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

Abstract

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.

Association between volume of lung damage and endoplasmic reticulum stress expression among severe COVID-19 ICU patients

“…The same study suggested that the plasma level of GRP78 among COVID-19 patients was associated with organ failure and severity of infection while we did not find an association between organ failure and GRP78 plasma level ( 15 ). It appears in agreement with our previous results in this cohort, which found no association between GRP78 plasma level at admission and clinical worsening in ICU ( 17 ). However, our patients had much higher plasma levels of GRP78 than the vast majority of this previous cohort, suggesting that this association could be influenced by the infection severity.…”

“…Les facteurs de risque de développer des formes graves associées à une atteinte pulmonaire importante commencent à être bien référencés dans la littérature médicale. On retrouve fréquemment : l'âge avancé, le genre masculin, des antécédents de diabète, d'obésité et d'hypertension artérielle, les pathologies chroniques, l'immunodépression, le score SOFA (Sequential Organ Failure Assessment score), une lymphopénie, des taux élevés d'IL-6, de forme soluble de récepteur aux produits de glycation avancée (SRAGE), de polynucléaires neutrophiles, de protéine C-réactive (CRP), de D-dimères, de plaquettes, de créatinine et d'enzymes hépatiques (10)(11)(12)(13)(14)(15). En outre, des études retrouvent un lien entre l'état inflammatoire et la sévérité scanographique chez des patients atteints de formes graves de COVID-19 (14,16).…”

“…Some data suggested that GRP78 acts as a pro-viral protein during SARS-CoV-2 infection ( 16 ). However, we recently found no association between GRP78 plasma level and clinical worsening from a “severe” toward a “critical” condition in ICU patients ( 17 ).…”

Association between volume of lung damage and endoplasmic reticulum stress expression among severe COVID-19 ICU patients

“…The same study suggested that the plasma level of GRP78 among COVID-19 patients was associated with organ failure and severity of infection while we did not nd an association between organ failure and GRP78 plasma levels (15). It appears in agreement with our previous results in this cohort, which found no association between GRP78 plasma levels at admission and clinical worsening in ICU (17).However, our patients had much higher plasma levels of GRP78 than the vast majority of this previous cohort, suggesting that this association could be in uenced by the infection severity. As the GRP78 plasma level at admission was higher in deceased patients' plasma than in survivors', our results are however compatible with the link between ERS expression and short-term prognosis among COVID-19 patients.…”

“…Some data suggested that GRP78 acts as a pro-viral protein during SARS-CoV-2 infection (16). However, we recently found no association between GRP78 plasma levels and clinical worsening from a "severe" towards a "critical" condition in ICU patients (17).…”