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

Abstract

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.

Keywords: Acute kidney injury; Acute respiratory distress syndrome; Cirrhosis; Endothelial dysfunction; Sepsis.

Fig. 1

Sequential organ failure assessment scores by cirrhosis diagnosis. Violin plots displaying the distribution of Sequential Organ Failure Assessment (SOFA) scores across different organ systems, for non-cirrhosis (n = 2591) and cirrhosis (n = 371) patients. The solid lines within the plots represent the median score, while the spread of the plots reflects the overall variability in organ dysfunction among the patient groups. a Pulmonary, b Cardiac, c Liver, d Renal, e Coagulation, f Central nervous system, g Total SOFA score

Fig. 2

Standardized risk of mortality, acute kidney injury, and acute respiratory distress syndrome by cirrhosis diagnosis. Standardized risk of 30-day mortality (a), 6-day AKI (b), and 6-day ARDS (c) by cirrhosis. For panels a and b, the dot represents the standardized risk of AKI and 30-day mortality, respectively, when adjusted for age, sex, APACHE-III score, and history of alcohol use. For panel c, the dot represents the standardized risk of ARDS when adjusted for age, sex, source of sepsis, APACHE-III score, and history of alcohol use. The bars represent the 95% CI around the standardized risk

Fig. 3

Plasma protein concentrations by cirrhosis diagnosis. Panels demonstrate plasma concentrations of a von Willebrand factor (vWF), b soluble thrombomodulin (STM), c angiopoietin-2 (Ang-2), d interleukin-6 (IL-6), e interleukin-10 (IL-10), f interleukin-1β (IL-1β), and g interleukin-1 receptor antiagonist (IL-1RA) by cirrhosis diagnosis. The box-and-whisker plots display the median value as a line within the boxes, the bounds of the box representing the IQR, and the whiskers representing the range of the data. P values are for the unadjusted comparison of cirrhosis and non-cirrhosis patients using the Wilcoxon rank-sum test. Sample sizes for endothelial biomarkers (a, b, c) are 105 cirrhosis and 606 non-cirrhosis patients. Sample sizes for inflammatory biomarkers (d, e, f, g) are 124 cirrhosis and 735 non-cirrhosis patients