Ascites Bacterial Burden and Immune Cell Profile Are Associated with Poor Clinical Outcomes in the Absence of Overt Infection

Abstract

Bacterial infections, most commonly spontaneous bacterial peritonitis in patients with ascites, occur in one third of admitted patients with cirrhosis, and account for a 4-fold increase in mortality. Bacteria are isolated from less than 40% of ascites infections by culture, necessitating empirical antibiotic treatment, but culture-independent studies suggest bacteria are commonly present, even in the absence of overt infection. Widespread detection of low levels of bacteria in ascites, in the absence of peritonitis, suggests immune impairment may contribute to higher susceptibility to infection in cirrhotic patients. However, little is known about the role of ascites leukocyte composition and function in this context. We determined ascites bacterial composition by quantitative PCR and 16S rRNA gene sequencing in 25 patients with culture-negative, non-neutrocytic ascites, and compared microbiological data with ascites and peripheral blood leukocyte composition and phenotype. Bacterial DNA was detected in ascitic fluid from 23 of 25 patients, with significant positive correlations between bacterial DNA levels and poor 6-month clinical outcomes (death, readmission). Ascites leukocyte composition was variable, but dominated by macrophages or T lymphocytes, with lower numbers of B lymphocytes and natural killer cells. Consistent with the hypothesis that impaired innate immunity contributes to susceptibility to infection, high bacterial DNA burden was associated with reduced major histocompatibility complex class II expression on ascites (but not peripheral blood) monocytes/macrophages. These data indicate an association between the presence of ascites bacterial DNA and early death and readmission in patients with decompensated cirrhosis. They further suggest that impairment of innate immunity contributes to increased bacterial translocation, risk of peritonitis, or both.

Impaired innate immune response of leukocytes from ascitic fluid of patients with spontaneous bacterial peritonitis

“…The marker expression of PosC-SBP, with low levels of HLA-DR, CD11b, CD16, and CD86, suggests an impaired ability for antigen presentation, phagocytosis, and adhesion [29]. A similar low HLA-DR expression has recently been described on ascitic macrophages from patients with NegC-SBP, and it has been associated with a high bacterial DNA burden [9].…”

CRIg-expressing peritoneal macrophages are associated with disease severity in patients with cirrhosis and ascites

“…We previously reported that, even in the absence of overt infection and despite SBP prophylaxis, ascites bacterial DNA levels were associated with poor clinical outcomes (death, hospital readmission) (7). Bacterial DNA levels were also associated with reduced HLA-DR expression on ascites macrophages/monocytes (CD14 + cells), suggesting a reduced antigen presentation capacity (7), which may contribute to susceptibility to infection in these patients (8). The presence of macrophages in general, however, correlated with reduced ascites neutrophils and bacterial DNA, suggesting that restoring macrophage function (e.g., HLA-DR expression; ref.…”

MicroRNA-155 is upregulated in ascites in patients with spontaneous bacterial peritonitis

“…MiR-125b and miR-155 are both involved in macrophage activation1015, which are next to lymphocytes the predominant cell population in ascites16. In murine peritoneal macrophages, miR-125b was upregulated after induction of peritonitis and re-stimulation with lipopolysaccharide (LPS); it was identified as a potential mediator of tolerance to LPS17.…”