Immune Dysfunction and Infections in Patients With Cirrhosis
Patients with cirrhosis are immunocompromised and susceptible to infections. Although detection and treatment of spontaneous bacterial peritonitis (SBP) have improved, overall survival rates have not increased greatly in recent decades—infection still increases mortality 4-fold among patients with cirrhosis. Hospitalized patients with cirrhosis have the highest risk of developing infections, especially patients with gastrointestinal (GI) hemorrhage. Bacterial infections occur in 32% to 34% of patients with cirrhosis who are admitted to the hospital and 45% of patients with GI hemorrhage. These rates are much higher than the overall rate of infection in hospitalized patients (5%–7%). The most common are SBP (25% of infections), urinary tract infection (20%), and pneumonia (15%). Bacterial overgrowth and transloca-tion from the GI tract are important steps in the pathogenesis of SBP and bacteremia—these processes increase levels of en-dotoxins and cytokines that induce the inflammatory response and can lead to septic shock, multiorgan dysfunction, and death. A number of other bacterial and fungal pathogens are more common and virulent in patients with cirrhosis than in the overall population. We review the pathogenesis of infections in these patients, along with diagnostic and management strategies.
Cirrhosis is considered an immunocompromised state that leads to a variety of infections, which then account for an approximate 30% mortality. Apart from early recognition and better treatment of spontaneous bacterial peritonitis (SBP) leading to better survival, there has been little improvement in overall survival rates in recent decades: infections still account for a 4-fold increase in mortality among patients with cirrhosis. Hospitalized patients with cirrhosis are at the highest risk of developing infection, especially in those with gastrointestinal (GI) hemorrhage. Bacterial infections occur in 32% to 34% of admitted patients with cirrhosis and in 45% of those with GI hemorrhage. These rates are drastically higher than the usual 5% to 7% overall rate of infection in hospitalized patients. The most common infections are SBP (25% of infections), urinary tract infection (UTI) (20%), and pneumonia (15%). Bacterial overgrowth and translocation from the GI tract are important steps in the pathogenesis of SBP and bacteremia.' This pathogenic process leads to increased levels of endotoxins and cytokines that trigger an excessive inflammatory host response, a cause for septic shock, multiorgan dysfunction, and death.
Pathogens such as Mycobacterium tuberculosis, Clostridium difficile, Cryptococcus neoformans, Vibrio vulnificus, Yersinia enteroco-litica, and Listeria monocytogenes, are more common and virulent in patients with cirrhosis than in the general population. Because of the high morbidity and mortality of infections in cirrhosis, prevention, early diagnosis, and proper management of these infections are necessary to improve survival.
State of Immune Dysfunction in Cirrhosis
Cirrhosis-associated immune dysfunction syndrome (CAIDS) is a multifactorial state of systemic immune dysfunction (Figure 1), which decreases their ability to clear cytokines, bacteria, and endotoxins from circulation. The liver contains 90% of the reticuloendothelial (RE) cells, such as Kupffer and sinusoidal endothelial cells, that are central to clearing bacteria. When radiolabeled E. coli and P. aeruginosa were injected intravenously, 70% and 96% of their populations, respectively, were found in the liver only 10 minutes later. Porto-systemic shunting, whereby blood is increasingly directed away from the liver, and reduced RE cells in patients with cirrhosis, allow less bacteria and endotoxins to be cleared by the liver from circulation.[1,7]
Monocyte spreading, chemotaxis, bacterial phagocytosis, and bacterial killing are significantly reduced in cirrhosis compared with controls. Patients with acute decompensated liver cirrhosis have reduced expression of the antigen presenting HLA-DR molecules on monocytes. This may also result in decreased monocyte activation and cytokine secretion.
In addition to RE system dysfunction, patients with cirrhosis have decreased neutrophil mobilization and phagocytic activity, a phenomenon that correlates with severity of liver disease.[10,11] The decreased phagocytic activity in cirrhosis has been attributed to reduced activity of tuftsin, and phospholipase C.[13,14] In addition, it has been suggested that hyperammonemia and hyponatremia function synergistically to affect neutrophil cell volume and impair phagocytosis. Neutropema, typically a result of hypersplenism in cirrhosis, is further exacerbated by shortened neutrophil survival via apoptosis.The Fas/Fas li-gand has been implicated in the regulation of apoptosis in neutrophils, but it is unclear how decreased levels of Fas in cirrhosis impact this mechanism.
The decreased phagocytic activity of the innate immune response is confounded by decreased bactericidal and opsonization capacity. Patients with cirrhosis have much lower levels of immunoglobulins IgM, IgG, and IgA in ascitic fluid. Further, C3, C4, and CH50 concentrations are significantly lower in both serum and ascitic fluid, thus leading to diminished bactericidal activity.[18,19]
Additional aspects of immunodeficiency are complicated by factors such as malnutrition, immunosuppressive medications, and alcohol intake.[20,21] Chronic and acute alcohol consumption are associated with a decrease in T cells, B cells, natural killer cells, monocytes, and an increase in proinflammatory cytokines.[22,23]
Bacterial translocation is the migration of bacteria or bacterial products from the intestinal lumen to mesenteric lymph nodes (Figure 2). Bacterial translocation is known to be increased in cirrhosis and has been pathogenetically linked to the development of SBP.[5,6] It has also been implicated as a cause of recurrent SBP. Patients with cirrhosis have slowed intestinal motility, which leads to intestinal bacterial overgrowth. This overgrowth, along with portosystemic shunting, enables perpetuation of bacteria and can lead to bacteremia. Further oxidative damage from increased endotoxins, proinflammatory cytokines, and nitric oxide (NO) alter the structure and permeability of intestinal mucosa in cirrhosis.In conjunction with the decreased local and impaired systemic immune function in cirrhosis, decreased gut motility and increased permeability facilitate the spread of intestinal bacteria to extraintestinal sites and predispose patients with cirrhosis to infections.