Identifying a unique signature of sepsis in patients with pre-existing cirrhosis.

Background: The pre-existing diagnosis of cirrhosis is a complicating factor in the progression and prognosis of sepsis; however, the unique epidemiology, sepsis characteristics, and underlying mechanisms of immune dysregulation in sepsis among patients with cirrhosis remain incompletely understood. Our primary objective was to identify clinical outcomes and biological characteristics that differ between patients with and without cirrhosis among critically ill patients with sepsis.

Methods: We analyzed data from a prospective cohort of critically ill patients presenting to single center with sepsis. Subjects were followed for 6 days for the development of acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), and 30 days for mortality. Inflammatory, endothelial, and coagulopathic proteins were measured in plasma collected at ICU admission in a subset of patients. We determined associations of cirrhosis with outcomes using multivariable logistic regression adjusting for pre-specified confounders. We tested differences in plasma protein levels by cirrhosis diagnosis using the Wilcoxon Rank-sum test.

Results: We enrolled 2962 subjects, 371 (13%) of whom had a pre-existing diagnosis of cirrhosis. Patients with cirrhosis had higher severity of illness scores, were more likely to have an abdominal source of sepsis, and had more significant clinically measured coagulation abnormalities relative to patients without cirrhosis. In multivariate analysis, cirrhosis was associated with higher AKI risk (adjusted OR 1.65; 95% CI 1.21 to 2.26; P = 0.002), and 30-day mortality (adjusted OR 1.38; 95% CI 1.05 to 1.82; P = 0.022). There was no significant difference in risk for ARDS (adjusted OR 1.02; 95% CI 0.69 to 1.50; P = 0.92). Cirrhosis was associated with higher plasma levels of angiopoietin-2 (P < 0.001), von Willebrand factor (P < 0.001), and soluble thrombomodulin (P < 0.001), as well as lower levels of interleukin (IL)-10 (P < 0.001), IL-1β (P = 0.008), and IL-1RA (P = 0.036). There were no significant differences in levels of IL-6 (P = 0.30).

Conclusions: We identified associations between pre-existing cirrhosis and endothelial injury, AKI, and mortality in sepsis. Patients with pre-existing cirrhosis who develop sepsis may display a unique phenotype of endothelial dysfunction that requires unique targeted approaches.