CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:727738

REVIEW
Immune Dysfunction and Infections in Patients With Cirrhosis
ALEXANDER R. BONNEL, CHALERMRAT BUNCHORNTAVAKUL, and K. RAJENDER REDDY
Division of Gastroenterology/Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Podcast interview: www.gastro.org/cghpodcast.

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 decadesinfection 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 translocation from the GI tract are important steps in the pathogenesis of SBP and bacteremiathese processes increase levels of endotoxins and cytokines that induce the inammatory 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. Keywords: Liver Disease; Ascites; Inammation; Therapy.

kines that trigger an excessive inammatory host response, a cause for septic shock, multiorgan dysfunction, and death. Pathogens such as Mycobacterium tuberculosis, Clostridium difcile, Cryptococcus neoformans, Vibrio vulnicus, Yersinia enterocolitica, 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,7 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.8 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 signicantly reduced in cirrhosis compared with controls. Patients with acute decompensated liver cirrhosis have reduced expression of the antigen presenting HLA-DR molecules on monocytes.9 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,12 and phospholipase C.13,14 In addition, it has been suggested that hyperammonemia and hyponatremia function synergistically to affect neutrophil cell
Abbreviations used in this paper: CAP, community-acquired pneumonia; GI, gastrointestinal; IE, infectious endocarditis; IL, interleukin; IV, intravenous; NO, nitric oxide; PMN, polymorphonuclear; PSC, primary sclerosing cholangitis; RE, reticuloendothelial; SBP, spontaneous bacterial peritonitis; SIRS, systemic inammatory response syndrome; TB, tuberculosis; TNF, tumor necrosis factor; UTI, urinary tract infection. 2011 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2011.02.031

irrhosis is considered an immunocompromised state that leads to a variety of infections, which then account for an approximate 30% mortality.1 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.2 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 cirrhosis3 and in 45% of those with GI hemorrhage.4 These rates are drastically higher than the usual 5% to 7% overall rate of infection in hospitalized patients.1 The most common infections are SBP (25% of infections), urinary tract infection (UTI) (20%), and pneumonia (15%).3 Bacterial overgrowth and translocation from the GI tract are important steps in the pathogenesis of SBP and bacteremia.5,6 This pathogenic process leads to increased levels of endotoxins and cyto-

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Figure 1. Cirrhosis-associated immune dysfunction syndrome (CAIDS).

volume and impair phagocytosis.15 Neutropenia, typically a result of hypersplenism in cirrhosis, is further exacerbated by shortened neutrophil survival via apoptosis.16 The Fas/Fas ligand has been implicated in the regulation of apoptosis in neutrophils,17 but it is unclear how decreased levels of Fas in cirrhosis impact this mechanism.16 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 uid.18 Further, C3, C4, and CH50 concentrations are signicantly lower in both serum and ascitic uid, thus leading to diminished bactericidal activity.18,19 Additional aspects of immunodeciency 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 proinammatory cytokines.22,23

Bacterial Translocation
Bacterial translocation is the migration of bacteria or bacterial products from the intestinal lumen to mesenteric lymph nodes (Figure 2).24 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.25 Patients with cirrhosis have slowed intestinal motility, which leads to intestinal bacterial overgrowth.26 This overgrowth, along with portosystemic shunting, enables perpetuation of bacteria and can lead to bacteremia. Further oxidative damage from increased endotoxins, proinammatory cytokines, and nitric oxide (NO) alter the structure and permeability of intestinal mucosa in cirrhosis.24 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.

SIRS, Sepsis, and Cirrhosis

Systemic inammatory response syndrome (SIRS) is not uncommon in cirrhosis, and sepsis is dened as SIRS in the

presence of conrmed bacterial infection (Figure 3).1,2,11,2730 Bacterial derived toxins, such as peptidoglycans from gram-positive bacteria or lipopolysaccharides from gram-negative bacteria, bind to Toll-like receptors which initiate a cascade of cell signaling. Toll-like receptors trigger either nuclear factor B or mitogen activated protein kinase, which in turn stimulate the release of NO and proinammatory cytokines tumor necrosis factor (TNF)- , interleukin (IL)-6, and IL-1.31 In SIRS, anti-inammatory cytokines (IL-10, IL-4, IL-13, prostaglandin E2) are unable to balance the proinammatory cytokines, also known as a cytokine storm, resulting in excessive inammation.1,32 SIRS and cirrhosis are interlinked determinants of survival outcomes. The severity of liver disease determines the development of SIRS, while SIRS leads to variceal bleeding, hepatic encephalopathy, and adversely affects survival.33 Certain aspects of cirrhosis can exacerbate SIRS and complicate its diagnosis. Patients with cirrhosis have higher levels of circulating endotoxins that inversely correlate with hepatic deterioration.34 After lipopolysaccharide challenge, those with cirrhosis had higher proinammatory cytokine levels than those without, particularly TNF- and IL-6.35,36 Protein C and high density lipoprotein, protective anti-inammatory, and antiapoptotic factors are thought to be reduced in cirrhosis.37 NO, whose metabolite concentrations are correlated with those of endotoxins, is increased in cirrhosis and is known to contribute to the oxidative stress and worsening vasodilatation of sepsis.38,39 Complications of cirrhosis may mask themselves as symptoms of SIRS. For example, hypersplenism may reduce white blood cell count, hyperdynamic circulation may elevate heart rate, and hepatic encephalopathy may cause hyperventilation.31 However, these indicators appear to be more exaggerated in patients with cirrhosis. The release of large amounts of cytokines in sepsis intensies this hyperdynamic state and serves as the link between bacterial infection and renal failure. Renal failure following SBP-related and non-SBP-related bacteremia has been observed in 1 third of patients with cirrhosis and ascites.28 30 Altered hemodynamics and widespread inammation lead to impaired tissue oxygenation, cell necrosis, and apoptosis, and ultimately organ failure. When organ function can no longer sustain homeostasis without intervention, the patient is

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Figure SBP.

2. Pathogenesis

of

deemed to have multiple organ dysfunction syndrome, a common result of cirrhosis and severe sepsis. Relative adrenal insufciency is common in patients with septic shock and is associated with hemodynamic instability, renal failure, and increased mortality.40 It is diagnosed in approximately 70% of septic shock patients with cirrhosis and is believed to be linked to their impaired cortisol synthesis and decreased high density lipoprotein levels.41,42 The use of hydrocortisone in patients with septic shock remains controver-

sial,41,43,44 however, a recent randomized trial found its use to be associated with an increase in shock relapse and GI bleeding.45

Infections in Cirrhosis Gastrointestinal BleedingAssociated Infections and Prophylaxis

GI bleeding is associated with an increased incidence of infection, and approximately 17% to 45% of cases lead to an

Figure 3. Consequences of sepsis in cirrhosis.

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episode of SBP or bacteremia.46 Conversely, the presence of infection has been found to increase the risk of early bleeding.47,48 Goulis et al49 hypothesize that bacterial endotoxins stimulate hepatic stellate cell contraction and endothelial NO production, which then increase sinusoidal pressure and inhibit platelet aggregation, respectively. Patients who present with acute episodes of GI bleeding require short-term antibiotic prophylaxis regardless of the presence of ascites. Most infections are caused by gram-negative bacteria and are preventable with selective decontamination by quinolones.50 Long-term SBP prophylaxis with noroxacin has resulted in quinolone-resistant gram-negative bacteria and an increased prevalence of gram-positive bacteria.3 Therefore, third-generation cephalosporins, which target both gram-negative and gram-positive bacteria, are preferred prophylactic strategies. In patients with advanced cirrhosis, 1 g of intravenous (IV) ceftriaxone for 7 days after bleeding was found to be more effective in preventing bacterial infections than oral noroxacin.51 Prospective randomized trials and a recent Cochrane Database review found antibiotic prophylaxis to signicantly reduce rates of infection, rebleeding, and mortality.5254 Based upon the endotoxin-induced sinusoidal pressure hypothesis,49 antibiotic decontamination may lower the risk of rebleeding via reduction of endotoxin levels and subsequent portal pressure. Nonselective beta blockers, commonly used to lower portal hypertension and prevent initial variceal hemorrhage, can also serve to decrease bacterial translocation during an acute hemorrhage. A recent meta-analysis55 found evidence that beta blockers increase gut motility and reduce translocation, thereby reducing the incidence of infection. A study by Chelarescu et al56 in the postsurgical setting found propranolol to reduce infections from 42% to 15%. However, the use of beta blockers in patients with refractory ascites may limit the compensatory increase in cardiac output and increase vulnerability to complications such as septic shock and renal failure.57,58 Prokinetic agents may also reduce dysmotility and bacterial translocation. Prophylaxis with noroxacin and cisapride was found to signicantly reduce the rate of SBP compared with noroxacin alone.59 There is some evidence to suggest that the use of probiotics promotes the growth of gram-positive bacteria at the expense of gram-negative bacteria,60 but it has yet to been shown to benet patients with cirrhosis.61,62 Given the increasingly negative implication of gram-positive bacteria in infections, replacing gram-negative bacterial populations may be of little use.

Spontaneous Bacterial Peritonitis: Diagnosis, Treatment, and Prevention

The prevalence of SBP in patients with cirrhosis and ascites admitted to the hospital ranges between 10% and 30%; approximately half of cases are present at the time of hospitalization and half develop during the hospitalization.63 The inhospital mortality rate from SBP is approximately 32%.64 The majority of these infections are caused by E. coli, Klebsiella spp., other Enterobacteriaceae, P. aeruginosa, enterococci, and streptococci (Table 1).65 The current recommendation is to perform a diagnostic paracentesis in all patients with ascites at the time of hospital admission and in those who manifest symptoms of peritoneal infection, systemic signs of infection, hepatic encephalopathy, or rapid impairment in renal function while hospitalized.63,66 The diagnosis cutoff of SBP is a polymorpho-

nuclear (PMN) count of 250 cells/mm3 while the highest specicity is reached at 500 cells/mm3.63 Up to 65% of patients with clinical evidence of SBP and increased ascites have negative cultures,67 but inoculation of 10 mL of ascitic uid in aerobic and anaerobic culture bottles at the bedside has improved sensitivity to approximately 80%.68 Recent applications of culture-independent methods have attempted to improve screening outcomes. Several types of leukocyte esterase reagent strips have been evaluated in the diagnosis of SBP and have demonstrated sensitivity and specicity ranging between 45% and 100% and 81% to 100%, respectively.69 A recent study demonstrated an esterase strip calibrated to an ascitic uid PMN count 250 cells/mm3 to be a good bedside screening tool.70 Preliminary application of molecular analysis to identify bacterial DNA has yielded promising results that may replace culture techniques in the future.71,72 Bacterascites and secondary peritonitis are unique conditions of SBP that require specic guidelines for identication and therapy. It is identied by a positive ascitic uid culture and an ascitic PMN 250 cells/mm3. The differentiation between SBP and secondary peritonitis, ie, bacterial peritonitis caused by perforation or acute inammation of organs, can be quite difcult. Secondary peritonitis, though only accounting for 4.5% of all peritonitis cases in cirrhosis,73 should be suspected in any of the following situations: (1) lack of a response to antibiotic therapy; (2) 2 or more organisms isolated (particularly anaerobes or fungi; (3) the presence of at least 2 of the following in ascitic uid: glucose 50 mg/dL, protein 1 g/dL, lactic dehydrogenase greater than normal serum levels.63 With intestinal perforation, secondary peritonitis may also be suspected if chorioembryonic antigen 5 ng/mL or alkaline phosphatase 240 U/L.74 After diagnosis of a cause of secondary peritonitis with a radiological study such as magnetic resonance imaging or computed tomography scan, patients should receive antibiotic therapy and undergo surgical evaluation.63,66,73,75 Because it is often a monobacterial infection with an associated white blood cell response, SBP is dened as culture positive. However, a variant of it called culture-negative neutrocytic ascites can be encountered and has similar clinical outcomes (Figure 4).66,74,76 79 The current standard for treatment of SBP is with a minimal dose of 2 g of intravenous cefotaxime every 12 hours for 5 days.80,81 In those with clinical improvement, a repeat of paracentesis is not necessary to assess for resolution of SBP. Equally effective alternative therapies include cephalosporins (ceftriaxone, ceftazidime, ceftizoxime), amoxicillin-clavulanic acid, and quinolones (ciprooxacin, ooxacin, levooxacin) for beta-lactam hypersensitive patients.31,63,82 When clinical signs of infection have improved, replacing IV cephalosporin with oral ciprooxacin to complete the course of therapy may be more cost-effective.83 Patients taking quinolones as prophylaxis should be aware of treatment failure because of antibiotic resistance or enterococcal infection. If clinical improvement and a sufcient drop in neutrophil count in ascites ( 25% of initial value) are not observed by day 3 of treatment, a switch of antibiotic therapy should be considered while the patient is evaluated for secondary peritonitis. Renal impairment develops in approximately 1 third of all SBP patients and is a strong predictor of mortality during hospitalization.27 The activation of the cytokine cascade and NO production in cirrhosis and SBP negatively impact renal function.28,84 The use

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Table 1. Pathogens Causing Infections and Unique Features in Patients With Cirrhosis
Organisms Bacteria E. coli, Klebsiella spp., and other gram-negative enteric bacteria Vibrio vulnicus Common clinical syndrome SBP, bacteremia, UTI Special comments Increased resistance in patients taking prophylactic quinolones and in nosocomial infections Increased incidence in cirrhosis, particularly hemochromatosis 50%60% mortality in septic form138 24% for localized wound infection139 Increased incidence and morbidity in advanced cirrhosis (mortality 24%)11 Increased morbidity Increased incidence and morbidity in cirrhosis Increased incidence in cirrhosis and iron overload state Increased incidence in cirrhosis, particularly hemochromatosis Increased incidence in cirrhosis and iron overload state Increased incidence and morbidity of C. perfringens in cirrhosis (mortality 54%65%)11 Increased incidence (may be related to the common use of antibiotics and PPI in patients with cirrhosis)122 Increased mortality (14%)121 Increased incidence in cirrhosis, particularly hospitalized patients Increased MRSA nasal carriage Increased incidence and morbidity Pneumococcal vaccine is recommended in patients with cirrhosis (vaccine efcacy has been validated in alcoholic cirrhosis) Increased incidence Increased incidence and morbidity Mortality rate approximately 25% (up to 50% in endocarditis form)114 Higher incidence, more virulent, and more extra-pulmonary forms in cirrhosis compare to non-cirrhosis Risk for multi-drug resistance TB Increased incidence in advanced cirrhosis Mortality rate up to 70%132 Identied in the bile up to 44% of PSC patients with cholangitis134,135

Soft tissue infection, bacteremia

Vibrio cholera (non-o1) Vibrio parahemolyticus Aeromonas spp. Yersinia spp. Listeria monocytogenes Plesiomonas shigelloides Clostridium spp.

Diarrhea, septicemia Diarrhea, septicemia Soft tissue infection, bacteremia Septicemia, hepatosplenic abscesses, peritonitis Septicemia, meningitis, peritonitis Septicemia, meningitis, soft tissue infection Septicemia, soft tissue infection, peritonitis

Clostridium difcile

Antibiotic-associated diarrhea and colitis

Staphylococcus aureus

Soft tissue infection, septicemia, endocarditis

Streptococcus pneumoniae

Septicemia, pneumonia, meningitis

Streptococcus group B Enterococcus spp.

Septicemia, peritonitis, skin and soft tissue infection SBP, septicemia, UTI, biliary tract infection, endocarditis Pulmonary TB, extrapulmonary TB, esp. peritonitis, disseminated TB

Mycobacterium tuberculosis (TB)

Fungi Cryptococcus neoformans Fungi Candida spp.

Peritonitis, meningitis, disseminated cryptococcosis Biliary tract infection, septicemia

of intravenous albumin (1.5 g/kg body weight within 6 hours of SBP diagnosis followed by 1 g/kg body weight on day 3) in conjunction with cefotaxime was found to reduce the incidence of renal impairment from 33% to 10% and mortality from 29% to 10%.28 Albumin increases mean arterial volume, binds TNF- and NO to counteract the inammatory response of infection, and removes toxins from circulation.84 86 These infusions are most effective in patients with baseline creatinine 1.0 mg/dL and total bilirubin 4.0 mg/dL.28,87 A recent pilot study by Cartier et al88 suggests polygeline (Gelafundin 4%; B Braun Medical AG, Crissier, Switzerland), a cheaper plasma expander, as a reasonable alternative to albumin. When treated effectively, recovery from SBP is seen in approximately 90% of patients and 30-day survival is in at least

80%.63 For patients who fail treatment, hospital mortality ranges from 50% to 80%.89 The rapid deterioration of liver function in SBP patients makes for generally poor long-term prognosis after an episode of SBP. Franca et al90 found the 1-year survival rate to be 28.5%. The recent shift in microbial etiology of SBP toward cefotaxime-resistant strains may complicate survival by delaying infection resolution. Patients recovering from an episode of SBP should be given antibiotic prophylaxis. In those without antibiotic prophylaxis, the rate of recurrence of SBP is 43% at 6 months, 69% at 1 year, and 74% at 2 years after the initial episode.91 Gins et al92 found that 400 mg per day oral noroxacin reduced recurrence of SBP from 68% to 20%. The use of 500 mg ciprooxacin per day, rather than the 750 mg once per week dosage previously sug-

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Figure 4. Ascites infection algorithm.

gested,93 is known to be effective.94 Intermittent dosing of prophylactic antibiotics may select resistant ora, therefore daily dosing is preferred. For patients intolerant to quinolones, daily double-strength oral trimethoprim/sulfamethoxazole is an effective alternative.95,96 The current time scale for long-term prophylaxis is indenite. Patients with advanced cirrhosis and low protein ascites may be candidates for primary prophylaxis against SBP.97 In a randomized controlled trial,98 patients with low protein ascites levels ( 1.5 g/dL) with advanced liver failure or impaired renal function who received noroxacin prophylaxis had a signicantly decreased probability of SBP, hepatorenal syndrome, and mortality.

residual volume as an explanation, however, this nding was not supported in a subsequent study.99 Treatment of UTI with quinolones is effective in approximately 95% of cases.99

Pneumonia
Pneumonia is the third leading cause of infections in patients with cirrhosis.1,50 Pulmonary clearance of pneumococci was signicantly decreased in a rat model of cirrhosis, most likely as a result of decreased complement levels.103 Community-acquired pneumonia (CAP) is most often caused by S. pneumoniae and H. inuenza.104 S. aureus, M. pneumoniae, M. catarrhalis, C. pneumoniae, Klebsiella spp., and Legionella spp. have also been implicated as causes of CAP. The risk of bacteremia in CAP is increased in patients with cirrhosis.105 Further, procedures such as tracheal intubation and esophageal tamponade put patients with cirrhosis at risk of hospital-acquired pneumonia.106 In the presence of comorbidities such as cirrhosis, treatment is ideal with IV beta-lactam plus macrolide or IV antipneumococcal quinolones.104 Pneumococcal vaccination is recommended in patients with cirrhosis.104,107

Other Infections in Cirrhosis Urinary Tract Infection

UTI occurs in approximately 15% to 20% of hospitalized patients with cirrhosis; it is twice as frequent in patients with cirrhosis compared with matched controls.3,99 Women have a 4 times higher rate of bacteriuria than men.99 Gram-negative bacilli, such as E. coli and Klebsiella spp., are the primary causative agents. Notably, bacteriuria is not associated with an increased risk of sepsis, SBP, or other infections often seen in patients with cirrhosis.99 Although more frequent among those with cirrhosis, UTI does not consistently correlate with the severity of liver disease and is more strongly associated with gender and diabetes.99 101 The high incidence of UTI in cirrhosis remains unexplained. Bercoff et al102 cite the increased bladder postvoid

Soft Tissue Infections

Chronic edema and increased bacterial translocation predispose patients with cirrhosis to soft tissue infections, which constitute approximately 11% of infections.108 Both gram-positive (S. aureus, group A Streptococci) and gram-negative bacteria (Klebsiella spp., Aeromonas spp., V. vulnicus) are common causes of soft tissue infections. Cellulitis is the most frequently

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observed skin infection in patients with cirrhosis and has a recurrence rate of 20%.109 Necrotizing fasciitis, a rare but severe form of soft tissue infection, is predominantly caused by gramnegative bacilli.110 Unlike the general population, necrotizing fasciitis in those with cirrhosis rarely develops from an obvious portal of entry in the extremities, thereby suggesting a potential pathway of bacterial translocation and bacteremia leading to soft tissue infections.110,111 Broad spectrum antibiotic treatment is necessary for proper management of soft tissue infections, and surgical intervention for deep infections may be needed.

Endocarditis
Approximately 10% of infectious endocarditis (IE) cases have cirrhosis as an underlying condition.112 IE is a concern for hospitalized patients with cirrhosis because of the increased risk of bacteremia associated with invasive procedures (transjugular intrahepatic portosystemic shunt, upper endoscopy, etc). Valve disorders are present in approximately 60% of patients with cirrhosis who have IE.112 Gram-positive bacteria such S. aureus, -hemolytic streptococci (S. agalactiae, S. pyogenes), and enterococci (E. faecalis, E. faecium) are the most commonly isolated organisms.112,113 Depending on the organism, a minimum of 4 weeks of antibiotic therapy is recommended.114 Patients with advanced liver cirrhosis have high surgical mortality rates;115 therefore surgical management of IE is reserved for selected patients who do not respond to medical therapy.

and gram-positive pathogens. Approximately 37% to 64% of bacterial infections, either nosocomial or in the context of antibiotic intervention in an outpatient setting, have been found to be multidrug-resistant.3,123,124 Gram-negative isolates in SBP, such as E. coli and K. pneumoniae, are being encountered with increasing rates of resistance.125 Gram-positive pathogens are increasingly common in patients with cirrhosis.125 Methicillin-resistant S. aureus has been noted to account for 24.8% of nosocomial SBP.125 E. faecalis and E. faecium have been isolated in nearly 10% to 24% of infections in the setting of cirrhosis and are associated with 25% mortality rate.3,125,126 Approximately a third of enterococcal bacteremia cases demonstrate vancomycin resistance and are associated with twice the mortality rate of nonresistant strains.127,128

Fungal Infections
Cirrhosis increases susceptibility to Cryptococcus neoformans, an encapsulated fungus that is typically associated with human immunodeciency virusinfected patients.129,130 Liver cirrhosis is an underlying condition in approximately a third of non human immunodeciency virus cryptococcaemia cases and is a stronger independent predictor of 30-day mortality than in those with acquired immunodeciency syndrome.131 Though uncommon, C. neoformans may infect ascites and cause spontaneous cryptococcal peritonitis. Unlike SBP, spontaneous cryptococcal peritonitis presents itself with an elevation in lymphocyte count and, because of late detection, has a very high mortality rate ( 70%).132 The pathogenesis of cryptococcal peritonitis may be via direct percutaneous inoculation during paracentesis, GI bleeding, or bacterial translocation.130,133 Candida infections can also be encountered particularly in patients with primary sclerosing cholangitis (PSC). Candida species have been identied in 44% of bile samples in PSC patients, particularly those with dominant strictures.134,135 A high prevalence of biliary candidiasis exists, however, the effect of antifungal therapies on treatment outcomes for recurrent cholangitis remains unknown.

Tuberculosis
The incidence and virulence of Mycobacterium tuberculosis infections are increased in patients with cirrhosis.116 In a cohort of tuberculosis (TB) patients with liver cirrhosis in Denmark, the 30-day case fatality rate was 27.3% and the 1-year case fatality rate was 47.7%.116 TB patients with liver cirrhosis show extrapulmonary involvement,117 such as TB peritonitis, more frequently. Compared with SBP, TB peritonitis is present in less advanced cirrhosis and is characterized by lower white blood cell count in ascites, higher proportion of mononuclear leukocytes, higher protein concentration, and higher levels of adenosine deaminase activity in ascites.118 Though adenosine deaminase level analysis is useful in the detection of TB peritonitis in patients without cirrhosis, the presence of cirrhosis reduces its sensitivity to 30%.119 Laparoscopic biopsies provide denitive diagnosis of TB peritonitis by revealing multiple whitish nodules scattered over the peritoneum.118,120 Patients with TB and cirrhosis respond well to anti-TB therapy, however they face a greater risk of hepatotoxicity.117

Specic Liver DiseaseRelated Infections

Iron overload state impairs cell-mediated response and enhances growth of various pathogens such as E. coli, Vibrio spp., and Listeria monocytogenes.136 Recent evidence suggests that decreased levels of hepcidin, an iron-regulator hormone with antimicrobial activity, serve as the link between liver disease and these infections.137 Patients with hemochromatosis face a 30fold greater risk of acquiring V. vulnicus, a bacterium acquired through ingestion of contaminated raw oysters.138 V. vulnicus septicemia has a 50% to 60% case mortality rate in patients with liver disease and 7% to 22% mortality for localized wound infection.138,139 Yersinia enterocolitica and Yersinia pseudotuberculosis, 2 gram-negative bacilli transmitted zoonotically, infect via systemic or portal vein bacteremia to cause hepatic abscesses with up to a 56% mortality rate.140 142 PSC is a risk factor for ascending cholangitis, which is associated with up to a 16% mortality rate.143,144 Generally, ascending cholangitis is relatively uncommon unless the biliary tree has been manipulated by endoscopic retrograde cholangiopancreotography. The most common infections after endoscopic retrograde cholangiopancreotography are caused by gram-negative bacteria such as E. coli, Klebsiella spp., and Enterobacter spp.143,144 However, if cholangitis occurs without any in-

Clostridium difcile
Clostridium difcile is an increasingly prevalent hospitalacquired infection that affects patients with cirrhosis. A recent study of over 80,000 patients with cirrhosis found patients with C. difcile-associated disease to have higher mortality and longer length of stay than those without infection.121 Antibiotics and proton pump inhibitors were independently associated with C. difcile infection. Thus it is recommended that antibiotic prophylaxis be limited to patients at highest risk of developing SBP and that proton pump inhibitors be used selectively.122

Drug-Resistant Infections
Nosocomial infections account for a signicant proportion of infections in patients with cirrhosis and an increasing number of these infections are caused by antibiotic-resistant

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tervention, the presence of stones, dominant strictures, or cholangiocarcinoma should be considered. In a study of explanted livers with PSC, bacteria were isolated in approximately 60% of cases.145 The most common bacteria isolated were alpha-hemolytic streptococci, enterococci, and staphylococci. Though the etiology of PSC is largely unknown, bacterial infection of the bile ducts with dominant stenoses has been implicated in the progression of the disease.146

Summary
Patients with cirrhosis are in a multifactorial immunocompromised state which predisposes them to a higher risk of infection. Bacterial infections, particularly SBP and bacteremia, are an important cause of morbidity and mortality in these patients. Gram-negative enteric bacteria appear to be the most common causative organisms. However, other unusual bacteria and fungi are also frequently observed and more virulent in patients with cirrhosis relative to those without liver disease. Moreover, these pathogens can present with various clinical syndromes that may be difcult to recognize. The relationship between immune dysfunction and infection in cirrhosis has been extensively investigated. Bacterial translocation appears to be an important step, which accounts for the increased levels of endotoxins, cytokines, and NO; these play a critical role in the development of an excessive inammatory response and hyperdynamic circulatory state of cirrhosis. As hepatic function deteriorates and portal hypertension progresses, overt infection is more likely to develop and subsequently can evolve to sepsis, leading to consequences such as septic shock, multiorgan failure, and death. Early diagnosis and proper management of infections in patients with cirrhosis are necessary. Generally, intravenous third generation cephalosporins are recommended as empiric antibiotic therapy for most cases of SBP and bacteremia. However, the risk of resistant organisms and unusual pathogens should be kept in mind, especially in patients with cirrhosis who are receiving quinolone prophylaxis or have hemochromatosis as an etiology of liver disease. Auxiliary therapy with intravenous albumin can signicantly reduce morbidity and mortality in SBP patients who are at high risk of developing renal failure. The importance of preventive strategies cannot be underscored. Patients with cirrhosis admitted with GI hemorrhage benet from short-term antibiotic prophylaxis, whereas long-term oral prophylaxis is recommended in those who have recovered from SBP. Despite recent advances in understanding of the mechanisms of infection in patients with cirrhosis, the outcomes of those patients with severe infections still remain poor. Further studies into mechanisms, diagnostic approaches, and potential preventive strategies are needed to improve the management of infections in patients with cirrhosis.

Supplementary Material
Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at doi:10.1016/ j.cgh.2011.02.031. References
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Reprint requests Address requests for reprints to: K. Rajender Reddy, MD, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. e-mail: rajender.reddy@uphs.upenn. edu; fax: (215) 615-1601. Acknowledgments The authors appreciate the in-depth review and comments of Dr Jasmohan Bajaj from Virginia Commonwealth University. Conicts of interest The authors disclose no conicts.