Preserved CETP Activity and Early Serum Amyloid A are Associated with Improved Outcomes in Sepsis-Associated ARDS
Background: Sepsis is a life-threatening condition characterized by organ dysfunction resulting from a dysregulated host response to infection. It is a leading cause of in-hospital mortality. The multicenter Acute Respiratory Distress Syndrome Network Statins for Acutely Injured Lungs from Sepsis (ARDSNet-SAILS) trial found that rosuvastatin (RS) did not improve clinical outcomes in patients with sepsis-associated ARDS and may increase hepatic and renal dysfunction. We evaluated associations of plasma cholesterol ester transfer protein (CETP) activity and Serum Amyloid A (SAA) levels with survival and clinical outcomes using plasma samples and clinical data from ARDSNet-SAILS trial. Methods: This secondary analysis included clinical data and plasma samples from 471 ARDSNet-SAILS participants, randomized to placebo (PL) or RS. Plasma CETP activities and SAA levels were measured at enrollment (Day 0, n=466) and Days 3 (n=425) and 6 (n=342). Treatment effects were assessed using linear mixed models, and associations with survival and outcomes using Cox, linear, beta-binomial, and zero-inflated negative binomial regression models. Results: CETP activities were significantly higher in the survivors compared to non-survivors on days 0, 3, and 6 of analysis, in both the treatment groups (p<0.01). Higher Day 0 and Day 3 CETP activities in PL patients independently predicted improved survival, with every 3-unit increase in activity associated with 18 to 19% lower mortality risk. In the RS treatment group, higher CETP at Day 0, Day 3, and Day 6 was significantly associated with reduced hazard of mortality (p=0.039, 0.005, and 0.022, and hazard ratios = 0.87, 0.82, and 0.80, respectively, for Days 0, 3, and 6). Higher CETP values on Days 3 and 6 were also significantly negatively associated with APACHE score and positively associated with increased renal dysfunction-free days (p=0.001). Plasma SAA levels decreased significantly over time in both treatment groups (p<0.0001). In the PL group, higher plasma SAA levels were associated with a lower hazard of mortality. Accordingly, survivors had significantly higher plasma SAA levels than non-survivors at Day 0 (p=0.005). Higher SAA levels at Days 0 and 3 were also inversely correlated with APACHE scores, while Day 0 SAA levels were positively associated with overall organ dysfunction-free days (p=0.002). In contrast, in the RS group, higher plasma SAA levels were associated with an increased hazard of mortality, reaching statistical significance at Day 6 (p<0.01). Despite this, higher SAA levels in the RS group were positively associated with renal dysfunction-free days (Day 3, p=0.004; Day 6, p=0.006), hepatic dysfunction-free days (Days 0, 3, and 6; all p[≤]0.001), and overall organ dysfunction-free days (Day 0, p=0.017; Days 3 and 6, both p<0.001). Analysis of SAA levels in FPLC fractions demonstrated higher SAA levels in the HDL fraction among survivors compared with non-survivors in the PL group on Days 0 and 3; however, this difference was not observed in the RS group. Conclusion: Taken together, these findings identify plasma CETP activities and early SAA levels as stable prognostic biomarkers associated with improved survival and reduced disease severity in sepsis. However, while both CETP activity and SAA levels were unaffected by RS treatment, it appeared to modify the association between SAA and mortality.