBC, D-D, LDH, Ferr or CRP were negative, ranging from -0.403 to -0.293 (P=0.009 to 0.014)., Conclusions: TTe, FTe and BavTe are prone to be low in patients with COVID-19, are negatively associated with disease severity and may be considered to have prognostic value.

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.

Current achievements in medical science and technological advancements in intensive care medicine have allowed better support of critically ill patients in intensive care units (ICUs) and have increased survival probability. Post-intensive care syndrome (PICS) is a relatively new term introduced almost 10 years ago, defined as "new or worsening impairments in physical, cognitive, or mental health status arising after critical illness and persisting beyond acute care hospitalization". A significant percentage of critically ill patients suffer from PICS for a prolonged period of time, with physical problems being the most common. The exact prevalence of PICS is unknown, and many risk factors have been described well. Coronavirus disease 2019 (COVID-19) survivors seem to be at especially high risk for developing PICS. The families of ICU survivors can also be affected as a response to the stress suffered during the critical illness of their kin. This separate entity is described as PICS family (PICS-F). A multidisciplinary approach is warranted for the treatment of PICS, involving healthcare professionals, clinicians, and scientists from different areas. Improving outcomes is both challenging and imperative for the critical care community. The review of the relevant literature and the study of the physical, cognitive, and mental sequelae could lead to the prevention and timely management of PICS and the subsequent improvement of the quality of life for ICU survivors.

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., (© 2021. The Author(s).)

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., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Acute kidney injury (AKI) is one of the most common complications in critically ill patients. In recent years, studies have focused on exploring new biomarkers for the early diagnosis and prognosis of AKI. The aim of this study was to investigate serum prognostic biomarkers (neutrophil gelatinase-associated lipocalin, NGAL, and creatinine) of AKI in critically ill patients. The study included 266 critically ill, initially nonseptic, patients admitted to a multidisciplinary ICU. Serum levels of NGAL and creatinine were measured at ICU admission. ROC curves were generated to estimate the prognostic value of the biomarkers, while a logistic regression analysis was performed to assess their association with an increased AKI risk. Patients were divided in two groups based on the development ( n = 98) or not ( n = 168) of AKI during their ICU stay. Serum NGAL levels at ICU admission were significantly higher in those who subsequently developed AKI compared to those who did not ( p < 0.0001). NGAL was shown to be more accurate in predicting AKI development than creatinine; furthermore, NGAL levels were associated with an increased risk of AKI development (1.005 (1.002-1.008), p < 0.0001). In the present study, we were able to demonstrate that increased serum NGAL levels at ICU admission might be predictive of AKI development during ICU hospitalization. Further studies are needed to support NGAL as a prognostic marker of acute kidney injury.

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

The hypothalamus-pituitary-adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged sword; whereas inflammation that is timely and of appropriate magnitude is beneficial, exuberant systemic inflammation incites tissue damage with potentially devastating consequences. Apart from its beneficial cardiovascular and metabolic effects, cortisol exerts a significant immunoregulatory role, a major attribute being that it restrains the excessive inflammatory reaction, thereby preventing unwanted tissue damage. In this review, we will discuss the role of the HPA axis in the normal stress response and in critical illness, especially in critically ill patients with coronavirus disease 2019 (COVID-19). Finally, a chapter will be dedicated to the findings from clinical studies in critical illness and COVID-19 on the expression of the mediator of glucocorticoid actions, the glucocorticoid receptor (GCR).

A bidirectional negative relationship between Hepatitis C virus (HCV) replication and gene expression of the catecholamine biosynthetic enzyme L-Dopa decarboxylase (DDC) was previously shown in the liver and attributed at least to an association of DDC with phosphatidylinositol 3-kinase (PI3K). Here, we report that the biosynthesis and uptake of catecholamines restrict HCV replication in hepatocytes, while HCV has developed ways to reduce catecholamine production. By employing gene silencing, chemical inhibition or induction of the catecholamine biosynthetic and metabolic enzymes and transporters, and by applying the substrates or the products of the respective enzymes, we unravel the role of the different steps of the pathway in viral infection. We also provide evidence that the effect of catecholamines on HCV is strongly related with oxidative stress that is generated by their autoxidation in the cytosol, while antioxidants or treatments that lower cytosolic catecholamine levels positively affect the virus. To counteract the effect of catecholamines, HCV, apart from the already reported effects on DDC, causes the down-regulation of tyrosine hydroxylase that encodes the rate-limiting enzyme of catecholamine biosynthesis and suppresses dopamine beta-hydroxylase mRNA and protein amounts, while increasing the catecholamine degradation enzyme monoamine oxidase. Moreover, the NS4B viral protein is implicated in the effect of HCV on the ratio of the ~50 kDa DDC monomer and a ~120 kDa DDC complex, while the NS5A protein has a negative effect on total DDC protein levels.

Autotaxin (ATX; ENPP2 ) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signaling in pulmonary injury, inflammation, and fibrosis. Here, increased ENPP2 mRNA levels were detected in immune cells from nasopharyngeal swab samples of COVID-19 patients, and increased ATX serum levels were found in severe COVID-19 patients. ATX serum levels correlated with the corresponding increased serum levels of IL-6 and endothelial damage biomarkers, suggesting an interplay of the ATX/LPA axis with hyperinflammation and the associated vascular dysfunction in COVID-19. Accordingly, dexamethasone (Dex) treatment of mechanically ventilated patients reduced ATX levels, as shown in two independent cohorts, indicating that the therapeutic benefits of Dex include the suppression of ATX. Moreover, large scale analysis of multiple single cell RNA sequencing datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, which exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, suggesting that its pharmacological targeting might represent an additional therapeutic option, both during and after hospitalization.

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.

25-hydroxyvitamin D [25(OH)D] is an important immunomodulator, whose deficiency may aggravate the incidence and outcome of infectious complications in patients admitted to the intensive care unit. The most recognized extra-skeletal action of vitamin D is the regulation of immune function. Host defense against intracellular pathogens depends upon both innate and adaptive immunity. It has been suggested that vitamin D regulates the pro-inflammatory endothelial response to lipopolysaccharide, rendering it a role in the sepsis cascade. Recent studies have indicated that vitamin D deficiency may be associated with worse outcomes in patients with coronavirus disease 2019 (COVID-19), such as more severe disease and higher mortality rates. To this end, clinical trials with vitamin D supplementation are being carried out in an effort to improve COVID-19 outcomes. In this review, we will discuss the role of vitamin D in the immune response, and more specifically its effect on immune cells. Subsequently, we will provide an overview of the studies that have investigated the predictive value of vitamin D in critical illness outcomes, and its therapeutic value as a supplement in critically ill patients. Finally, the emerging role of vitamin D deficiency in COVID-19 infection risk, and worse outcomes will be discussed., Competing Interests: There is no conflict of interest to disclose., (© 2021 The Authors.)

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.

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.

The glucocorticoid receptor (GCR) and the mineralocorticoid receptor (MR) are members of the steroid receptor superfamily of hormone-dependent transcription factors. The receptors are structurally and functionally related. They are localized in the cytosol and translocate into the nucleus after ligand binding. GCRs and MRs can be co-expressed within the same cell, and it is believed that the balance in GCR and MR expression is crucial for homeostasis and plays a key role in normal adaptation. In critical illness, the hypothalamic-pituitary-adrenal axis is activated, and as a consequence, serum cortisol concentrations are high. However, a number of patients exhibit relatively low cortisol levels for the degree of illness severity. Glucocorticoid (GC) actions are facilitated by GCR, whose dysfunction leads to GC tissue resistance. The MR is unique in this family in that it binds to both aldosterone and cortisol. Endogenous GCs play a critical role in controlling inflammatory responses in critical illness. Intracellular GC concentrations can differ greatly from blood levels due to the action of the two 11β-hydroxysteroid dehydrogenase isozymes, type 1 and type 2. 11β-hydroxysteroid dehydrogenases interconvert endogenous active cortisol and intrinsically inert cortisone. The degree of expression of the two isozymes has the potential to dramatically influence local GC availability within cells and tissues. In this review, we will explore the clinical studies that aimed to elucidate the role of MR and GCR expression in the inflammatory response seen in critical illness., Competing Interests: Conflict-of-interest statement: There is no conflict of interest associated with the senior author or any other co-author who contributed his/her efforts in this manuscript., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

The physical and psychological consequences of critical illness may affect intensive care unit survivors for up to five years, and hence, health-related quality of life has emerged as an important measure of outcome in this population. We aimed at investigating the quality of life, the presence of anxiety and depression symptoms, and the correlations of clinical and psychological parameters with the quality of life scores in survivors of critical illness one year after discharge from intensive care. Widely used scales that have been validated for the Greek population were used. One thousand two hundred and seventy (1270) patients were assessed for eligibility. Inclusion criteria were age between 18 and 68 years and the presence of critical illness requiring endotracheal intubation and mechanical ventilation for more than three days. One hundred and four (104) patients were included in the final analysis; forty-nine age and sex-matched healthy volunteers were included for comparison. One year following intensive care unit discharge, survivors of critical illness had impaired quality of life scores, as measured with the WHOQOL-Bref, compared to healthy subjects ( p < 0.001 for the physical and psychological domains, and p = 0.006 for the domain of social relationships). In addition, we found that quality of life scores were significantly lower in patients with comorbidities ( p < 0.01), and correlated with the duration of ICU stay (r = -0.19, p = 0.04) and with the presence of symptoms suggestive of depression (r = -0.66, p < 0.0001) and post-traumatic stress disorder (r = -0.61, p < 0.0001). Approximately one-third of our patients scored high in the CES-D scale for depression, while the majority of them scored high in the STAI scale for anxiety symptoms.

L-Dopa decarboxylase (DDC) is the most significantly co-expressed gene with ACE2, which encodes for the SARS-CoV-2 receptor angiotensin-converting enzyme 2 and the interferon-inducible truncated isoform dACE2. Our group previously showed the importance of DDC in viral infections. We hereby aimed to investigate DDC expression in COVID-19 patients and cultured SARS-CoV-2-infected cells, also in association with ACE2 and dACE2. We concurrently evaluated the expression of the viral infection- and interferon-stimulated gene ISG56 and the immune-modulatory, hypoxia-regulated gene EPO. Viral load and mRNA levels of DDC, ACE2, dACE2, ISG56 and EPO were quantified by RT-qPCR in nasopharyngeal swab samples from COVID-19 patients, showing no or mild symptoms, and from non-infected individuals. Samples from influenza-infected patients were analyzed in comparison. SARS-CoV-2-mediated effects in host gene expression were validated in cultured virus-permissive epithelial cells. We found substantially higher gene expression of DDC in COVID-19 patients (7.6-fold; p = 1.2e-13) but not in influenza-infected ones, compared to non-infected subjects. dACE2 was more elevated (2.9-fold; p = 1.02e-16) than ACE2 (1.7-fold; p = 0.0005) in SARS-CoV-2-infected individuals. ISG56 (2.5-fold; p = 3.01e-6) and EPO (2.6-fold; p = 2.1e-13) were also increased. Detected differences were not attributed to enrichment of specific cell populations in nasopharyngeal tissue. While SARS-CoV-2 virus load was positively associated with ACE2 expression (r≥0.8, p<0.001), it negatively correlated with DDC, dACE2 (r≤-0.7, p<0.001) and EPO (r≤-0.5, p<0.05). Moreover, a statistically significant correlation between DDC and dACE2 expression was observed in nasopharyngeal swab and whole blood samples of both COVID-19 and non-infected individuals (r≥0.7). In VeroE6 cells, SARS-CoV-2 negatively affected DDC, ACE2, dACE2 and EPO mRNA levels, and induced cell death, while ISG56 was enhanced at early hours post-infection. Thus, the regulation of DDC, dACE2 and EPO expression in the SARS-CoV-2-infected nasopharyngeal tissue is possibly related with an orchestrated antiviral response of the infected host as the virus suppresses these genes to favor its propagation., Competing Interests: The authors have declared that no competing interests exist.

Objective: Following the evolution of COVID-19 pandemic, reports pointed on a high prevalence of thyroiditis-related thyrotoxicosis. Interpretation of thyroid tests during illness, however, is hampered by changes occurring in the context of non-thyroidal illness syndrome (NTIS). In order to elucidate these findings, we studied thyroid function in carefully selected cohorts of COVID-19 positive and negative patients., Design: Cohort observational study., Methods: We measured TSH, FT4, T3 within 24 h of admission in 196 patients without thyroid disease and/or confounding medications. In this study, 102 patients were SARS-CoV-2 positive; 41 admitted in the ICU, 46 in the ward and 15 outpatients. Controls consisted of 94 SARS-CoV-2 negative patients; 39 in the ICU and 55 in the ward. We designated the thyroid hormone patterns as consistent with NTIS, thyrotoxicosis and hypothyroidism., Results: A NTIS pattern was encountered in 60% of ICU and 36% of ward patients, with similar frequencies between SARS-CoV-2 positive and negative patients (46.0% vs 46.8%, P = NS). A thyrotoxicosis pattern was observed in 14.6% SARS-CoV-2 ICU patients vs 7.7% in ICU negative (P = NS) and, overall in 8.8% of SARS-CoV-2 positive vs 7.4% of negative patients. In these patients, thyroglobulin levels were similar to those with normal thyroid function or NTIS. The hypothyroidism pattern was rare., Conclusions: NTIS pattern is common and relates to the severity of disease rather than SARS-CoV-2 infection. A thyrotoxicosis pattern is less frequently observed with similar frequency between patients with and without COVID-19. It is suggested that thyroid hormone monitoring in COVID-19 should not differ from other critically ill patients.

Objective: We aimed to measure insulin-like growth factor 1 (IGF1) and growth hormone (GH) in critically and non-critically ill patients with Covid-19 and assess them vis-a-vis clinical and laboratory parameters and prognostic tools., Subjects and Methods: We included patients who were admitted to the wards or the ICU of the largest Covid-19 referral hospital in Greece; patients with non-Covid-19 pneumonia served as controls. Apart from the routine laboratory work-up for Covid-19 we measured GH and IGF1 (and calculated normalized IGF-1 values as standard deviation scores; SDS), after blood sampling upon admission to the wards or the ICU., Results: We studied 209 critically and non-critically ill patients with Covid-19 and 39 control patients. Patients with Covid-19 who were ICU non-survivors were older and presented with a worse hematological/biochemical profile (including white blood cell count, troponin, glucose, aminotransferases and lactate dehydrogenase) compared to ICU survivors or Covid-19 survivors in the wards. Overall, IGF-1 SDS was higher in Covid-19 survivors compared to non-survivors (-0.96 ± 1.89 vs -2.05 ± 2.48, respectively, p=0.030). No significant differences were noted in GH between the groups. Nevertheless, in critically ill patients with Covid-19, the prognostic value of IGF-1 (raw data), IGF-1 (SDS) and GH for survival/non-survival was on a par with that of APACHE II and SOFA (with a marginal difference between GH and SOFA)., Conclusion: In conclusion, our findings suggest that there might be an association between low IGF1 (and possibly GH) and poor outcome in patients with Covid-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ilias, Diamantopoulos, Botoula, Athanasiou, Zacharis, Tsipilis, Jahaj, Vassiliou, Vassiliadi, Kotanidou, Tsagarakis and Dimopoulou.)

Background: The increased oxidative stress resulting from the inflammatory responses in sepsis initiates changes in mitochondrial function which may result in organ damage, the most common cause of death in the intensive care unit (ICU). Deficiency of coenzyme Q10 (CoQ10), a key cofactor in the mitochondrial respiratory chain, could potentially disturb mitochondrial bioenergetics and oxidative stress, and may serve as a biomarker of mitochondrial dysfunction. Hence, we aimed to investigate in initially non-septic patients whether CoQ10 levels are decreased in sepsis and septic shock compared to ICU admission, and to evaluate its associations with severity scores, inflammatory biomarkers, and ICU outcomes., Methods: Observational retrospective analysis on 86 mechanically-ventilated, initially non-septic, ICU patients. CoQ10 was sequentially measured on ICU admission, sepsis, septic shock or at ICU discharge. CoQ10 was additionally measured in 25 healthy controls. Inflammatory biomarkers were determined at baseline and sepsis., Results: On admission, ICU patients who developed sepsis had lower CoQ10 levels compared to healthy controls (0.89 vs. 1.04 µg/ml, p < 0.05), while at sepsis and septic shock CoQ10 levels decreased further (0.63 µg/ml; p < 0.001 and 0.42 µg/ml; p < 0.0001, respectively, from admission). In ICU patients who did not develop sepsis, admission CoQ10 levels were also lower than healthy subjects (0.81 µg/ml; p < 0.001) and were maintained at the same levels until discharge., Conclusion: CoQ10 levels in critically-ill patients are low on ICU admission compared to healthy controls and exhibit a further decrease in sepsis and septic shock. These results suggest that sepsis severity leads to CoQ10 depletion.