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 sus-
ceptible 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 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 pathogenesis
of SBP and bacteremiathese 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 pathogens
are more common and virulent in patients with cirrhosis than
in 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.
C 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 cirrho-
sis.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 patho-
genic process leads to increased levels of endotoxins and cyto-
kines that trigger an excessive inflammatory host response, a
cause 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 virulent
in patients with cirrhosis than in the general population. Be-
cause 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 dysfunc-
tion (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 intra-
venously, 70% and 96% of their populations, respectively, were
found 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 less
bacteria 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 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 attrib-
uted 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 pneumo-
nia; GI, gastrointestinal; IE, infectious endocarditis; IL, interleukin; IV,
intravenous; NO, nitric oxide; PMN, polymorphonuclear; PSC, primary
sclerosing cholangitis; RE, reticuloendothelial; SBP, spontaneous bacte-
rial 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
728 BONNEL ET AL
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 li-
gand 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 opsoniza-
tion capacity. Patients with cirrhosis have much lower levels of
immunoglobulins IgM, IgG, and IgA in ascitic fluid.18 Further,
C3, C4, and CH50 concentrations are significantly lower in
both serum and ascitic fluid, thus leading to diminished bac-
tericidal activity.18,19
Additional aspects of immunodeficiency are complicated by
factors such as malnutrition, immunosuppressive medications,
and alcohol intake.20,21 Chronic and acute alcohol consumption
are associated with a decrease in T cells, B cells, natural killer cells,
monocytes, and an increase in proinflammatory cytokines.22,23
Bacterial Translocation
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 intesti-
nal 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, proinflammatory
cytokines, and nitric oxide (NO) alter the structure and perme-
ability 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 inflammatory response syndrome (SIRS) is not
uncommon in cirrhosis, and sepsis is defined as SIRS in the
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9
Figure 1. Cirrhosis-associated im-
mune dysfunction syndrome (CAIDS).
presence of confirmed bacterial infection (Figure 3).1,2,11,2730 Bac-
terial 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 proinflammatory cytokines tumor necrosis factor (TNF)-,
interleukin (IL)-6, and IL-1.31 In SIRS, anti-inflammatory cytokines
(IL-10, IL-4, IL-13, prostaglandin E2) are unable to balance the
proinflammatory cytokines, also known as a cytokine storm,
resulting in excessive inflammation.1,32
SIRS and cirrhosis are interlinked determinants of survival
outcomes. The severity of liver disease determines the develop-
ment 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 endo-
toxins that inversely correlate with hepatic deterioration.34 After
lipopolysaccharide challenge, those with cirrhosis had higher
proinflammatory cytokine levels than those without, particu-
larly TNF- and IL-6.35,36 Protein C and high density lipopro-
tein, protective anti-inflammatory, and antiapoptotic factors
are thought to be reduced in cirrhosis.37 NO, whose metabolite
concentrations are correlated with those of endotoxins, is in-
creased in cirrhosis and is known to contribute to the oxidative
stress and worsening vasodilatation of sepsis.38,39 Complica-
tions 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
intensifies this hyperdynamic state and serves as the link be-
tween bacterial infection and renal failure. Renal failure follow-
ing SBP-related and non-SBP-related bacteremia has been ob-
served in 1 third of patients with cirrhosis and ascites.28 30
Altered hemodynamics and widespread inflammation 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
September 2011
Figure 2. Pathogenesis of
SBP.
deemed to have multiple organ dysfunction syndrome, a com-
mon result of cirrhosis and severe sepsis.
Relative adrenal insufficiency is common in patients with
septic shock and is associated with hemodynamic instability,
renal failure, and increased mortality.40 It is diagnosed in ap-
proximately 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 hydro-
cortisone in patients with septic shock remains controver-
IMMUNE DYSFUNCTION AND INFECTION IN CIRRHOSIS 729
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.
730 BONNEL ET AL
episode of SBP or bacteremia.46 Conversely, the presence of
infection has been found to increase the risk of early bleed-
ing.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 pres-
ence of ascites. Most infections are caused by gram-negative
bacteria and are preventable with selective decontamination by
quinolones.50 Long-term SBP prophylaxis with norfloxacin 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-neg-
ative and gram-positive bacteria, are preferred prophylactic
strategies. In patients with advanced cirrhosis, 1 g of intrave-
nous (IV) ceftriaxone for 7 days after bleeding was found to be
more effective in preventing bacterial infections than oral nor-
floxacin.51 Prospective randomized trials and a recent Cochrane
Database review found antibiotic prophylaxis to significantly
reduce rates of infection, rebleeding, and mortality.5254 Based
upon the endotoxin-induced sinusoidal pressure hypothe-
sis,49 antibiotic decontamination may lower the risk of rebleed-
ing 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 Che-
larescu 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 com-
pensatory 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 norfloxacin and cisapride was
found to significantly reduce the rate of SBP compared with
norfloxacin 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 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 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 hospital-
ization and half develop during the hospitalization.63 The in-
hospital 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 strep-
tococci (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 en-
cephalopathy, or rapid impairment in renal function while
hospitalized.63,66 The diagnosis cutoff of SBP is a polymorpho-
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9
nuclear (PMN) count of 250 cells/mm3 while the highest spec-
ificity 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 fluid in aerobic and anaerobic culture bottles at
the 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 specificity
ranging between 45% and 100% and 81% to 100%, respectively.69
A recent study demonstrated an esterase strip calibrated to an
ascitic fluid 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 condi-
tions of SBP that require specific guidelines for identification
and therapy. It is identified by a positive ascitic fluid culture
and an ascitic PMN 250 cells/mm3. The differentiation be-
tween SBP and secondary peritonitis, ie, bacterial peritonitis
caused by perforation or acute inflammation of organs, can be
quite difficult. Secondary peritonitis, though only accounting
for 4.5% of all peritonitis cases in cirrhosis,73 should be sus-
pected in any of the following situations: (1) lack of a response
to antibiotic therapy; (2) 2 or more organisms isolated (partic-
ularly anaerobes or fungi; (3) the presence of at least 2 of the
following 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
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 sur-
gical evaluation.63,66,73,75 Because it is often a monobacterial
infection with an associated white blood cell response, SBP is
defined 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 para-
centesis is not necessary to assess for resolution of SBP. Equally
effective alternative therapies include cephalosporins (ceftriax-
one, ceftazidime, ceftizoxime), amoxicillin-clavulanic acid, and
quinolones (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 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 sufficient 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 hospitaliza-
tion.27 The activation of the cytokine cascade and NO production
in cirrhosis and SBP negatively impact renal function.28,84 The use
September 2011 IMMUNE DYSFUNCTION AND INFECTION IN CIRRHOSIS 731

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 vulnificus
Vibrio cholera (non-o1)
Vibrio parahemolyticus
Aeromonas spp.
Yersinia spp.
Listeria monocytogenes
Plesiomonas shigelloides
Clostridium spp.
Clostridium difficile
Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus group B
Enterococcus spp.
Mycobacterium tuberculosis (TB)
Fungi
Cryptococcus neoformans
Fungi
Candida spp.
Common clinical syndrome
SBP, bacteremia, UTI
Soft tissue infection, bacteremia
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
Antibiotic-associated diarrhea and colitis
Soft tissue infection, septicemia, endocarditis
Septicemia, pneumonia, meningitis
Septicemia, peritonitis, skin and soft tissue
infection
SBP, septicemia, UTI, biliary tract infection,
endocarditis
Pulmonary TB, extrapulmonary TB, esp.
peritonitis, disseminated TB
Peritonitis, meningitis, disseminated
cryptococcosis
Biliary tract infection, septicemia
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 efficacy 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
Identified in the bile up to 44% of PSC
patients with cholangitis134,135

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 inflammatory 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 alterna-
tive to albumin.
When treated effectively, recovery from SBP is seen in ap-
proximately 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 com-
plicate 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 norfloxacin reduced recurrence of SBP
from 68% to 20%. The use of 500 mg ciprofloxacin per day,
rather than the 750 mg once per week dosage previously sug-
732 BONNEL ET AL
gested,93 is known to be effective.94 Intermittent dosing of
prophylactic antibiotics may select resistant flora, 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 indefinite.
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 norfloxacin prophylaxis had a significantly decreased
probability of SBP, hepatorenal syndrome, and mortality.
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
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9
Figure 4. Ascites infection
algorithm.
residual volume as an explanation, however, this finding 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 significantly decreased in a rat model of cirrhosis, most
likely 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-
lis, 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
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. vulnificus) are common
causes of soft tissue infections. Cellulitis is the most frequently
September 2011
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 gram-
negative 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 intra-
hepatic portosystemic shunt, upper endoscopy, etc). Valve disor-
ders 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 Depend-
ing 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.
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 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 of
cirrhosis reduces its sensitivity to 30%.119 Laparoscopic biopsies
provide definitive 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
Clostridium difficile
Clostridium difficile is an increasingly prevalent hospital-
acquired infection that affects patients with cirrhosis. A recent
study of over 80,000 patients with cirrhosis found patients with
C. difficile-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.
difficile infection. Thus it is recommended that antibiotic pro-
phylaxis 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 significant propor-
tion of infections in patients with cirrhosis and an increasing
number of these infections are caused by antibiotic-resistant
IMMUNE DYSFUNCTION AND INFECTION IN CIRRHOSIS 733
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 Methi-
cillin-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 neofor-
mans, an encapsulated fungus that is typically associated with
human immunodeficiency virusinfected patients.129,130 Liver
cirrhosis is an underlying condition in approximately a third of
non human immunodeficiency virus cryptococcaemia cases
and is a stronger independent predictor of 30-day mortality
than in those with acquired immunodeficiency 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 peri-
tonitis may be via direct percutaneous inoculation during para-
centesis, 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
identified in 44% of bile samples in PSC patients, particularly
those 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 remains
unknown.
Specific 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 de-
creased 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 30-
fold greater risk of acquiring V. vulnificus, a bacterium acquired
through ingestion of contaminated raw oysters.138 V. vulnificus
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 pseudotuberculo-
sis, 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 cholangio-
pancreotography. The most common infections after endo-
scopic retrograde cholangiopancreotography are caused by
gram-negative bacteria such as E. coli, Klebsiella spp., and Entero-
bacter spp.143,144 However, if cholangitis occurs without any in-
734 BONNEL ET AL
tervention, the presence of stones, dominant strictures, or chol-
angiocarcinoma 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-hemo-
lytic 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 immuno-
compromised 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
difficult to recognize. The relationship between immune dysfunc-
tion 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 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 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. How-
ever, 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 hemochroma-
tosis as an etiology of liver disease. Auxiliary therapy with
intravenous albumin can significantly 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 hemor-
rhage benefit 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 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.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9
2. Arvaniti V, DAmico G, Fede G, et al. Infections in patients with
cirrhosis increase mortality 4-fold and should be used in deter-
mining prognosis. Gastroenterology 1256;2010:1246 1256,
e1241 e1245.
3. Fernndez J, Navasa M, Gmez J, et al. Bacterial infections in
cirrhosis: epidemiological changes with invasive procedures and
norfloxacin prophylaxis. Hepatology 2002;35:140 148.
4. Borzio M, Salerno F, Piantoni L, et al. Bacterial infection in
patients with advanced cirrhosis: a multicentre prospective
study. Dig Liver Dis 2001;33:41 48.
5. Runyon BA, Squier S, Borzio M. Translocation of gut bacteria in
rats with cirrhosis to mesenteric lymph nodes partially explains
the pathogenesis of spontaneous bacterial peritonitis. J Hepatol
1994;21:792796.
6. Garcia-Tsao G, Wiest R. Gut microflora in the pathogenesis of
the complications of cirrhosis. Best Pract Res Clin Gastroenterol
2004;18:353372.
7. Ghassemi S, Garcia-Tsao G. Prevention and treatment of infec-
tions in patients with cirrhosis. Best Pract Res Clin Gastroen-
terol 2007;21:7793.
8. Katz S, Jimenez MA, Lehmkuhler WE, et al. Liver bacterial clear-
ance following hepatic artery ligation and portocaval shunt.
J Surg Res 1991;51:267270.
9. Wasmuth HE, Kunz D, Yagmur E, et al. Patients with acute on
chronic liver failure display sepsis-like immune paralysis.
J Hepatol 2005;42:195201.
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-related
morbidity and mortality in cirrhosis. Am J Gastroenterol 2007;
102:1510 1517.
12. Trevisani F, Castelli E, Foschi FG, et al. Impaired tuftsin activity
in cirrhosis: relationship with splenic function and clinical out-
come. Gut 2002;50:707712.
13. Garfia C, Garca-Ruiz I, Sols-Herruzo JA. Deficient phospho-
lipase C activity in blood polimorphonuclear neutrophils from
patients 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 impairs
neutrophil phagocytic function in liver disease. Hepatology
2008;48:12021212.
16. Kusaba N, Kumashiro R, Ogata H, et al. In vitro study of neu-
trophil apoptosis in liver cirrhosis. Intern Med 1998;37:1117.
17. Liles WC, Kiener PA, Ledbetter JA, et al. Differential expression
of Fas (CD95) and Fas ligand on normal human phagocytes:
implications for the regulation of apoptosis in neutrophils. J Exp
Med 1996;184:429 440.
18. Ono Y, Watanabe T, Matsumoto K, et al. Opsonophagocytic
dysfunction in patients with liver cirrhosis and low responses to
tumor 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 of
human ascitic fluid: a potentially important protective mecha-
nism against spontaneous bacterial peritonitis. Hepatology
1985;5:634 637.
20. Gomez F, Ruiz P, Schreiber AD. Impaired function of macro-
phage Fc gamma receptors and bacterial infection in alcoholic
cirrhosis. N Engl J Med 1994;331:11221128.
21. Ferri C, Antonelli A, Mascia MT, et al. HCV-related autoimmune
and neoplastic disorders: the HCV syndrome. Dig Liver Dis
2007;39 Suppl 1:S13S21.
22. Romeo J, Warnberg J, Marcos A. Drinking pattern and socio-
cultural aspects on immune response: an overview. Proc Nutr
Soc 2010;69:341346.
September 2011
23. Laso FJ, Lapea P, Madruga JI, et al. Alterations in tumor
necrosis 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 disease
and 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 dysmotility
and bacterial overgrowth in cirrhotic patients with spontaneous
bacterial peritonitis. Hepatology 1998;28:11871190.
26. Chesta J, Defilippi C, Defilippi C. Abnormalities in proximal small
bowel motility in patients with cirrhosis. Hepatology 1993;17:
828 832.
27. Follo A, Llovet JM, Navasa M, et al. Renal impairment after
spontaneous bacterial peritonitis in cirrhosis: incidence, clinical
course, predictive factors and prognosis. Hepatology 1994;20:
14951501.
28. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin
on renal impairment and mortality in patients with cirrhosis and
spontaneous bacterial peritonitis. N Engl J Med 1999;341:
403 409.
29. Terra C, Guevara M, Torre A, et al. Renal failure in patients with
cirrhosis 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 and
bacterial infections in patients with cirrhosis: epidemiology and
clinical features. Hepatology 2007;45:223229.
31. Wong F, Bernardi M, Balk R, et al. Sepsis in cirrhosis: report on
the 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;50:20222033.
33. Cazzaniga M, Dionigi E, Gobbo G, et al. The systemic inflamma-
tory response syndrome in cirrhotic patients: relationship with
their in-hospital outcome. J Hepatol 2009;51:475 482.
34. Chan CC, Hwang SJ, Lee FY, et al. Prognostic value of plasma
endotoxin levels in patients with cirrhosis. Scand J Gastroen-
terol 1997;32:942946.
35. Byl B, Roucloux I, Crusiaux A, et al. Tumor necrosis factor alpha
and interleukin 6 plasma levels in infected cirrhotic patients.
Gastroenterology 1993;104:14921497.
36. Wang SS, Lee FY, Chan CC, et al. Sequential changes in plasma
cytokine and endotoxin levels in cirrhotic patients with bacterial
infection. 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 Int
2003;23:440 448.
38. Lee KC, Yang YY, Wang YW, et al. Increased plasma malondi-
aldehyde in patients with viral cirrhosis and its relationships to
plasma nitric oxide, endotoxin, and portal pressure. Dig Dis Sci
2010;55:20772085.
39. Guarner C, Soriano G, Tomas A, et al. Increased serum nitrite
and nitrate levels in patients with cirrhosis: relationship to
endotoxemia. Hepatology 1993;18:1139 1143.
40. Tsai MH, Peng YS, Chen YC, et al. Adrenal insufficiency in
patients with cirrhosis, severe sepsis and septic shock. Hepa-
tology 2006;43:673 681.
41. Fernndez J, Escorsell A, Zabalza M, et al. Adrenal insufficiency
in patients with cirrhosis and septic shock: effect of treatment
with 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.
IMMUNE DYSFUNCTION AND INFECTION IN CIRRHOSIS 735
43. Annane D, Sbille V, Charpentier C, et al. Effect of treatment
with 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 for
patients with septic shock. N Engl J Med 2008;358:111124.
45. Arabi YM, Aljumah A, Dabbagh O, et al. Low-dose hydrocortisone
in patients with cirrhosis and septic shock: a randomized con-
trolled trial. CMAJ 2010;182:19711977.
46. Bernard B, Grang JD, Khac EN, et al. Antibiotic prophylaxis for
the prevention of bacterial infections in cirrhotic patients with
gastrointestinal bleeding: a meta-analysis. Hepatology 1999;
29:16551661.
47. Bernard B, Cadranel JF, Valla D, et al. Prognostic significance of
bacterial infection in bleeding cirrhotic patients: a prospective
study. Gastroenterology 1995;108:1828 1834.
48. Vivas S, Manuel R, Palacio A, et al. Presence of bacterial
infection in bleeding cirrhotic patients is independently associ-
ated with early mortality and failure to control bleeding. Dig Dis
Sci 2001;46:27522757.
49. Goulis J, Patch D, Burroughs AK. Bacterial infection in the
pathogenesis of variceal bleeding. Lancet 1999;353:139 142.
50. Caly WR, Strauss E. A prospective study of bacterial infections
in patients with cirrhosis. J Hepatol 1993;18:353358.
51. Fernndez J, Ruiz del Arbol L, Gmez C, et al. Norfloxacin vs
ceftriaxone in the prophylaxis of infections in patients with
advanced cirrhosis and hemorrhage. Gastroenterology 2006;
131:1049 1056.
52. Jun CH, Park CH, Lee WS, et al. Antibiotic prophylaxis using third
generation cephalosporins can reduce the risk of early rebleed-
ing in the first acute gastroesophageal variceal hemorrhage: a
prospective 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 protect
against spontaneous bacterial peritonitis in cirrhotic patients: a
meta-analysis. Liver Int 2009;29:1189 1193.
56. Chelarescu O, Chelarescu D, Tircoveanu E, et al. Propranolol
administration on post surgical infections in cirrhotic patients.
Am J Gastroenterol 2003;38:A173.
57. Serst T, Melot C, Francoz C, et al. Deleterious effects of
beta-blockers on survival in patients with cirrhosis and refractory
ascites. Hepatology 2010;52:10171022.
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 cisapride
combination decreases the incidence of spontaneous bacterial
peritonitis 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;39:14411449.
61. Tandon P, Moncrief K, Madsen K, et al. Effects of probiotic
therapy on portal pressure in patients with cirrhosis: a pilot
study. Liver Int 2009;29:1110 1115.
62. Pereg D, Kotliroff A, Gadoth N, et al. Probiotics for patients with
compensated liver cirrhosis: a double-blind placebo-controlled
study. Nutrition 2011;27:177181.
63. Rimola A, Garca-Tsao G, Navasa M, et al. Diagnosis, treatment
and prophylaxis of spontaneous bacterial peritonitis: a consen-
sus document. International Ascites Club. J Hepatol 2000;32:
142153.
736 BONNEL ET AL
64. Thuluvath PJ, Morss S, Thompson R. Spontaneous bacterial
peritonitis--in-hospital mortality, predictors of survival, and
health care costs from 1988 to 1998. Am J Gastroenterol
2001;96:12321236.
65. Navasa M, Follo A, Llovet JM, et al. Randomized, comparative
study of oral ofloxacin versus intravenous cefotaxime in spon-
taneous bacterial peritonitis. Gastroenterology 1996;111:
10111017.
66. Runyon BA, AASLD Practice Guidelines Committee. Manage-
ment of adult patients with ascites due to cirrhosis: an update.
Hepatology 2009;49:20872107.
67. Runyon BA, Canawati HN, Akriviadis EA. Optimization of ascitic
fluid culture technique. Gastroenterology 1988;95:13511355.
68. Bobadilla M, Sifuentes J, Garcia-Tsao G. Improved method for
bacteriological diagnosis of spontaneous bacterial peritonitis.
J Clin Microbiol 1989;27:21452147.
69. Nguyen-Khac E, Cadranel JF, Thevenot T, et al. Review article:
the utility of reagent strips in the diagnosis of infected ascites in
cirrhotic patients. Aliment Pharmacol Ther 2008;28:282288.
70. Mendler MH, Agarwal A, Trimzi M, et al. A new highly sensitive
point of care screen for spontaneous bacterial peritonitis using
the leukocyte esterase method. J Hepatol 2010;53:477 483.
71. Rogers GB, Russell LE, Preston PG, et al. Characterisation of
bacteria in ascitesreporting the potential of culture-indepen-
dent, molecular analysis. Eur J Clin Microbiol Infect Dis 2010;
29:533541.
72. Bruns T, Sachse S, Straube E, et al. Identification of bacterial
DNA in neutrocytic and non-neutrocytic cirrhotic ascites by
means of a multiplex polymerase chain reaction. Liver Int 2009;
29:1206 1214.
73. Soriano G, Castellote J, Alvarez C, et al. Secondary bacterial
peritonitis in cirrhosis: a retrospective study of clinical and
analytical characteristics, diagnosis and management. J Hepa-
tol 2010;52:39 44.
74. Wu SS, Lin OS, Chen YY, et al. Ascitic fluid carcinoembryonic
antigen and alkaline phosphatase levels for the differentiation
of primary from secondary bacterial peritonitis with intestinal
perforation. J Hepatol 2001;34:215221.
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;3:161173.
76. Runyon BA, Hoefs JC. Culture-negative neutrocytic ascites: a
variant 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;146:21732175.
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 differentiating
spontaneous from secondary bacterial peritonitis. Gastroenter-
ology 1990;98:127133.
80. Rimola A, Salmern JM, Clemente G, et al. Two different dos-
ages of cefotaxime in the treatment of spontaneous bacterial
peritonitis in cirrhosis: results of a prospective, randomized,
multicenter study. Hepatology 1995;21:674 679.
81. Simmons BP, Gelfand MS, Grogan J, et al. Cefotaxime twice
daily versus ceftriaxone once daily. A randomized controlled
study in patients with serious infections. Diagn Microbiol Infect
Dis 1995;22:155157.
82. Yakar T, Gl M, Serin E, et al. A recent evaluation of empirical
cephalosporin treatment and antibiotic resistance of changing
bacterial profiles in spontaneous bacterial peritonitis. Dig Dis
Sci 2010;55:1149 1154.
83. Angeli P, Guarda S, Fasolato S, et al. Switch therapy with
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9
ciprofloxacin vs. intravenous ceftazidime in the treatment of
spontaneous 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 albumin
on endotoxin removal, cytokines, and nitric oxide production in
patients with cirrhosis and spontaneous bacterial peritonitis.
Scand J Gastroenterol 2009;44:619 625.
85. Fernndez J, Navasa M, Garcia-Pagan JC, et al. Effect of intra-
venous albumin on systemic and hepatic hemodynamics and
vasoactive neurohormonal systems in patients with cirrhosis
and spontaneous bacterial peritonitis. J Hepatol 2004;41:384
390.
86. Jalan R, Schnurr K, Mookerjee RP, et al. Alterations in the
functional capacity of albumin in patients with decompensated
cirrhosis is associated with increased mortality. Hepatology
2009;50:555564.
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 cirrhotic
patients with spontaneous bacterial peritonitis. Aliment Phar-
macol Ther 2009;32:43 48.
89. Toledo C, Salmern JM, Rimola A, et al. Spontaneous bacterial
peritonitis in cirrhosis: predictive factors of infection resolution
and survival in patients treated with cefotaxime. Hepatology
1993;17:251257.
90. Frana AV, De Souza JB, Silva CM, et al. Long-term prognosis of
cirrhosis after spontaneous bacterial peritonitis treated with
ceftriaxone. J Clin Gastroenterol 2001;33:295298.
91. Tit L, Rimola A, Gins P, et al. Recurrence of spontaneous
bacterial peritonitis in cirrhosis: frequency and predictive fac-
tors. Hepatology 1988;8:2731.
92. Gins P, Rimola A, Planas R, et al. Norfloxacin prevents spon-
taneous bacterial peritonitis recurrence in cirrhosis: results of
a double-blind, placebo-controlled trial. Hepatology 1990;12:
716 724.
93. Rolachon A, Cordier L, Bacq Y, et al. Ciprofloxacin and long-term
prevention of spontaneous bacterial peritonitis: results of a
prospective controlled trial. Hepatology 1995;22:11711174.
94. Terg R, Llano K, Cobas SM, et al. Effects of oral ciprofloxacin on
aerobic gram-negative fecal flora in patients with cirrhosis: re-
sults of short- and long-term administration, with daily and
weekly 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 in
cirrhosis: 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, and
survival in cirrhotic rats. Dig Dis Sci 1999;44:19571962.
97. Loomba R, Wesley R, Bain A, et al. Role of fluoroquinolones in
the primary prophylaxis of spontaneous bacterial peritonitis:
meta-analysis. Clin Gastroenterol Hepatol 2009;7:487 493.
98. Fernndez J, Navasa M, Planas R, et al. Primary prophylaxis of
spontaneous bacterial peritonitis delays hepatorenal syndrome
and improves survival in cirrhosis. Gastroenterology 2007;133:
818 824.
99. Cadranel JF, Denis J, Pauwels A, et al. Prevalence and risk
factors 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;16:7376.
September 2011
101. Amato A, Precone D, Carannante N, et al. Prevalence and risk
factors for bacteriuria in patients with cirrhosis. Infez Med
2005;2:103108.
102. Bercoff E, Dechelotte P, Weber J, et al. Urinary tract infection in
cirrhotic patients, an urodynamic explanation. Lancet 1985;
325:987.
103. Mellencamp MA, Preheim LC. Pneumococcal pneumonia in a rat
model of cirrhosis: effects of cirrhosis on pulmonary defense
mechanisms against Streptococcus pneumoniae. J Infect Dis
1991;163:102108.
104. Niederman MS, Mandell LA, Anzueto A, et al. Guidelines for the
management of adults with community-acquired pneumonia.
Diagnosis, assessment of severity, antimicrobial therapy, and
prevention. Am J Respir Crit Care Med 2001;163:1730 1754.
105. Falguera M, Trujillano J, Caro S, et al. A prediction rule for
estimating 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;93:901915, viiiix.
108. Liu BM, Chung KJ, Chen CH, et al. Risk factors for the outcome
of cirrhotic patients with soft tissue infections. J Clin Gastroen-
terol 2008;42:312316.
109. Rongey C, Lim NH, Runyon BA. Cellulitis in patients with cirrho-
sis and edema: an under-recognized complication currently
more common than spontaneous bacterial peritonitis. The Open
Gastroenterol Journal 2008;2:24 27.
110. Lee CC, Chi CH, Lee NY, et al. Necrotizing fasciitis in patients
with 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: clinical
features in patients with liver cirrhosis. Br J Plast Surg 2005;
58:702707.
112. Fernndez Guerrero ML, Gonzlez Lpez J, Grgolas M. Infec- 128. Park MK, Lee JH, Byun YH, et al. Changes in the profiles of
tious endocarditis in patients with cirrhosis of the liver: a model
of infection in the frail patient. Eur J Clin Microbiol Infect Dis
2010;29:12711275.
113. Fernndez-Guerrero ML, Herrero L, Bellver M, et al. Nosocomial
enterococcal endocarditis: a serious hazard for hospitalized
patients 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 the
Councils on Clinical Cardiology, Stroke, and Cardiovascular Sur-
gery and Anesthesia, American Heart Association: endorsed by
the Infectious Diseases Society of America. Circulation 2005;
111:e394 e434.
115. An Y, Xiao YB, Zhong QJ. Open-heart surgery in patients with
liver cirrhosis: indications, risk factors, and clinical outcomes.
Eur Surg Res 2007;39:6774.
116. Thulstrup AM, Mlle I, Svendsen N, et al. Incidence and prog-
nosis of tuberculosis in patients with cirrhosis of the liver. A
Danish nationwide population based study. Epidemiol Infect
2000;124:221225.
117. Cho YJ, Lee SM, Yoo CG, et al. Clinical characteristics of
tuberculosis in patients with liver cirrhosis. Respirology 2007;
12:401 405.
118. Kim NJ, Choo EJ, Kwak YG, et al. Tuberculous peritonitis in
cirrhotic patients: comparison of spontaneous bacterial perito-
nitis caused by Escherichia coli with tuberculous peritonitis.
Scand J Infect Dis 2009;41:852 856.
IMMUNE DYSFUNCTION AND INFECTION IN CIRRHOSIS 737
119. Hillebrand DJ, Runyon BA, Yasmineh WG, et al. Ascitic fluid
adenosine deaminase insensitivity in detecting tuberculous
peritonitis 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 United
States. Gastrointest Endosc 1988;34:422 426.
121. Bajaj JS, Ananthakrishnan AN, Hafeezullah M, et al. Clostridium
difficile 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 J
Gastroenterol 2010;105:114 116.
123. Cheong HS, Kang CI, Lee JA, et al. Clinical significance and
outcome of nosocomial acquisition of spontaneous bacterial
peritonitis in patients with liver cirrhosis. Clin Infect Dis 2009;
48:1230 1236.
124. Merli M, Lucidi C, Giannelli V, et al. Cirrhotic patients are at risk
for health care-associated bacterial infections. Clin Gastroen-
terol Hepatol 2010;8:979 985.
125. 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;35:110.
126. McBride SJ, Upton A, Roberts SA. Clinical characteristics and
outcomes of patients with vancomycin-susceptible Enterococ-
cus faecalis and Enterococcus faecium bacteraemiaa five-
year retrospective review. Eur J Clin Microbiol Infect Dis 2010;
29:107114.
127. 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.
causative agents and antibiotic resistance rate for spontaneous
bacterial peritonitis: an analysis of cultured microorganisms in
recent 12 years [in Korean]. Korean J Hepatol 2007;13:370 377.
129. Albert-Braun S, Venema F, Bausch J, et al. Cryptococcus neo-
formans peritonitis in a patient with alcoholic cirrhosis: case
report and review of the literature. Infection 2005;33:282288.
130. Mabee CL, Mabee SW, Kirkpatrick RB, et al. A risk factor for
cryptococcal peritonitis. Am J Gastroenterol 1995;90:2042
2045.
131. Jean SS, Fang CT, Shau WY, et al. Cryptococcaemia: clinical
features and prognostic factors. QJM 2002;95:511518.
132. Park WB, Choe YJ, Lee KD, et al. Spontaneous cryptococcal
peritonitis in patients with liver cirrhosis. Am J Med 2006;119:
169 171.
133. Saif MW, Raj M. Cryptococcal peritonitis complicating hepatic
failure: case report and review of the literature. J Appl Res
2006;6:4350.
134. 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.
135. Kulaksiz H, Rudolph G, Kloeters-Plachky P, et al. Biliary Candida
infections in primary sclerosing cholangitis. J Hepatol 2006;45:
711716.
136. Khan FA, Fisher MA, Khakoo RA. Association of hemochroma-
tosis with infectious diseases: expanding spectrum. Int J Infect
Dis 2007;11:482 487.
137. Ashrafian H. Hepcidin: the missing link between hemochroma-
tosis and infections. Infect Immun 2003;71:6693 6700.
138. Kizer KW. Vibrio vulnificus hazard in patients with liver disease.
West J Med 1994;161:64 65.
738 BONNEL ET AL
139. Brann OS. Infectious complications of cirrhosis. Curr Gastroen-
terol Rep 2001;3:285292.
140. Vadillo M, Corbella X, Pac V, et al. Multiple liver abscesses
due to Yersinia enterocolitica discloses primary hemochro-
matosis: three cases reports and review. Clin Infect Dis
1994;18:938 941.
141. Olesen LL, Ejlertsen T, Paulsen SM, et al. Liver abscesses due
to Yersinia enterocolitica in patients with haemochromatosis.
J Intern Med 1989;225:351354.
142. Mennecier D, Lapprand M, Hernandez E, et al. Liver abscesses
due to Yersinia pseudotuberculosis discloses a genetic hemo-
chromatosis [in French]. Gastroenterol Clin Biol 2001;25:
11131115.
143. Melzer M, Toner R, Lacey S, et al. Biliary tract infection and
bacteraemia: presentation, structural abnormalities, causative
organisms and clinical outcomes. Postgrad Med J 2007;83:
773776.
144. Subhani JM, Kibbler C, Dooley JS. Review article: antibiotic
prophylaxis for endoscopic retrograde cholangiopancreatogra-
phy (ERCP). Aliment Pharmacol Ther 1999;13:103116.
145. Olsson R, Bjrnsson E, Bckman L, et al. Bile duct bacterial
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9
isolates in primary sclerosing cholangitis: a study of explanted
livers. J Hepatol 1998;28:426 432.
146. Pohl J, Ring A, Stremmel W, et al. The role of dominant
stenoses in bacterial infections of bile ducts in primary
sclerosing cholangitis. Eur J Gastroenterol Hepatol 2006;
18:69 74.
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.