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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:727–738

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

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Patients with cirrhosis are immunocompromised and sus-ceptible to infections. Although detection and treatment ofspontaneous bacterial peritonitis (SBP) have improved,overall survival rates have not increased greatly in recentdecades—infection still increases mortality 4-fold amongpatients with cirrhosis. Hospitalized patients with cirrhosishave the highest risk of developing infections, especiallypatients with gastrointestinal (GI) hemorrhage. Bacterialinfections occur in 32% to 34% of patients with cirrhosis whoare admitted to the hospital and 45% of patients with GIhemorrhage. These rates are much higher than the overall rateof infection in hospitalized patients (5%–7%). The most com-mon 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 pathogenesisof SBP and bacteremia—these processes increase levels of en-dotoxins and cytokines that induce the inflammatory re-sponse and can lead to septic shock, multiorgan dysfunction,and death. A number of other bacterial and fungal pathogensare more common and virulent in patients with cirrhosis thanin the overall population. We review the pathogenesis of in-fections in these patients, along with diagnostic and manage-ment strategies.

Keywords: Liver Disease; Ascites; Inflammation; Therapy.

Cirrhosis is considered an immunocompromised state thatleads to a variety of infections, which then account for an

pproximate 30% mortality.1 Apart from early recognition andetter treatment of spontaneous bacterial peritonitis (SBP)

eading to better survival, there has been little improvement inverall survival rates in recent decades: infections still accountor a 4-fold increase in mortality among patients with cirrho-is.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% ofadmitted patients with cirrhosis3 and in 45% of those with GIhemorrhage.4 These rates are drastically higher than the usual5% to 7% overall rate of infection in hospitalized patients.1 The

ost common infections are SBP (25% of infections), urinaryract infection (UTI) (20%), and pneumonia (15%).3 Bacterial

overgrowth and translocation from the GI tract are importantsteps in the pathogenesis of SBP and bacteremia.5,6 This patho-

genic process leads to increased levels of endotoxins and cyto-

kines that trigger an excessive inflammatory host response, acause for septic shock, multiorgan dysfunction, and death.

Pathogens such as Mycobacterium tuberculosis, Clostridium dif-ficile, Cryptococcus neoformans, Vibrio vulnificus, Yersinia enteroco-litica, and Listeria monocytogenes, are more common and virulentin patients with cirrhosis than in the general population. Be-cause of the high morbidity and mortality of infections incirrhosis, prevention, early diagnosis, and proper managementof these infections are necessary to improve survival.

State of Immune Dysfunction inCirrhosisCirrhosis-associated immune dysfunction syndrome

(CAIDS) is a multifactorial state of systemic immune dysfunc-tion (Figure 1), which decreases their ability to clear cytokines,bacteria, and endotoxins from circulation. The liver contains90% of the reticuloendothelial (RE) cells,7 such as Kupffer andsinusoidal endothelial cells, that are central to clearing bacteria.When radiolabeled E. coli and P. aeruginosa were injected intra-enously, 70% and 96% of their populations, respectively, wereound in the liver only 10 minutes later.8 Porto-systemic shunt-

ing, whereby blood is increasingly directed away from the liver,and reduced RE cells in patients with cirrhosis, allow lessbacteria and endotoxins to be cleared by the liver from circu-lation.1,7

Monocyte spreading, chemotaxis, bacterial phagocytosis,and bacterial killing are significantly reduced in cirrhosis com-pared with controls. Patients with acute decompensated livercirrhosis have reduced expression of the antigen presentingHLA-DR molecules on monocytes.9 This may also result in

ecreased monocyte activation and cytokine secretion.In addition to RE system dysfunction, patients with cirrhosis

ave decreased neutrophil mobilization and phagocytic activity,phenomenon that correlates with severity of liver disease.10,11

The decreased phagocytic activity in cirrhosis has been attrib-uted to reduced activity of tuftsin,12 and phospholipase C.13,14

In addition, it has been suggested that hyperammonemia andhyponatremia function synergistically to affect neutrophil cell

Abbreviations used in this paper: CAP, community-acquired pneumo-nia; GI, gastrointestinal; IE, infectious endocarditis; IL, interleukin; IV,intravenous; NO, nitric oxide; PMN, polymorphonuclear; PSC, primarysclerosing cholangitis; RE, reticuloendothelial; SBP, spontaneous bacte-rial peritonitis; SIRS, systemic inflammatory response syndrome; TB,tuberculosis; TNF, tumor necrosis factor; UTI, urinary tract infection.

© 2011 by the AGA Institute1542-3565/$36.00

doi:10.1016/j.cgh.2011.02.031

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728 BONNEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9

volume and impair phagocytosis.15 Neutropenia, typically aesult of hypersplenism in cirrhosis, is further exacerbated byhortened neutrophil survival via apoptosis.16 The Fas/Fas li-and has been implicated in the regulation of apoptosis ineutrophils,17 but it is unclear how decreased levels of Fas inirrhosis impact this mechanism.16

The decreased phagocytic activity of the innate immuneresponse is confounded by decreased bactericidal and opsoniza-tion capacity. Patients with cirrhosis have much lower levels ofimmunoglobulins IgM, IgG, and IgA in ascitic fluid.18 Further,C3, C4, and CH50 concentrations are significantly lower inboth serum and ascitic fluid, thus leading to diminished bac-tericidal activity.18,19

Additional aspects of immunodeficiency are complicated byfactors such as malnutrition, immunosuppressive medications,and alcohol intake.20,21 Chronic and acute alcohol consumptionre associated with a decrease in T cells, B cells, natural killer cells,onocytes, and an increase in proinflammatory cytokines.22,23

Bacterial TranslocationBacterial translocation is the migration of bacteria or

bacterial products from the intestinal lumen to mesentericlymph nodes (Figure 2).24 Bacterial translocation is known to beincreased in cirrhosis and has been pathogenetically linked tothe development of SBP.5,6 It has also been implicated as a causeof recurrent SBP.25 Patients with cirrhosis have slowed intesti-nal motility, which leads to intestinal bacterial overgrowth.26

This overgrowth, along with portosystemic shunting, enablesperpetuation of bacteria and can lead to bacteremia. Furtheroxidative damage from increased endotoxins, proinflammatorycytokines, and nitric oxide (NO) alter the structure and perme-ability of intestinal mucosa in cirrhosis.24 In conjunction withhe decreased local and impaired systemic immune function inirrhosis, decreased gut motility and increased permeabilityacilitate the spread of intestinal bacteria to extraintestinal sitesnd predispose patients with cirrhosis to infections.

SIRS, Sepsis, and CirrhosisSystemic inflammatory response syndrome (SIRS) is not

uncommon in cirrhosis, and sepsis is defined as SIRS in the

presence of confirmed bacterial infection (Figure 3).1,2,11,27–30 Bac-erial derived toxins, such as peptidoglycans from gram-positiveacteria or lipopolysaccharides from gram-negative bacteria, bindo Toll-like receptors which initiate a cascade of cell signaling.oll-like receptors trigger either nuclear factor �B or mitogen

activated protein kinase, which in turn stimulate the release of NOand proinflammatory cytokines tumor necrosis factor (TNF)-�,interleukin (IL)-6, and IL-1.31 In SIRS, anti-inflammatory cytokinesIL-10, IL-4, IL-13, prostaglandin E2) are unable to balance theroinflammatory cytokines, also known as a “cytokine storm,”esulting in excessive inflammation.1,32

SIRS and cirrhosis are interlinked determinants of survivaloutcomes. The severity of liver disease determines the develop-ment of SIRS, while SIRS leads to variceal bleeding, hepaticencephalopathy, and adversely affects survival.33 Certain aspects

f cirrhosis can exacerbate SIRS and complicate its diagnosis.atients with cirrhosis have higher levels of circulating endo-oxins that inversely correlate with hepatic deterioration.34 Afteripopolysaccharide challenge, those with cirrhosis had higherroinflammatory cytokine levels than those without, particu-

arly TNF-� and IL-6.35,36 Protein C and high density lipopro-ein, protective anti-inflammatory, and antiapoptotic factorsre thought to be reduced in cirrhosis.37 NO, whose metaboliteoncentrations are correlated with those of endotoxins, is in-reased in cirrhosis and is known to contribute to the oxidativetress and worsening vasodilatation of sepsis.38,39 Complica-ions of cirrhosis may mask themselves as symptoms of SIRS.or example, hypersplenism may reduce white blood cell count,yperdynamic circulation may elevate heart rate, and hepaticncephalopathy may cause hyperventilation.31 However, thesendicators appear to be more exaggerated in patients withirrhosis. The release of large amounts of cytokines in sepsisntensifies this hyperdynamic state and serves as the link be-ween bacterial infection and renal failure. Renal failure follow-ng SBP-related and non-SBP-related bacteremia has been ob-erved in 1 third of patients with cirrhosis and ascites.28 –30

Altered hemodynamics and widespread inflammation lead toimpaired tissue oxygenation, cell necrosis, and apoptosis, andultimately organ failure. When organ function can no longer

Figure 1. Cirrhosis-associated im-mune dysfunction syndrome (CAIDS).

sustain homeostasis without intervention, the patient is

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September 2011 IMMUNE DYSFUNCTION AND INFECTION IN CIRRHOSIS 729

deemed to have multiple organ dysfunction syndrome, a com-mon result of cirrhosis and severe sepsis.

Relative adrenal insufficiency is common in patients withseptic shock and is associated with hemodynamic instability,renal failure, and increased mortality.40 It is diagnosed in ap-

roximately 70% of septic shock patients with cirrhosis and iselieved to be linked to their impaired cortisol synthesis andecreased high density lipoprotein levels.41,42 The use of hydro-ortisone in patients with septic shock remains controver-

Figure 2. Pathogenesis ofSBP.

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

Infections in CirrhosisGastrointestinal Bleeding–AssociatedInfections and ProphylaxisGI 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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730 BONNEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9

episode of SBP or bacteremia.46 Conversely, the presence ofinfection has been found to increase the risk of early bleed-ing.47,48 Goulis et al49 hypothesize that bacterial endotoxinsstimulate hepatic stellate cell contraction and endothelial NOproduction, which then increase sinusoidal pressure and inhibitplatelet aggregation, respectively.

Patients who present with acute episodes of GI bleedingrequire short-term antibiotic prophylaxis regardless of the pres-ence of ascites. Most infections are caused by gram-negativebacteria and are preventable with selective decontamination byquinolones.50 Long-term SBP prophylaxis with norfloxacin hasesulted in quinolone-resistant gram-negative bacteria and anncreased prevalence of gram-positive bacteria.3 Therefore,hird-generation cephalosporins, which target both gram-neg-tive and gram-positive bacteria, are preferred prophylactictrategies. In patients with advanced cirrhosis, 1 g of intrave-ous (IV) ceftriaxone for 7 days after bleeding was found to beore effective in preventing bacterial infections than oral nor-

oxacin.51 Prospective randomized trials and a recent Cochraneatabase review found antibiotic prophylaxis to significantly

educe rates of infection, rebleeding, and mortality.52–54 Basedpon the “endotoxin-induced sinusoidal pressure” hypothe-is,49 antibiotic decontamination may lower the risk of rebleed-ng via reduction of endotoxin levels and subsequent portalressure. Nonselective beta blockers, commonly used to lowerortal hypertension and prevent initial variceal hemorrhage,an also serve to decrease bacterial translocation during ancute 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 Che-larescu et al56 in the postsurgical setting found propranolol toreduce infections from 42% to 15%. However, the use of betablockers in patients with refractory ascites may limit the com-pensatory increase in cardiac output and increase vulnerabilityto complications such as septic shock and renal failure.57,58

Prokinetic agents may also reduce dysmotility and bacterialtranslocation. Prophylaxis with norfloxacin and cisapride wasfound to significantly reduce the rate of SBP compared withnorfloxacin alone.59 There is some evidence to suggest that theuse of probiotics promotes the growth of gram-positive bacteriaat the expense of gram-negative bacteria,60 but it has yet to beenshown to benefit patients with cirrhosis.61,62 Given the increas-ingly negative implication of gram-positive bacteria in infec-tions, replacing gram-negative bacterial populations may be oflittle use.

Spontaneous Bacterial Peritonitis: Diagnosis,Treatment, and PreventionThe 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 hospital-ization and half develop during the hospitalization.63 The in-

ospital mortality rate from SBP is approximately 32%.64 Themajority of these infections are caused by E. coli, Klebsiella spp.,other Enterobacteriaceae, P. aeruginosa, enterococci, and strep-tococci (Table 1).65 The current recommendation is to perform

diagnostic paracentesis in all patients with ascites at the timef hospital admission and in those who manifest symptoms oferitoneal infection, systemic signs of infection, hepatic en-ephalopathy, or rapid impairment in renal function while

ospitalized.63,66 The diagnosis cutoff of SBP is a polymorpho-

uclear (PMN) count of 250 cells/mm3 while the highest spec-ficity is reached at 500 cells/mm3.63

Up to 65% of patients with clinical evidence of SBP andincreased ascites have negative cultures,67 but inoculation of 10mL of ascitic fluid in aerobic and anaerobic culture bottles atthe bedside has improved sensitivity to approximately 80%.68

Recent applications of culture-independent methods have at-tempted to improve screening outcomes. Several types of leu-kocyte esterase reagent strips have been evaluated in the diag-nosis of SBP and have demonstrated sensitivity and specificityranging between 45% and 100% and 81% to 100%, respectively.69

A recent study demonstrated an esterase strip calibrated to anascitic fluid PMN count �250 cells/mm3 to be a good bedsidecreening tool.70 Preliminary application of molecular analysiso identify bacterial DNA has yielded promising results that

ay replace culture techniques in the future.71,72

Bacterascites and secondary peritonitis are unique condi-tions of SBP that require specific guidelines for identificationand therapy. It is identified by a positive ascitic fluid cultureand an ascitic PMN �250 cells/mm3. The differentiation be-tween SBP and secondary peritonitis, ie, bacterial peritonitiscaused by perforation or acute inflammation of organs, can bequite difficult. Secondary peritonitis, though only accountingfor 4.5% of all peritonitis cases in cirrhosis,73 should be sus-

ected in any of the following situations: (1) lack of a responseo antibiotic therapy; (2) 2 or more organisms isolated (partic-larly anaerobes or fungi; (3) the presence of at least 2 of theollowing in ascitic fluid: glucose �50 mg/dL, protein �1

g/dL, lactic dehydrogenase greater than normal serum lev-els.63 With intestinal perforation, secondary peritonitis may

lso be suspected if chorioembryonic antigen �5 ng/mL orlkaline phosphatase �240 U/L.74 After diagnosis of a causef secondary peritonitis with a radiological study such asagnetic resonance imaging or computed tomography scan,

atients should receive antibiotic therapy and undergo sur-ical evaluation.63,66,73,75 Because it is often a monobacterial

infection with an associated white blood cell response, SBP isdefined as culture positive. However, a variant of it calledculture-negative neutrocytic ascites can be encountered andhas similar clinical outcomes (Figure 4).66,74,76 –79

The current standard for treatment of SBP is with a minimaldose of 2 g of intravenous cefotaxime every 12 hours for 5days.80,81 In those with clinical improvement, a repeat of para-centesis is not necessary to assess for resolution of SBP. Equallyeffective alternative therapies include cephalosporins (ceftriax-one, ceftazidime, ceftizoxime), amoxicillin-clavulanic acid, andquinolones (ciprofloxacin, ofloxacin, levofloxacin) for beta-lac-tam hypersensitive patients.31,63,82 When clinical signs of infec-tion have improved, replacing IV cephalosporin with oral cip-rofloxacin to complete the course of therapy may be morecost-effective.83 Patients taking quinolones as prophylaxishould be aware of treatment failure because of antibioticesistance or enterococcal infection. If clinical improvementnd a sufficient drop in neutrophil count in ascites (�25% ofnitial value) are not observed by day 3 of treatment, a switch ofntibiotic therapy should be considered while the patient isvaluated for secondary peritonitis.

Renal impairment develops in approximately 1 third of all SBPatients and is a strong predictor of mortality during hospitaliza-ion.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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of intravenous albumin (1.5 g/kg body weight within 6 hours ofSBP diagnosis followed by 1 g/kg body weight on day 3) inconjunction with cefotaxime was found to reduce the incidence ofrenal impairment from 33% to 10% and mortality from 29% to10%.28 Albumin increases mean arterial volume, binds TNF-� andNO to counteract the inflammatory response of infection, andremoves toxins from circulation.84–86 These infusions are mostffective in patients with baseline creatinine �1.0 mg/dL and totalilirubin �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 alterna-tive to albumin.

When treated effectively, recovery from SBP is seen in ap-

able 1. Pathogens Causing Infections and Unique Features

Organisms Common clinica

acteriaE. coli, Klebsiella spp., and other

gram-negative enteric bacteriaSBP, bacteremia, UTI

Vibrio vulnificus Soft tissue infection, bacte

Vibrio cholera (non-o1) Diarrhea, septicemia

Vibrio parahemolyticus Diarrhea, septicemiaAeromonas spp. Soft tissue infection, bacteYersinia spp. Septicemia, hepatosplenic

Listeria monocytogenes Septicemia, meningitis, per

Plesiomonas shigelloides Septicemia, meningitis, sof

Clostridium spp. Septicemia, soft tissue infe

Clostridium difficile Antibiotic-associated diarrhe

Staphylococcus aureus Soft tissue infection, septic

Streptococcus pneumoniae Septicemia, pneumonia, me

Streptococcus group B Septicemia, peritonitis, skininfection

Enterococcus spp. SBP, septicemia, UTI, biliarendocarditis

Mycobacterium tuberculosis (TB) Pulmonary TB, extrapulmonperitonitis, disseminated

FungiCryptococcus neoformans Peritonitis, meningitis, diss

cryptococcosisFungi

Candida spp. Biliary tract infection, septic

proximately 90% of patients and 30-day survival is in at least

80%.63 For patients who fail treatment, hospital mortalityranges from 50% to 80%.89 The rapid deterioration of liverunction in SBP patients makes for generally poor long-termrognosis after an episode of SBP. Franca et al90 found the-year survival rate to be 28.5%. The recent shift in microbialtiology of SBP toward cefotaxime-resistant strains may com-licate survival by delaying infection resolution.

Patients recovering from an episode of SBP should be givenntibiotic prophylaxis. In those without antibiotic prophylaxis,he rate of recurrence of SBP is 43% at 6 months, 69% at 1 year,nd 74% at 2 years after the initial episode.91 Ginés et al92 found

that 400 mg per day oral norfloxacin reduced recurrence of SBPfrom 68% to 20%. The use of 500 mg ciprofloxacin per day,

tients With Cirrhosis

rome Special comments

Increased resistance in patients takingprophylactic quinolones and in nosocomialinfections

Increased incidence in cirrhosis, particularlyhemochromatosis

50%–60% mortality in septic form138

24% for localized wound infection139

Increased incidence and morbidity inadvanced cirrhosis (mortality 24%)11

Increased morbidityIncreased incidence and morbidity in cirrhosis

sses, peritonitis Increased incidence in cirrhosis and ironoverload state

is Increased incidence in cirrhosis, particularlyhemochromatosis

ue infection Increased incidence in cirrhosis and ironoverload state

, peritonitis Increased incidence and morbidity of C.perfringens in cirrhosis (mortality54%–65%)11

d colitis Increased incidence (may be related to thecommon use of antibiotics and PPI inpatients with cirrhosis)122

Increased mortality (14%)121

, endocarditis Increased incidence in cirrhosis, particularlyhospitalized patients

Increased MRSA nasal carriageitis Increased incidence and morbidity

Pneumococcal vaccine is recommended inpatients with cirrhosis (vaccine efficacy hasbeen validated in alcoholic cirrhosis)

soft tissue Increased incidence

t infection, Increased incidence and morbidityMortality rate approximately 25% (up to 50%

in endocarditis form)114

, esp. Higher incidence, more virulent, and moreextra-pulmonary forms in cirrhosis compareto non-cirrhosis

Risk for multi-drug resistance TB

ted Increased incidence in advanced cirrhosisMortality rate up to 70%132

Identified in the bile up to 44% of PSCpatients with cholangitis134,135

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732 BONNEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9

gested,93 is known to be effective.94 Intermittent dosing ofrophylactic antibiotics may select resistant flora, thereforeaily dosing is preferred. For patients intolerant to quinolones,aily double-strength oral trimethoprim/sulfamethoxazole isn effective alternative.95,96 The current time scale for long-term

prophylaxis is indefinite.Patients with advanced cirrhosis and low protein ascites may be

candidates for primary prophylaxis against SBP.97 In a randomizedontrolled trial,98 patients with low protein ascites levels (�1.5

g/dL) with advanced liver failure or impaired renal function whoreceived norfloxacin prophylaxis had a significantly decreasedprobability of SBP, hepatorenal syndrome, and mortality.

Other Infections in CirrhosisUrinary Tract InfectionUTI occurs in approximately 15% to 20% of hospitalized

patients with cirrhosis; it is twice as frequent in patients withcirrhosis compared with matched controls.3,99 Women have a 4imes higher rate of bacteriuria than men.99 Gram-negative

bacilli, such as E. coli and Klebsiella spp., are the primary causativeagents. Notably, bacteriuria is not associated with an increasedrisk of sepsis, SBP, or other infections often seen in patientswith cirrhosis.99 Although more frequent among those withcirrhosis, UTI does not consistently correlate with the severityof liver disease and is more strongly associated with gender anddiabetes.99 –101 The high incidence of UTI in cirrhosis remains

nexplained. Bercoff et al102 cite the increased bladder postvoid c

residual volume as an explanation, however, this finding wasnot supported in a subsequent study.99 Treatment of UTI withquinolones is effective in approximately 95% of cases.99

PneumoniaPneumonia is the third leading cause of infections in

patients with cirrhosis.1,50 Pulmonary clearance of pneumococcias significantly decreased in a rat model of cirrhosis, most

ikely as a result of decreased complement levels.103 Communi-ty-acquired pneumonia (CAP) is most often caused by S. pneu-moniae and H. influenza.104 S. aureus, M. pneumoniae, M. catarrha-is, C. pneumoniae, Klebsiella spp., and Legionella spp. have also beenmplicated as causes of CAP. The risk of bacteremia in CAP isncreased in patients with cirrhosis.105 Further, procedures such

as tracheal intubation and esophageal tamponade put patientswith cirrhosis at risk of hospital-acquired pneumonia.106 In the

resence of comorbidities such as cirrhosis, treatment is idealith IV beta-lactam plus macrolide or IV antipneumococcaluinolones.104 Pneumococcal vaccination is recommended inatients with cirrhosis.104,107

Soft Tissue InfectionsChronic edema and increased bacterial translocation

predispose patients with cirrhosis to soft tissue infections,which constitute approximately 11% of infections.108 Both

ram-positive (S. aureus, group A Streptococci) and gram-negativeacteria (Klebsiella spp., Aeromonas spp., V. vulnificus) are common

Figure 4. Ascites infectionalgorithm.

auses of soft tissue infections. Cellulitis is the most frequently

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September 2011 IMMUNE DYSFUNCTION AND INFECTION IN CIRRHOSIS 733

observed skin infection in patients with cirrhosis and has arecurrence rate of 20%.109 Necrotizing fasciitis, a rare but severeorm of soft tissue infection, is predominantly caused by gram-egative bacilli.110 Unlike the general population, necrotizing

fasciitis in those with cirrhosis rarely develops from an obviousportal of entry in the extremities, thereby suggesting a potentialpathway of bacterial translocation and bacteremia leading tosoft tissue infections.110,111 Broad spectrum antibiotic treatments necessary for proper management of soft tissue infections,nd surgical intervention for deep infections may be needed.

EndocarditisApproximately 10% of infectious endocarditis (IE) cases

have cirrhosis as an underlying condition.112 IE is a concern forhospitalized patients with cirrhosis because of the increased risk ofbacteremia associated with invasive procedures (transjugular intra-hepatic portosystemic shunt, upper endoscopy, etc). Valve disor-ders are present in approximately 60% of patients with cirrhosiswho have IE.112 Gram-positive bacteria such S. aureus, �-hemolytictreptococci (S. agalactiae, S. pyogenes), and enterococci (E. faecalis, E.aecium) are the most commonly isolated organisms.112,113 Depend-ng on the organism, a minimum of 4 weeks of antibiotic therapys recommended.114 Patients with advanced liver cirrhosis haveigh surgical mortality rates;115 therefore surgical management of

E is reserved for selected patients who do not respond to medicalherapy.

TuberculosisThe incidence and virulence of Mycobacterium tuberculosis

nfections are increased in patients with cirrhosis.116 In a cohort oftuberculosis (TB) patients with liver cirrhosis in Denmark, the30-day case fatality rate was 27.3% and the 1-year case fatality ratewas 47.7%.116 TB patients with liver cirrhosis show extrapulmonaryinvolvement,117 such as TB peritonitis, more frequently. Comparedwith SBP, TB peritonitis is present in less advanced cirrhosis andis characterized by lower white blood cell count in ascites, higherproportion of mononuclear leukocytes, higher protein concentra-tion, and higher levels of adenosine deaminase activity in ascites.118

Though adenosine deaminase level analysis is useful in the detec-tion of TB peritonitis in patients without cirrhosis, the presence ofcirrhosis reduces its sensitivity to 30%.119 Laparoscopic biopsies

rovide definitive diagnosis of TB peritonitis by revealing multiplehitish nodules scattered over the peritoneum.118,120 Patients withB and cirrhosis respond well to anti-TB therapy, however they

ace a greater risk of hepatotoxicity.117

Clostridium difficileClostridium difficile is an increasingly prevalent hospital-

acquired infection that affects patients with cirrhosis. A recentstudy of over 80,000 patients with cirrhosis found patients withC. difficile-associated disease to have higher mortality and longerlength of stay than those without infection.121 Antibiotics andproton pump inhibitors were independently associated with C.difficile infection. Thus it is recommended that antibiotic pro-phylaxis be limited to patients at highest risk of developing SBPand that proton pump inhibitors be used selectively.122

Drug-Resistant InfectionsNosocomial infections account for a significant propor-

tion of infections in patients with cirrhosis and an increasing

number of these infections are caused by antibiotic-resistant b

and gram-positive pathogens. Approximately 37% to 64% ofbacterial infections, either nosocomial or in the context ofantibiotic intervention in an outpatient setting, have beenfound to be multidrug-resistant.3,123,124 Gram-negative isolatesin SBP, such as E. coli and K. pneumoniae, are being encounteredwith increasing rates of resistance.125 Gram-positive pathogens

re increasingly common in patients with cirrhosis.125 Methi-cillin-resistant S. aureus has been noted to account for 24.8% ofnosocomial SBP.125 E. faecalis and E. faecium have been isolatedin nearly 10% to 24% of infections in the setting of cirrhosis andare associated with 25% mortality rate.3,125,126 Approximately athird of enterococcal bacteremia cases demonstrate vancomycinresistance and are associated with twice the mortality rate ofnonresistant strains.127,128

Fungal InfectionsCirrhosis increases susceptibility to Cryptococcus neofor-

mans, an encapsulated fungus that is typically associated withhuman immunodeficiency virus–infected patients.129,130 Livercirrhosis is an underlying condition in approximately a third ofnon– human immunodeficiency virus cryptococcaemia casesand is a stronger independent predictor of 30-day mortalitythan in those with acquired immunodeficiency syndrome.131

Though uncommon, C. neoformans may infect ascites and causespontaneous cryptococcal peritonitis. Unlike SBP, spontaneouscryptococcal peritonitis presents itself with an elevation inlymphocyte count and, because of late detection, has a very highmortality rate (�70%).132 The pathogenesis of cryptococcal peri-tonitis may be via direct percutaneous inoculation during para-centesis, GI bleeding, or bacterial translocation.130,133 Candidanfections can also be encountered particularly in patients withrimary sclerosing cholangitis (PSC). Candida species have been

dentified in 44% of bile samples in PSC patients, particularlyhose with dominant strictures.134,135 A high prevalence of bil-

iary candidiasis exists, however, the effect of antifungal thera-pies on treatment outcomes for recurrent cholangitis remainsunknown.

Specific Liver Disease–Related InfectionsIron 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 de-creased levels of hepcidin, an iron-regulator hormone withantimicrobial activity, serve as the link between liver disease andthese infections.137 Patients with hemochromatosis face a 30-old greater risk of acquiring V. vulnificus, a bacterium acquiredhrough ingestion of contaminated raw oysters.138 V. vulnificus

septicemia has a 50% to 60% case mortality rate in patients withliver disease and 7% to 22% mortality for localized woundinfection.138,139 Yersinia enterocolitica and Yersinia pseudotuberculo-is, 2 gram-negative bacilli transmitted zoonotically, infect viaystemic or portal vein bacteremia to cause hepatic abscessesith up to a 56% mortality rate.140 –142

PSC is a risk factor for ascending cholangitis, which isassociated with up to a 16% mortality rate.143,144 Generally,ascending cholangitis is relatively uncommon unless the biliarytree has been manipulated by endoscopic retrograde cholangio-pancreotography. The most common infections after endo-scopic retrograde cholangiopancreotography are caused bygram-negative bacteria such as E. coli, Klebsiella spp., and Entero-

acter spp.143,144 However, if cholangitis occurs without any in-

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734 BONNEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9

tervention, the presence of stones, dominant strictures, or chol-angiocarcinoma should be considered. In a study of explantedlivers with PSC, bacteria were isolated in approximately 60% ofcases.145 The most common bacteria isolated were alpha-hemo-ytic streptococci, enterococci, and staphylococci. Though thetiology of PSC is largely unknown, bacterial infection of theile ducts with dominant stenoses has been implicated in therogression of the disease.146

SummaryPatients with cirrhosis are in a multifactorial immuno-

compromised state which predisposes them to a higher risk ofinfection. Bacterial infections, particularly SBP and bacteremia, arean important cause of morbidity and mortality in these patients.Gram-negative enteric bacteria appear to be the most commoncausative organisms. However, other unusual bacteria and fungiare also frequently observed and more virulent in patients withcirrhosis relative to those without liver disease. Moreover, thesepathogens can present with various clinical syndromes that may bedifficult to recognize. The relationship between immune dysfunc-tion and infection in cirrhosis has been extensively investigated.Bacterial translocation appears to be an important step, whichaccounts for the increased levels of endotoxins, cytokines, and NO;these play a critical role in the development of an excessive inflam-matory response and hyperdynamic circulatory state of cirrhosis.As hepatic function deteriorates and portal hypertension pro-gresses, overt infection is more likely to develop and subsequentlycan evolve to sepsis, leading to consequences such as septic shock,multiorgan failure, and death.

Early diagnosis and proper management of infections inpatients with cirrhosis are necessary. Generally, intravenousthird generation cephalosporins are recommended as empiricantibiotic therapy for most cases of SBP and bacteremia. How-ever, the risk of resistant organisms and unusual pathogensshould be kept in mind, especially in patients with cirrhosiswho are receiving quinolone prophylaxis or have hemochroma-tosis as an etiology of liver disease. Auxiliary therapy withintravenous albumin can significantly reduce morbidity andmortality in SBP patients who are at high risk of developingrenal failure. The importance of preventive strategies cannot beunderscored. Patients with cirrhosis admitted with GI hemor-rhage benefit from short-term antibiotic prophylaxis, whereaslong-term oral prophylaxis is recommended in those who haverecovered from SBP. Despite recent advances in understandingof the mechanisms of infection in patients with cirrhosis, theoutcomes of those patients with severe infections still remainpoor. Further studies into mechanisms, diagnostic approaches,and potential preventive strategies are needed to improve themanagement of infections in patients with cirrhosis.

Supplementary MaterialNote: To access the supplementary material accompa-

nying this article, visit the online version of Clinical Gastroenter-ology and Hepatology at www.cghjournal.org, and at doi:10.1016/j.cgh.2011.02.031.

References

1. Tandon P, Garcia-Tsao G. Bacterial infections, sepsis, and mul-

tiorgan failure in cirrhosis. Semin Liver Dis 2008;28:26–42.

2. Arvaniti V, D’Amico G, Fede G, et al. Infections in patients withcirrhosis increase mortality 4-fold and should be used in deter-mining prognosis. Gastroenterology 1256;2010:1246–1256,e1241–e1245.

3. Fernández J, Navasa M, Gómez J, et al. Bacterial infections incirrhosis: epidemiological changes with invasive procedures andnorfloxacin prophylaxis. Hepatology 2002;35:140–148.

4. Borzio M, Salerno F, Piantoni L, et al. Bacterial infection inpatients with advanced cirrhosis: a multicentre prospectivestudy. Dig Liver Dis 2001;33:41–48.

5. Runyon BA, Squier S, Borzio M. Translocation of gut bacteria inrats with cirrhosis to mesenteric lymph nodes partially explainsthe pathogenesis of spontaneous bacterial peritonitis. J Hepatol1994;21:792–796.

6. Garcia-Tsao G, Wiest R. Gut microflora in the pathogenesis ofthe complications of cirrhosis. Best Pract Res Clin Gastroenterol2004;18:353–372.

7. Ghassemi S, Garcia-Tsao G. Prevention and treatment of infec-tions in patients with cirrhosis. Best Pract Res Clin Gastroen-terol 2007;21:77–93.

8. Katz S, Jimenez MA, Lehmkuhler WE, et al. Liver bacterial clear-ance following hepatic artery ligation and portocaval shunt.J Surg Res 1991;51:267–270.

9. Wasmuth HE, Kunz D, Yagmur E, et al. Patients with acute onchronic liver failure display “sepsis-like” immune paralysis.J Hepatol 2005;42:195–201.

10. Fiuza C, Salcedo M, Clemente G, et al. In vivo neutrophil dys-function in cirrhotic patients with advanced liver disease. J In-fect Dis 2000;182:526–533.

11. Christou L, Pappas G, Falagas ME. Bacterial infection-relatedmorbidity and mortality in cirrhosis. Am J Gastroenterol 2007;102:1510–1517.

12. Trevisani F, Castelli E, Foschi FG, et al. Impaired tuftsin activityin cirrhosis: relationship with splenic function and clinical out-come. Gut 2002;50:707–712.

13. Garfia C, García-Ruiz I, Solís-Herruzo JA. Deficient phospho-lipase C activity in blood polimorphonuclear neutrophils frompatients with liver cirrhosis. J Hepatol 2004;40:749–756.

14. Laffi G, Carloni V, Baldi E, et al. Impaired superoxide anion,platelet-activating factor, and leukotriene B4 synthesis by neu-trophils in cirrhosis. Gastroenterology 1993;105:170–177.

15. Shawcross DL, Wright GA, Stadlbauer V, et al. Ammonia impairsneutrophil phagocytic function in liver disease. Hepatology2008;48:1202–1212.

16. Kusaba N, Kumashiro R, Ogata H, et al. In vitro study of neu-trophil apoptosis in liver cirrhosis. Intern Med 1998;37:11–17.

17. Liles WC, Kiener PA, Ledbetter JA, et al. Differential expressionof Fas (CD95) and Fas ligand on normal human phagocytes:implications for the regulation of apoptosis in neutrophils. J ExpMed 1996;184:429–440.

18. Ono Y, Watanabe T, Matsumoto K, et al. Opsonophagocyticdysfunction in patients with liver cirrhosis and low responses totumor necrosis factor-alpha and lipopolysaccharide in patients’blood. J Infect Chemother 2004;10:200–207.

19. Runyon BA, Morrissey RL, Hoefs JC, et al. Opsonic activity ofhuman ascitic fluid: a potentially important protective mecha-nism against spontaneous bacterial peritonitis. Hepatology1985;5:634–637.

20. Gomez F, Ruiz P, Schreiber AD. Impaired function of macro-phage Fc gamma receptors and bacterial infection in alcoholiccirrhosis. N Engl J Med 1994;331:1122–1128.

21. Ferri C, Antonelli A, Mascia MT, et al. HCV-related autoimmuneand neoplastic disorders: the HCV syndrome. Dig Liver Dis2007;39 Suppl 1:S13–S21.

22. Romeo J, Warnberg J, Marcos A. Drinking pattern and socio-cultural aspects on immune response: an overview. Proc Nutr

Soc 2010;69:341–346.

September 2011 IMMUNE DYSFUNCTION AND INFECTION IN CIRRHOSIS 735

23. Laso FJ, Lapeña P, Madruga JI, et al. Alterations in tumornecrosis factor-alpha, interferon-gamma, and interleukin-6 pro-duction by natural killer cell-enriched peripheral blood mononu-clear cells in chronic alcoholism: relationship with liver diseaseand ethanol intake. Alcohol Clin Exp Res 1997;21:1226–1231.

24. Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis.Hepatology 2005;41:422–433.

25. Chang CS, Chen GH, Lien HC, et al. Small intestine dysmotilityand bacterial overgrowth in cirrhotic patients with spontaneousbacterial peritonitis. Hepatology 1998;28:1187–1190.

26. Chesta J, Defilippi C, Defilippi C. Abnormalities in proximal smallbowel motility in patients with cirrhosis. Hepatology 1993;17:828–832.

27. Follo A, Llovet JM, Navasa M, et al. Renal impairment afterspontaneous bacterial peritonitis in cirrhosis: incidence, clinicalcourse, predictive factors and prognosis. Hepatology 1994;20:1495–1501.

28. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albuminon renal impairment and mortality in patients with cirrhosis andspontaneous bacterial peritonitis. N Engl J Med 1999;341:403–409.

29. Terra C, Guevara M, Torre A, et al. Renal failure in patients withcirrhosis and sepsis unrelated to spontaneous bacterial perito-nitis: value of MELD score. Gastroenterology 2005;129:1944–1953.

30. Fasolato S, Angeli P, Dallagnese L, et al. Renal failure andbacterial infections in patients with cirrhosis: epidemiology andclinical features. Hepatology 2007;45:223–229.

31. Wong F, Bernardi M, Balk R, et al. Sepsis in cirrhosis: report onthe 7th meeting of the International Ascites Club. Gut 2005;54:718–725.

32. Gustot T, Durand F, Lebrec D, et al. Severe sepsis in cirrhosis.Hepatology 2009;50:2022–2033.

33. Cazzaniga M, Dionigi E, Gobbo G, et al. The systemic inflamma-tory response syndrome in cirrhotic patients: relationship withtheir in-hospital outcome. J Hepatol 2009;51:475–482.

34. Chan CC, Hwang SJ, Lee FY, et al. Prognostic value of plasmaendotoxin levels in patients with cirrhosis. Scand J Gastroen-terol 1997;32:942–946.

35. Byl B, Roucloux I, Crusiaux A, et al. Tumor necrosis factor alphaand interleukin 6 plasma levels in infected cirrhotic patients.Gastroenterology 1993;104:1492–1497.

36. Wang SS, Lee FY, Chan CC, et al. Sequential changes in plasmacytokine and endotoxin levels in cirrhotic patients with bacterialinfection. Clin Sci (Lond) 2000;98:419–425.

37. Plessier A, Denninger MH, Consigny Y, et al. Coagulation disor-ders in patients with cirrhosis and severe sepsis. Liver Int2003;23:440–448.

38. Lee KC, Yang YY, Wang YW, et al. Increased plasma malondi-aldehyde in patients with viral cirrhosis and its relationships toplasma nitric oxide, endotoxin, and portal pressure. Dig Dis Sci2010;55:2077–2085.

39. Guarner C, Soriano G, Tomas A, et al. Increased serum nitriteand nitrate levels in patients with cirrhosis: relationship toendotoxemia. Hepatology 1993;18:1139–1143.

40. Tsai MH, Peng YS, Chen YC, et al. Adrenal insufficiency inpatients with cirrhosis, severe sepsis and septic shock. Hepa-tology 2006;43:673–681.

41. Fernández J, Escorsell A, Zabalza M, et al. Adrenal insufficiencyin patients with cirrhosis and septic shock: effect of treatmentwith hydrocortisone on survival. Hepatology 2006;44:1288–1295.

42. Marik PE, Gayowski T, Starzl TE. The hepatoadrenal syndrome:a common yet unrecognized clinical condition. Crit Care Med

2005;33:1254–1259.

43. Annane D, Sébille V, Charpentier C, et al. Effect of treatmentwith low doses of hydrocortisone and fludrocortisone on mortal-ity in patients with septic shock. JAMA 2002;288:862–871.

44. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy forpatients with septic shock. N Engl J Med 2008;358:111–124.

45. Arabi YM, Aljumah A, Dabbagh O, et al. Low-dose hydrocortisonein patients with cirrhosis and septic shock: a randomized con-trolled trial. CMAJ 2010;182:1971–1977.

46. Bernard B, Grangé JD, Khac EN, et al. Antibiotic prophylaxis forthe prevention of bacterial infections in cirrhotic patients withgastrointestinal bleeding: a meta-analysis. Hepatology 1999;29:1655–1661.

47. Bernard B, Cadranel JF, Valla D, et al. Prognostic significance ofbacterial infection in bleeding cirrhotic patients: a prospectivestudy. Gastroenterology 1995;108:1828–1834.

48. Vivas S, Manuel R, Palacio A, et al. Presence of bacterialinfection in bleeding cirrhotic patients is independently associ-ated with early mortality and failure to control bleeding. Dig DisSci 2001;46:2752–2757.

49. Goulis J, Patch D, Burroughs AK. Bacterial infection in thepathogenesis of variceal bleeding. Lancet 1999;353:139–142.

50. Caly WR, Strauss E. A prospective study of bacterial infectionsin patients with cirrhosis. J Hepatol 1993;18:353–358.

51. Fernández J, Ruiz del Arbol L, Gómez C, et al. Norfloxacin vsceftriaxone in the prophylaxis of infections in patients withadvanced cirrhosis and hemorrhage. Gastroenterology 2006;131:1049–1056.

52. Jun CH, Park CH, Lee WS, et al. Antibiotic prophylaxis using thirdgeneration cephalosporins can reduce the risk of early rebleed-ing in the first acute gastroesophageal variceal hemorrhage: aprospective randomized study. J Korean Med Sci 2006;21:883–890.

53. Hou MC, Lin HC, Liu TT, et al. Antibiotic prophylaxis after endo-scopic therapy prevents rebleeding in acute variceal hemor-rhage: a randomized trial. Hepatology 2004;39:746–753.

54. Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila FI, et al.Antibiotic prophylaxis for cirrhotic patients with upper gast-rointestinal bleeding. Cochrane Database Syst Rev 2010:CD002907.

55. Senzolo M, Cholongitas E, Burra P, et al. Beta-Blockers protectagainst spontaneous bacterial peritonitis in cirrhotic patients: ameta-analysis. Liver Int 2009;29:1189–1193.

56. Chelarescu O, Chelarescu D, Tircoveanu E, et al. Propranololadministration on post surgical infections in cirrhotic patients.Am J Gastroenterol 2003;38:A173.

57. Sersté T, Melot C, Francoz C, et al. Deleterious effects ofbeta-blockers on survival in patients with cirrhosis and refractoryascites. Hepatology 2010;52:1017–1022.

58. Wong F, Salerno F. Beta-blockers in cirrhosis: friend and foe?Hepatology 2010;52:811–813.

59. Sandhu BS, Gupta R, Sharma J, et al. Norfloxacin and cisapridecombination decreases the incidence of spontaneous bacterialperitonitis in cirrhotic ascites. J Gastroenterol Hepatol 2005;20:599–605.

60. Liu Q, Duan ZP, Ha DK, et al. Synbiotic modulation of gut flora:effect on minimal hepatic encephalopathy in patients with cir-rhosis. Hepatology 2004;39:1441–1449.

61. Tandon P, Moncrief K, Madsen K, et al. Effects of probiotictherapy on portal pressure in patients with cirrhosis: a pilotstudy. Liver Int 2009;29:1110–1115.

62. Pereg D, Kotliroff A, Gadoth N, et al. Probiotics for patients withcompensated liver cirrhosis: a double-blind placebo-controlledstudy. Nutrition 2011;27:177–181.

63. Rimola A, García-Tsao G, Navasa M, et al. Diagnosis, treatmentand prophylaxis of spontaneous bacterial peritonitis: a consen-sus document. International Ascites Club. J Hepatol 2000;32:

142–153.

736 BONNEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9

64. Thuluvath PJ, Morss S, Thompson R. Spontaneous bacterialperitonitis--in-hospital mortality, predictors of survival, andhealth care costs from 1988 to 1998. Am J Gastroenterol2001;96:1232–1236.

65. Navasa M, Follo A, Llovet JM, et al. Randomized, comparativestudy of oral ofloxacin versus intravenous cefotaxime in spon-taneous bacterial peritonitis. Gastroenterology 1996;111:1011–1017.

66. Runyon BA, AASLD Practice Guidelines Committee. Manage-ment of adult patients with ascites due to cirrhosis: an update.Hepatology 2009;49:2087–2107.

67. Runyon BA, Canawati HN, Akriviadis EA. Optimization of asciticfluid culture technique. Gastroenterology 1988;95:1351–1355.

68. Bobadilla M, Sifuentes J, Garcia-Tsao G. Improved method forbacteriological diagnosis of spontaneous bacterial peritonitis.J Clin Microbiol 1989;27:2145–2147.

69. Nguyen-Khac E, Cadranel JF, Thevenot T, et al. Review article:the utility of reagent strips in the diagnosis of infected ascites incirrhotic patients. Aliment Pharmacol Ther 2008;28:282–288.

70. Mendler MH, Agarwal A, Trimzi M, et al. A new highly sensitivepoint of care screen for spontaneous bacterial peritonitis usingthe leukocyte esterase method. J Hepatol 2010;53:477–483.

71. Rogers GB, Russell LE, Preston PG, et al. Characterisation ofbacteria in ascites—reporting the potential of culture-indepen-dent, molecular analysis. Eur J Clin Microbiol Infect Dis 2010;29:533–541.

72. Bruns T, Sachse S, Straube E, et al. Identification of bacterialDNA in neutrocytic and non-neutrocytic cirrhotic ascites bymeans of a multiplex polymerase chain reaction. Liver Int 2009;29:1206–1214.

73. Soriano G, Castellote J, Alvarez C, et al. Secondary bacterialperitonitis in cirrhosis: a retrospective study of clinical andanalytical characteristics, diagnosis and management. J Hepa-tol 2010;52:39–44.

74. Wu SS, Lin OS, Chen YY, et al. Ascitic fluid carcinoembryonicantigen and alkaline phosphatase levels for the differentiationof primary from secondary bacterial peritonitis with intestinalperforation. J Hepatol 2001;34:215–221.

75. Mazuski JE, Sawyer RG, Nathens AB, et al. The Surgical Infec-tion Society guidelines on antimicrobial therapy for intra-abdom-inal infections: an executive summary. Surg Infect (Larchmt)2002;3:161–173.

76. Runyon BA, Hoefs JC. Culture-negative neutrocytic ascites: avariant of spontaneous bacterial peritonitis. Hepatology 1984;4:1209–1211.

77. Runyon BA, Hoefs JC, Canawati HN. Polymicrobial bacteras-cites. A unique entity in the spectrum of infected ascitic fluid.Arch Intern Med 1986;146:2173–2175.

78. Runyon BA. Monomicrobial nonneutrocytic bacterascites: a vari-ant of spontaneous bacterial peritonitis. Hepatology 1990;12:710–715.

79. Akriviadis EA, Runyon BA. Utility of an algorithm in differentiatingspontaneous from secondary bacterial peritonitis. Gastroenter-ology 1990;98:127–133.

80. Rimola A, Salmerón JM, Clemente G, et al. Two different dos-ages of cefotaxime in the treatment of spontaneous bacterialperitonitis in cirrhosis: results of a prospective, randomized,multicenter study. Hepatology 1995;21:674–679.

81. Simmons BP, Gelfand MS, Grogan J, et al. Cefotaxime twicedaily versus ceftriaxone once daily. A randomized controlledstudy in patients with serious infections. Diagn Microbiol InfectDis 1995;22:155–157.

82. Yakar T, Güçlü M, Serin E, et al. A recent evaluation of empiricalcephalosporin treatment and antibiotic resistance of changingbacterial profiles in spontaneous bacterial peritonitis. Dig DisSci 2010;55:1149–1154.

83. Angeli P, Guarda S, Fasolato S, et al. Switch therapy with

ciprofloxacin vs. intravenous ceftazidime in the treatment ofspontaneous bacterial peritonitis in patients with cirrhosis:similar efficacy at lower cost. Aliment Pharmacol Ther 2006;23:75–84.

84. Chen TA, Tsao YC, Chen A, et al. Effect of intravenous albuminon endotoxin removal, cytokines, and nitric oxide production inpatients with cirrhosis and spontaneous bacterial peritonitis.Scand J Gastroenterol 2009;44:619–625.

85. Fernández J, Navasa M, Garcia-Pagan JC, et al. Effect of intra-venous albumin on systemic and hepatic hemodynamics andvasoactive neurohormonal systems in patients with cirrhosisand spontaneous bacterial peritonitis. J Hepatol 2004;41:384–390.

86. Jalan R, Schnurr K, Mookerjee RP, et al. Alterations in thefunctional capacity of albumin in patients with decompensatedcirrhosis is associated with increased mortality. Hepatology2009;50:555–564.

87. Terg R, Gadano A, Cartier M, et al. Serum creatinine and biliru-bin predict renal failure and mortality in patients with spontane-ous bacterial peritonitis: a retrospective study. Liver Int 2009;29:415–419.

88. Cartier M, Terg R, Lucero R, et al. Pilot study: Gelafundin (poly-geline) 4% plus antibiotics in the treatment of high-risk cirrhoticpatients with spontaneous bacterial peritonitis. Aliment Phar-macol Ther 2009;32:43–48.

89. Toledo C, Salmerón JM, Rimola A, et al. Spontaneous bacterialperitonitis in cirrhosis: predictive factors of infection resolutionand survival in patients treated with cefotaxime. Hepatology1993;17:251–257.

90. França AV, De Souza JB, Silva CM, et al. Long-term prognosis ofcirrhosis after spontaneous bacterial peritonitis treated withceftriaxone. J Clin Gastroenterol 2001;33:295–298.

91. Titó L, Rimola A, Ginès P, et al. Recurrence of spontaneousbacterial peritonitis in cirrhosis: frequency and predictive fac-tors. Hepatology 1988;8:27–31.

92. Ginés P, Rimola A, Planas R, et al. Norfloxacin prevents spon-taneous bacterial peritonitis recurrence in cirrhosis: results ofa double-blind, placebo-controlled trial. Hepatology 1990;12:716–724.

93. Rolachon A, Cordier L, Bacq Y, et al. Ciprofloxacin and long-termprevention of spontaneous bacterial peritonitis: results of aprospective controlled trial. Hepatology 1995;22:1171–1174.

94. Terg R, Llano K, Cobas SM, et al. Effects of oral ciprofloxacin onaerobic gram-negative fecal flora in patients with cirrhosis: re-sults of short- and long-term administration, with daily andweekly dosages. J Hepatol 1998;29:437–442.

95. Singh N, Gayowski T, Yu VL, et al. Trimethoprim-sulfamethoxa-zole for the prevention of spontaneous bacterial peritonitis incirrhosis: a randomized trial. Ann Intern Med 1995;122:595–598.

96. Guarner C, Runyon BA, Heck M, et al. Effect of long-term trim-ethoprim-sulfamethoxazole prophylaxis on ascites formation,bacterial translocation, spontaneous bacterial peritonitis, andsurvival in cirrhotic rats. Dig Dis Sci 1999;44:1957–1962.

97. Loomba R, Wesley R, Bain A, et al. Role of fluoroquinolones inthe primary prophylaxis of spontaneous bacterial peritonitis:meta-analysis. Clin Gastroenterol Hepatol 2009;7:487–493.

98. Fernández J, Navasa M, Planas R, et al. Primary prophylaxis ofspontaneous bacterial peritonitis delays hepatorenal syndromeand improves survival in cirrhosis. Gastroenterology 2007;133:818–824.

99. Cadranel JF, Denis J, Pauwels A, et al. Prevalence and riskfactors of bacteriuria in cirrhotic patients: a prospective case-control multicenter study in 244 patients. J Hepatol 1999;31:464–468.

100. Rabinovitz M, Prieto M, Gavaler JS, et al. Bacteriuria in patients

with cirrhosis. J Hepatol 1992;16:73–76.

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

September 2011 IMMUNE DYSFUNCTION AND INFECTION IN CIRRHOSIS 737

101. Amato A, Precone D, Carannante N, et al. Prevalence and riskfactors for bacteriuria in patients with cirrhosis. Infez Med2005;2:103–108.

102. Bercoff E, Dechelotte P, Weber J, et al. Urinary tract infection incirrhotic patients, an urodynamic explanation. Lancet 1985;325:987.

103. Mellencamp MA, Preheim LC. Pneumococcal pneumonia in a ratmodel of cirrhosis: effects of cirrhosis on pulmonary defensemechanisms against Streptococcus pneumoniae. J Infect Dis1991;163:102–108.

104. Niederman MS, Mandell LA, Anzueto A, et al. Guidelines for themanagement of adults with community-acquired pneumonia.Diagnosis, assessment of severity, antimicrobial therapy, andprevention. Am J Respir Crit Care Med 2001;163:1730–1754.

105. Falguera M, Trujillano J, Caro S, et al. A prediction rule forestimating the risk of bacteremia in patients with community-acquired pneumonia. Clin Infect Dis 2009;49:409–416.

106. Yang YY, Lin HC. Bacterial Infections in Patients with Cirrhosis.J Chin Med Assoc 2005;68:447–451.

107. Mehta G, Rothstein KD. Health maintenance issues in cirrhosis.Med Clin North Am 2009;93:901–915, viii–ix.

108. Liu BM, Chung KJ, Chen CH, et al. Risk factors for the outcomeof cirrhotic patients with soft tissue infections. J Clin Gastroen-terol 2008;42:312–316.

109. Rongey C, Lim NH, Runyon BA. Cellulitis in patients with cirrho-sis and edema: an under-recognized complication currentlymore common than spontaneous bacterial peritonitis. The OpenGastroenterol Journal 2008;2:24–27.

110. Lee CC, Chi CH, Lee NY, et al. Necrotizing fasciitis in patientswith liver cirrhosis: predominance of monomicrobial Gram-neg-ative bacillary infections. Diagn Microbiol Infect Dis 2008;62:219–225.

111. Cheng NC, Tai HC, Tang YB, et al. Necrotising fasciitis: clinicalfeatures in patients with liver cirrhosis. Br J Plast Surg 2005;58:702–707.

112. Fernández Guerrero ML, González López J, Górgolas M. Infec-tious endocarditis in patients with cirrhosis of the liver: a modelof infection in the frail patient. Eur J Clin Microbiol Infect Dis2010;29:1271–1275.

113. Fernández-Guerrero ML, Herrero L, Bellver M, et al. Nosocomialenterococcal endocarditis: a serious hazard for hospitalizedpatients with enterococcal bacteraemia. J Intern Med 2002;252:510–515.

114. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis:diagnosis, antimicrobial therapy, and management of complica-tions: a statement for healthcare professionals from the Com-mittee on Rheumatic Fever, Endocarditis, and Kawasaki Dis-ease, Council on Cardiovascular Disease in the Young, and theCouncils on Clinical Cardiology, Stroke, and Cardiovascular Sur-gery and Anesthesia, American Heart Association: endorsed bythe Infectious Diseases Society of America. Circulation 2005;111:e394–e434.

115. An Y, Xiao YB, Zhong QJ. Open-heart surgery in patients withliver cirrhosis: indications, risk factors, and clinical outcomes.Eur Surg Res 2007;39:67–74.

116. Thulstrup AM, Mølle I, Svendsen N, et al. Incidence and prog-nosis of tuberculosis in patients with cirrhosis of the liver. ADanish nationwide population based study. Epidemiol Infect2000;124:221–225.

117. Cho YJ, Lee SM, Yoo CG, et al. Clinical characteristics oftuberculosis in patients with liver cirrhosis. Respirology 2007;12:401–405.

118. Kim NJ, Choo EJ, Kwak YG, et al. Tuberculous peritonitis incirrhotic patients: comparison of spontaneous bacterial perito-nitis caused by Escherichia coli with tuberculous peritonitis.

Scand J Infect Dis 2009;41:852–856.

119. Hillebrand DJ, Runyon BA, Yasmineh WG, et al. Ascitic fluidadenosine deaminase insensitivity in detecting tuberculousperitonitis in the United States. Hepatology 1996;24:1408–1412.

120. Reddy KR, DiPrima RE, Raskin JB, et al. Tuberculous peritonitis:laparoscopic diagnosis of an uncommon disease in the UnitedStates. Gastrointest Endosc 1988;34:422–426.

121. Bajaj JS, Ananthakrishnan AN, Hafeezullah M, et al. Clostridiumdifficile is associated with poor outcomes in patients with cir-rhosis: a national and tertiary center perspective. Am J Gastro-enterol 2010;105:106–113.

122. Garcia-Tsao G, Surawicz CM. Editorial: Clostridium difficile in-fection: yet another predictor of poor outcome in cirrhosis. Am JGastroenterol 2010;105:114–116.

23. Cheong HS, Kang CI, Lee JA, et al. Clinical significance andoutcome of nosocomial acquisition of spontaneous bacterialperitonitis in patients with liver cirrhosis. Clin Infect Dis 2009;48:1230–1236.

24. Merli M, Lucidi C, Giannelli V, et al. Cirrhotic patients are at riskfor health care-associated bacterial infections. Clin Gastroen-terol Hepatol 2010;8:979–985.

25. Campillo B, Richardet JP, Kheo T, et al. Nosocomial spontane-ous bacterial peritonitis and bacteremia in cirrhotic patients:impact of isolate type on prognosis and characteristics of in-fection. Clin Infect Dis 2002;35:1–10.

26. McBride SJ, Upton A, Roberts SA. Clinical characteristics andoutcomes of patients with vancomycin-susceptible Enterococ-cus faecalis and Enterococcus faecium bacteraemia—a five-year retrospective review. Eur J Clin Microbiol Infect Dis 2010;29:107–114.

27. Bhavnani SM, Drake JA, Forrest A, et al. A nationwide, multi-center, case-control study comparing risk factors, treatment,and outcome for vancomycin-resistant and -susceptible entero-coccal bacteremia. Diagn Microbiol Infect Dis 2000;36:145–158.

28. Park MK, Lee JH, Byun YH, et al. Changes in the profiles ofcausative agents and antibiotic resistance rate for spontaneousbacterial peritonitis: an analysis of cultured microorganisms inrecent 12 years [in Korean]. Korean J Hepatol 2007;13:370–377.

29. Albert-Braun S, Venema F, Bausch J, et al. Cryptococcus neo-formans peritonitis in a patient with alcoholic cirrhosis: casereport and review of the literature. Infection 2005;33:282–288.

30. Mabee CL, Mabee SW, Kirkpatrick RB, et al. A risk factor forcryptococcal peritonitis. Am J Gastroenterol 1995;90:2042–2045.

31. Jean SS, Fang CT, Shau WY, et al. Cryptococcaemia: clinicalfeatures and prognostic factors. QJM 2002;95:511–518.

32. Park WB, Choe YJ, Lee KD, et al. Spontaneous cryptococcalperitonitis in patients with liver cirrhosis. Am J Med 2006;119:169–171.

33. Saif MW, Raj M. Cryptococcal peritonitis complicating hepaticfailure: case report and review of the literature. J Appl Res2006;6:43–50.

34. Lenz P, Conrad B, Kucharzik T, et al. Prevalence, associations,and trends of biliary-tract candidiasis: a prospective observa-tional study. Gastrointest Endosc 2009;70:480–487.

35. Kulaksiz H, Rudolph G, Kloeters-Plachky P, et al. Biliary Candidainfections in primary sclerosing cholangitis. J Hepatol 2006;45:711–716.

36. Khan FA, Fisher MA, Khakoo RA. Association of hemochroma-tosis with infectious diseases: expanding spectrum. Int J InfectDis 2007;11:482–487.

37. Ashrafian H. Hepcidin: the missing link between hemochroma-tosis and infections. Infect Immun 2003;71:6693–6700.

38. Kizer KW. Vibrio vulnificus hazard in patients with liver disease.

West J Med 1994;161:64–65.

738 BONNEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9

139. Brann OS. Infectious complications of cirrhosis. Curr Gastroen-terol Rep 2001;3:285–292.

140. Vadillo M, Corbella X, Pac V, et al. Multiple liver abscessesdue to Yersinia enterocolitica discloses primary hemochro-matosis: three cases reports and review. Clin Infect Dis1994;18:938–941.

141. Olesen LL, Ejlertsen T, Paulsen SM, et al. Liver abscesses dueto Yersinia enterocolitica in patients with haemochromatosis.J Intern Med 1989;225:351–354.

142. Mennecier D, Lapprand M, Hernandez E, et al. Liver abscessesdue to Yersinia pseudotuberculosis discloses a genetic hemo-chromatosis [in French]. Gastroenterol Clin Biol 2001;25:1113–1115.

143. Melzer M, Toner R, Lacey S, et al. Biliary tract infection andbacteraemia: presentation, structural abnormalities, causativeorganisms and clinical outcomes. Postgrad Med J 2007;83:773–776.

144. Subhani JM, Kibbler C, Dooley JS. Review article: antibioticprophylaxis for endoscopic retrograde cholangiopancreatogra-phy (ERCP). Aliment Pharmacol Ther 1999;13:103–116.

145. Olsson R, Björnsson E, Bäckman L, et al. Bile duct bacterial

isolates in primary sclerosing cholangitis: a study of explantedlivers. J Hepatol 1998;28:426–432.

146. Pohl J, Ring A, Stremmel W, et al. The role of dominantstenoses in bacterial infections of bile ducts in primarysclerosing cholangitis. Eur J Gastroenterol Hepatol 2006;18:69–74.

Reprint requestsAddress 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.

AcknowledgmentsThe authors appreciate the in-depth review and comments of Dr

Jasmohan Bajaj from Virginia Commonwealth University.

Conflicts of interest

The authors disclose no conflicts.