SAT-430 Deficiency of Triantennary Asn347 Site Glycoforms of Corticosteroid binding globulin (CBG) is Associated with Septic Shock Mortality and Morbidity

Abstract Disclosure: J.H. Lee: None. Z. Sumer-Bayraktar: None. R. Rushworth: None. M. Nenke: None. M. Thaysen-Andersen: None. E.J. Meyer: None. D.J. Torpy: None. Low serum corticosteroid binding globulin (CBG) concentration (<200 nmol/L) is independently associated with 3-fold greater intensive care unit (ICU) mortality in septic shock patients. CBG deficient mice have greater mortality on sepsis simulation via lipopolysaccharide (LPS) administration; restoration of CBG reduced mortality to that of controls. CBG is variably glycosylated at six sites, and Asn347 site glycosylation affects susceptibility to neutrophil elastase (NE) cleavage. NE cleavage of CBG results in irreversible reduction in cortisol binding affinity by 90%. We hypothesized that CBG Asn347 glycosylation is associated with septic shock clinical outcome, possibly by affecting tissue cortisol delivery. Asn347 site glycosylation profiling of CBG was performed by mass spectrometry following CBG immunoprecipitation from serum of 135 septic shock patients taken on day 1 and last day (up to day 7) of ICU admission. This was correlated with clinical outcome data including ICU mortality, requirement for mechanical ventilation, inotropes and renal replacement therapy, and Sequential Organ Failure Assessment (SOFA) score, a measure of sepsis severity. Mean serum triantennary trisialylated (TS3) Asn347 CBG glycoform concentrations were lower in septic shock non-survivors compared to survivors (29.74 vs 45.16 nmol/L, P=0.007). Lower triantennary trisialylated core-fucosylated (TS3F) glycoform concentrations were associated with mechanical ventilation requirement (37.9 vs 52.6 nmol/L, P=0.002), and higher total SOFA score (r= -0.335, P <0.001), indicative of greater illness severity. No clinical associations were seen with other CBG Asn347 glycoforms. Throughout ICU admission, concentrations of TS3 and TS3F CBG Asn347 glycoforms showed the most pronounced reduction of 38.8% (42.3 vs 25.9 nmol/L, P<0.001) and 22.9% (44.2 vs 34.1 nmol/L, P=0.002), respectively, compared to 13.2% reduction in BS2 (101.8 vs 88.4 nmol/L, P=0.03), and no change in BS2F (22.4 vs 22.4 nmol/L, P=0.99). Low concentrations of CBG Asn347 TS3 and TS3F glycoforms are associated with mortality and morbidity in septic shock, respectively. Hence, the association between low total CBG and septic shock mortality reported previously seem to be attributable to the depletion of the TS3/TS3F Asn347 CBG glycoforms, specifically. This has significant therapeutic implications in considering CBG administration as treatment for septic shock. Presentation: Saturday, July 12, 2025