High levels of soluble RAGE are associated with a greater risk of mortality in COVID-19 patients treated with dexamethasone.

Blood levels of the soluble receptor for advanced glycation end-products (sRAGE) are acutely elevated during the host inflammatory response to infection and predict mortality in COVID-19. However, the prognostic performance of this biomarker in the context of treatments to reduce inflammation is unclear. In this study we investigated the association between sRAGE and mortality in dexamethasone-treated COVID-19 patients. We studied 89 SARS-CoV-2 positive subjects and 22 controls attending the emergency department of a University Teaching Hospital during the second wave of COVID-19 and measured sRAGE at admission. In positive individuals sRAGE increased with disease severity and correlated with the National Early Warning Score 2 (Pearson's r = 0.56, p < 0.001). Fourteen out of 72 patients treated with dexamethasone died during 28 days of follow-up. Survival rates were significantly lower in patients with high sRAGE (> 3532 pg/mL) than in those with low sRAGE (p = 0.01). Higher sRAGE levels were associated with an increased risk of death after adjustment for relevant covariates. In contrast, IL-6 did not predict mortality in these patients. These results demonstrate that sRAGE remains an independent predictor of mortality among COVID-19 patients treated with dexamethasone. Determination of sRAGE could be useful for the clinical management of this patient population.

Soluble RAGE as a Prognostic Marker of Worsening in Patients Admitted to the ICU for COVID-19 Pneumonia: A Prospective Cohort Study.

BACKGROUND: The different waves of SARS-CoV-2 infection have strained hospital resources and, notably, intensive care units (ICUs). Identifying patients at risk of developing a critical condition is essential to correctly refer patients to the appropriate structure and to spare limited resources. The soluble form of RAGE (sRAGE), the endoplasmic stress response and its surrogates, GRP78 and VEGF-A, may be interesting markers. METHODS: This was a prospective monocenter cohort study of adult patients admitted to the ICU for severe COVID-19 pneumonia. The plasma levels of sRAGE, GRP78 and VEGF-A were measured within the first 24 h. Patients were classified as critical if they further needed vasopressor therapy, renal replacement therapy, or invasive mechanical ventilation, or died during their ICU stay, and were otherwise classified as not critical. RESULTS: A total of 98 patients were included and 39 developed a critical condition. Critical patients presented higher sRAGE (626 [450-1043] vs. 227 [137-404] pg/mL, p < 0.0001), interleukin-6 (43 [15-112] vs. 11 [5-20] pg/mL, p < 0.0001), troponin T (17 [9-39] vs. 10 [6-18] pg/mL, p = 0.003) and NT-pro-BNP (321 [118-446] vs. 169 [63-366] pg/mL, p = 0.009) plasma levels. No difference was observed for VEGF-A and GRP78. The variables independently associated with worsening in the ICU were sRAGE (1.03 [1.01-1.05] per 10 pg/mL) and age (1.7 [1.2-2.4] per 5 years). An sRAGE value of 449.5 pg/mL predicted worsening with a sensitivity of 77% and a specificity of 80%. CONCLUSION: sRAGE may allow the identification of patients at risk of developing a critical form of COVID-19 pneumonia, and thus may be useful to correctly refer patients to the appropriate structure of care.

Increased ACE2, sRAGE, and immune activation, but lowered calcium and magnesium in COVID-19.

BACKGROUND: The characterization of new biomarkers that could help to externally validate the diagnosis of COVID-19 and to optimize treatments is extremely important. Many studies established changes in immune-inflammatory and antibody levels, but few studies measured the soluble receptor for advanced glycation end product (sRAGE), angiotensin-converting enzyme 2 (ACE2), calcium and magnesium in COVID-19. OBJECTIVE: To evaluate serum advanced glycation end-product receptor (sRAGE) and angiotensin converting enzyme (ACE)2 and peripheral oxygen saturation (SpO2) and chest CT scan abnormalities (CCTA) in COVID-19. METHODS: sRAGE, ACE2, interleukin (IL)-6, IL-10, C-reactive protein (CRP), calcium, magnesium, and albumin were measured in 60 COVID-19 patients and 30 healthy controls. RESULTS: COVID-19 is characterized by significantly increased IL-6, CRP, IL-10, sRAGE, ACE2, and lowered SpO2, albumin, magnesium and calcium. COVID-19 with CCTAs showed lower SpO2 and albumin. SpO2 was significantly inversely correlated with IL-6, IL-10, CRP, sRAGE, and ACE2, and positively with albumin, magnesium and calcium. Neural networks showed that a combination of calcium, IL-6, CRP, and sRAGE yielded an accuracy of 100% in detecting COVID-19 patients with calcium being the most important predicter followed by IL-6, and CRP. Patients with positive IgG results showed a significant elevation in the serum level of IL-6, sRAGE, and ACE2 compared to the negatively IgG patient subgroup. CONCLUSION: The results show that immune-inflammatory and RAGE pathways biomarkers may be used as external validating criterion for the diagnosis COVID-19. Those pathways coupled with lowered SpO2, calcium and magnesium are drug targets that may help to reduce the consequences of COVID-19.

Association of soluble receptor for advanced glycation end-products (sRAGE) serum on COVID-19 severity: A cross-sectional study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a new health problem discovered in 2019 thus requires biomarkers that can detect early tissue damage. Soluble receptor for advanced glycation end-products (sRAGE) is a biomarker that can be used to identify early lung damage. OBJECTIVE: Analyzing the association of serum sRAGE on COVID-19 severity. METHODS: This study employed a cross-sectional design with a consecutive sampling method. It was conducted from May 2020-October 2021. The number of participants in this study was 145 participants which were divided into 2 groups (non-severe = 47 and severe = 98). Association of sRAGE serum on COVID-19 severity was analyzed using the chi-square test, Fisher's exact test, independence t-test, Mann Withney test, and Spearman's rank test with p-value <0.05. RESULTS: The results of blood analysis showed several blood components such as leukocytes (9896.51 ± 4949.64/µL; z = 2.431; p = 0.015), lymphocytes (13.55 ± 8.48%; z = 2.256; p = 0.024), neutrophils (78.91 ± 10.50%; z = 2.464; p = 0.014), procalcitonin (0.92 ± 3.22 ng/mL; z = 3.323; p = 0.001), CRP (8.59 ± 7.62 mg/L; z = 2.114; p = 0.034), D-dimer (4360.29 ± 7797.81 ng/mL; z = 2.186; p = 0.029), and fibrinogen (474.58 ± 168.90 mg/dL; t = 0.383; p = 0.703). There was a significant comparison in serum sRAGE values in the non-severe group (0.78 [0.63-1.00] ng/mL) and severe group (1.47 [0.97-2.25] ng/mL; r = 7.154; p <0.001). There was a significant association between serum sRAGE and COVID-19 severity (r = 0.598; p <0.001). The cut-off value for serum sRAGE between the severe and non-severe groups was 0.985 ng/mL. This study obtained sensitivity of 73.5%, specificity of 74.5% OR 8.077 and AUC 0.868 95% CI. CONCLUSION: There is a significant association between serum sRAGE and COVID-19 severity and there is also a significant difference in serum sRAGE in the two groups.

Soluble Receptor for Advanced Glycation End Products and Its Forms in COVID-19 Patients with and without Diabetes Mellitus: A Pilot Study on Their Role as Disease Biomarkers.

The receptor for advanced glycation end products (RAGE), a well-known player of diabetes mellitus (DM)-related morbidities, was supposed to be involved in coronavirus disease-19 (COVID-19), but no data exist about COVID-19, DM, and the soluble RAGE (sRAGE) forms. We quantified total sRAGE and its forms, the endogenously secretory esRAGE and the membrane-cleaved cRAGE, in COVID-19 patients with and without DM and in healthy individuals to explore how COVID-19 may affect these molecules and their potential role as biomarkers. Circulating sRAGE and esRAGE were quantified by enzyme-linked-immunosorbent assays. cRAGE was obtained by subtracting esRAGE from total sRAGE. sRAGE, esRAGE, cRAGE, and the cRAGE/esRAGE ratio did not differ between DM and non-DM patients and had the same trend when compared to healthy individuals. Levels of total sRAGE, cRAGE, and cRAGE/esRAGE ratio were upregulated, while esRAGE was downregulated. The lack of difference between DM and non-DM COVID-19 patients in the levels of sRAGE and its forms supports the hypothesis that in COVID-19 the RAGE system is modulated regardless of glycemic control. Identifying how sRAGE and its forms associate to COVID-19 prognosis and the potential of RAGE as a therapeutic target to control inflammatory burden seem of relevance to help treatment of COVID-19.