Glucocorticoid receptor response and glucocorticoid-induced leucine zipper expression in neutrophils of critically ill patients with traumatic and non-traumatic brain injury.

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.

Adrenal function in relation to cytokines and outcome in non-critically ill patients with COVID-19.

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.

Accuracy of T2 magnetic resonance assays as point-of-care methods in the intensive care unit.

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.

Ghrelin alterations during experimental and human sepsis.

BACKGROUND: Ghrelin is a hormone mainly produced by cells of the gastric mucosa, which has been shown to possess anti-inflammatory and immunomodulatory properties. The objective of the study was to investigate ghrelin levels during sepsis, as well as in an experimental sepsis model. METHODS: All consecutive admissions to the ICU of a tertiary hospital in Athens, Greece were screened for eligibility during the study. Thirty four non-septic patients upon ICU admission who subsequently developed sepsis were enrolled. Clinical data and scores were recorded, and blood samples were obtained at baseline (upon ICU admission), and at sepsis development. Total and active ghrelin, leptin, and cytokines were measured. Moreover, lipopolysaccharide (LPS) was administered to mice in order to induce endotoxemia and at specified time points, blood and tissue samples were collected. RESULTS: In patients, serum total and active ghrelin concentrations were significantly elevated in sepsis compared to baseline (553.8 ±â€¯213.4 vs 193.5 ±â€¯123.2, p < 0.001; 254.3 ±â€¯70.6 vs 56.49 ±â€¯16.3, p < 0.001). Active ghrelin levels at the sepsis stage were inversely correlated with SOFA score and length of stay in the ICU (p = 0.023 and p = 0.027 respectively). In the mouse endotoxemia model ghrelin levels were elevated following LPS treatment, and the same trend was observed for leptin, TNFα and IL-6. Ghrelin administration managed to reduce IL-6 levels in mouse serum and in BALF. Pulmonary expression of ghrelin and its receptor GHSR1a was found decreased in LPS-treated mice. CONCLUSIONS: In a well-defined cohort of ICU patients, we have demonstrated that active and total ghrelin increase in sepsis. The same is true for the experimental sepsis model used in the study. The inverse correlation of active ghrelin levels with SOFA score and length of ICU stay among septic patients is indicative of a potential protective role of active ghrelin during the septic process.

Elevated soluble endothelial protein C receptor levels at ICU admission are associated with sepsis development.

BACKGROUND: 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 the septic process is under investigation. In this study, we assessed the role of sEPCR levels as an early indicator of sepsis development. METHODS: Plasma sEPCR levels were measured in 59 critically-ill non-septic patients at the time of admission to the intensive care unit (ICU). Multiple logistic regression analysis was performed to identify potential risk factors for sepsis development and Cox-Regression models were fitted for variables to examine their relationship with time to sepsis development. RESULTS: Thirty patients subsequently developed sepsis and 29 did not. At ICU admission, sequential organ failure assessment (SOFA) scores were significantly higher in the subsequent sepsis group as compared to the non sepsis group (mean ± SD: 6.4±2.7 and 5±2.3, respectively, P=0.037). sEPCR levels were also higher in the patients who subsequently developed sepsis compared to the patients who did not (median and interquartile range: 173.4 [104.5-223.5] ng/mL vs. 98.3 [69.8-147.7] ng/mL, respectively; P=0.004). Cox regression analysis identified sEPCR as the only parameter related to sepsis development with time (relative risk: 1.078, 95% confidence interval: 1.016-1.144, by 10 units; P=0.013). CONCLUSION: Upon ICU admission, sEPCR levels in initially non-septic critically-ill patients appear elevated in the subjects who will subsequently become septic.