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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

kines that trigger an excessive inflammatory host response, a


Podcast interview: www.gastro.org/cghpodcast. cause for septic shock, multiorgan dysfunction, and death.
Pathogens such as Mycobacterium tuberculosis, Clostridium dif-
Patients with cirrhosis are immunocompromised and sus- ficile, Cryptococcus neoformans, Vibrio vulnificus, Yersinia enteroco-
ceptible to infections. Although detection and treatment of litica, and Listeria monocytogenes, are more common and virulent
spontaneous bacterial peritonitis (SBP) have improved, in patients with cirrhosis than in the general population. Be-
overall survival rates have not increased greatly in recent cause of the high morbidity and mortality of infections in
decadesinfection still increases mortality 4-fold among cirrhosis, prevention, early diagnosis, and proper management
patients with cirrhosis. Hospitalized patients with cirrhosis of these infections are necessary to improve survival.
have the highest risk of developing infections, especially
patients with gastrointestinal (GI) hemorrhage. Bacterial State of Immune Dysfunction in
infections occur in 32% to 34% of patients with cirrhosis who Cirrhosis
are admitted to the hospital and 45% of patients with GI Cirrhosis-associated immune dysfunction syndrome
hemorrhage. These rates are much higher than the overall rate (CAIDS) is a multifactorial state of systemic immune dysfunc-
of infection in hospitalized patients (5%7%). The most com- tion (Figure 1), which decreases their ability to clear cytokines,
mon are SBP (25% of infections), urinary tract infection (20%), bacteria, and endotoxins from circulation. The liver contains
and pneumonia (15%). Bacterial overgrowth and transloca- 90% of the reticuloendothelial (RE) cells,7 such as Kupffer and
tion from the GI tract are important steps in the pathogenesis sinusoidal endothelial cells, that are central to clearing bacteria.
of SBP and bacteremiathese processes increase levels of en- When radiolabeled E. coli and P. aeruginosa were injected intra-
dotoxins and cytokines that induce the inflammatory re- venously, 70% and 96% of their populations, respectively, were
sponse and can lead to septic shock, multiorgan dysfunction, found in the liver only 10 minutes later.8 Porto-systemic shunt-
and death. A number of other bacterial and fungal pathogens ing, whereby blood is increasingly directed away from the liver,
are more common and virulent in patients with cirrhosis than and reduced RE cells in patients with cirrhosis, allow less
in the overall population. We review the pathogenesis of in- bacteria and endotoxins to be cleared by the liver from circu-
fections in these patients, along with diagnostic and manage- lation.1,7
ment strategies. Monocyte spreading, chemotaxis, bacterial phagocytosis,
Keywords: Liver Disease; Ascites; Inflammation; Therapy. 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

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
decreased monocyte activation and cytokine secretion.
In addition to RE system dysfunction, patients with cirrhosis
have decreased neutrophil mobilization and phagocytic activity,
better treatment of spontaneous bacterial peritonitis (SBP) a phenomenon that correlates with severity of liver disease.10,11
leading to better survival, there has been little improvement in The decreased phagocytic activity in cirrhosis has been attrib-
overall survival rates in recent decades: infections still account uted to reduced activity of tuftsin,12 and phospholipase C.13,14
for a 4-fold increase in mortality among patients with cirrho- In addition, it has been suggested that hyperammonemia and
sis.2 Hospitalized patients with cirrhosis are at the highest risk hyponatremia function synergistically to affect neutrophil cell
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 Abbreviations used in this paper: CAP, community-acquired pneumo-
hemorrhage.4 These rates are drastically higher than the usual nia; GI, gastrointestinal; IE, infectious endocarditis; IL, interleukin; IV,
intravenous; NO, nitric oxide; PMN, polymorphonuclear; PSC, primary
5% to 7% overall rate of infection in hospitalized patients.1 The
sclerosing cholangitis; RE, reticuloendothelial; SBP, spontaneous bacte-
most common infections are SBP (25% of infections), urinary
rial peritonitis; SIRS, systemic inammatory response syndrome; TB,
tract infection (UTI) (20%), and pneumonia (15%).3 Bacterial tuberculosis; TNF, tumor necrosis factor; UTI, urinary tract infection.
overgrowth and translocation from the GI tract are important 2011 by the AGA Institute
steps in the pathogenesis of SBP and bacteremia.5,6 This patho- 1542-3565/$36.00
genic process leads to increased levels of endotoxins and cyto- doi:10.1016/j.cgh.2011.02.031
728 BONNEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9

Figure 1. Cirrhosis-associated im-


mune dysfunction syndrome (CAIDS).

volume and impair phagocytosis.15 Neutropenia, typically a presence of confirmed bacterial infection (Figure 3).1,2,11,2730 Bac-
result of hypersplenism in cirrhosis, is further exacerbated by terial derived toxins, such as peptidoglycans from gram-positive
shortened neutrophil survival via apoptosis.16 The Fas/Fas li- bacteria or lipopolysaccharides from gram-negative bacteria, bind
gand has been implicated in the regulation of apoptosis in to Toll-like receptors which initiate a cascade of cell signaling.
neutrophils,17 but it is unclear how decreased levels of Fas in Toll-like receptors trigger either nuclear factor B or mitogen
cirrhosis impact this mechanism.16 activated protein kinase, which in turn stimulate the release of NO
The decreased phagocytic activity of the innate immune and proinflammatory cytokines tumor necrosis factor (TNF)-,
response is confounded by decreased bactericidal and opsoniza- interleukin (IL)-6, and IL-1.31 In SIRS, anti-inflammatory cytokines
tion capacity. Patients with cirrhosis have much lower levels of (IL-10, IL-4, IL-13, prostaglandin E2) are unable to balance the
immunoglobulins IgM, IgG, and IgA in ascitic fluid.18 Further, proinflammatory cytokines, also known as a cytokine storm,
C3, C4, and CH50 concentrations are significantly lower in resulting in excessive inflammation.1,32
both serum and ascitic fluid, thus leading to diminished bac- SIRS and cirrhosis are interlinked determinants of survival
tericidal activity.18,19 outcomes. The severity of liver disease determines the develop-
Additional aspects of immunodeficiency are complicated by ment of SIRS, while SIRS leads to variceal bleeding, hepatic
factors such as malnutrition, immunosuppressive medications, encephalopathy, and adversely affects survival.33 Certain aspects
and alcohol intake.20,21 Chronic and acute alcohol consumption of cirrhosis can exacerbate SIRS and complicate its diagnosis.
are associated with a decrease in T cells, B cells, natural killer cells, Patients with cirrhosis have higher levels of circulating endo-
monocytes, and an increase in proinflammatory cytokines.22,23 toxins that inversely correlate with hepatic deterioration.34 After
lipopolysaccharide challenge, those with cirrhosis had higher
Bacterial Translocation proinflammatory cytokine levels than those without, particu-
Bacterial translocation is the migration of bacteria or larly TNF- and IL-6.35,36 Protein C and high density lipopro-
bacterial products from the intestinal lumen to mesenteric tein, protective anti-inflammatory, and antiapoptotic factors
lymph nodes (Figure 2).24 Bacterial translocation is known to be are thought to be reduced in cirrhosis.37 NO, whose metabolite
increased in cirrhosis and has been pathogenetically linked to concentrations are correlated with those of endotoxins, is in-
the development of SBP.5,6 It has also been implicated as a cause creased in cirrhosis and is known to contribute to the oxidative
of recurrent SBP.25 Patients with cirrhosis have slowed intesti- stress and worsening vasodilatation of sepsis.38,39 Complica-
nal motility, which leads to intestinal bacterial overgrowth.26 tions of cirrhosis may mask themselves as symptoms of SIRS.
This overgrowth, along with portosystemic shunting, enables For example, hypersplenism may reduce white blood cell count,
perpetuation of bacteria and can lead to bacteremia. Further hyperdynamic circulation may elevate heart rate, and hepatic
oxidative damage from increased endotoxins, proinflammatory encephalopathy may cause hyperventilation.31 However, these
cytokines, and nitric oxide (NO) alter the structure and perme- indicators appear to be more exaggerated in patients with
ability of intestinal mucosa in cirrhosis.24 In conjunction with cirrhosis. The release of large amounts of cytokines in sepsis
the decreased local and impaired systemic immune function in intensifies this hyperdynamic state and serves as the link be-
cirrhosis, decreased gut motility and increased permeability tween bacterial infection and renal failure. Renal failure follow-
facilitate the spread of intestinal bacteria to extraintestinal sites ing SBP-related and non-SBP-related bacteremia has been ob-
and predispose patients with cirrhosis to infections. served in 1 third of patients with cirrhosis and ascites.28 30
Altered hemodynamics and widespread inflammation lead to
SIRS, Sepsis, and Cirrhosis impaired tissue oxygenation, cell necrosis, and apoptosis, and
Systemic inflammatory response syndrome (SIRS) is not ultimately organ failure. When organ function can no longer
uncommon in cirrhosis, and sepsis is defined as SIRS in the sustain homeostasis without intervention, the patient is
September 2011 IMMUNE DYSFUNCTION AND INFECTION IN CIRRHOSIS 729

Figure 2. Pathogenesis of
SBP.

deemed to have multiple organ dysfunction syndrome, a com- sial,41,43,44 however, a recent randomized trial found its use to be
mon result of cirrhosis and severe sepsis. associated with an increase in shock relapse and GI bleeding.45
Relative adrenal insufficiency is common in patients with
septic shock and is associated with hemodynamic instability, Infections in Cirrhosis
renal failure, and increased mortality.40 It is diagnosed in ap-
proximately 70% of septic shock patients with cirrhosis and is Gastrointestinal BleedingAssociated
believed to be linked to their impaired cortisol synthesis and Infections and Prophylaxis
decreased high density lipoprotein levels.41,42 The use of hydro- GI bleeding is associated with an increased incidence of
cortisone in patients with septic shock remains controver- infection, and approximately 17% to 45% of cases lead to an

Figure 3. Consequences of
sepsis in cirrhosis.
730 BONNEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9

episode of SBP or bacteremia.46 Conversely, the presence of nuclear (PMN) count of 250 cells/mm3 while the highest spec-
infection has been found to increase the risk of early bleed- ificity is reached at 500 cells/mm3.63
ing.47,48 Goulis et al49 hypothesize that bacterial endotoxins Up to 65% of patients with clinical evidence of SBP and
stimulate hepatic stellate cell contraction and endothelial NO increased ascites have negative cultures,67 but inoculation of 10
production, which then increase sinusoidal pressure and inhibit mL of ascitic fluid in aerobic and anaerobic culture bottles at
platelet aggregation, respectively. the bedside has improved sensitivity to approximately 80%.68
Patients who present with acute episodes of GI bleeding Recent applications of culture-independent methods have at-
require short-term antibiotic prophylaxis regardless of the pres- tempted to improve screening outcomes. Several types of leu-
ence of ascites. Most infections are caused by gram-negative kocyte esterase reagent strips have been evaluated in the diag-
bacteria and are preventable with selective decontamination by nosis of SBP and have demonstrated sensitivity and specificity
quinolones.50 Long-term SBP prophylaxis with norfloxacin has ranging between 45% and 100% and 81% to 100%, respectively.69
resulted in quinolone-resistant gram-negative bacteria and an A recent study demonstrated an esterase strip calibrated to an
increased prevalence of gram-positive bacteria.3 Therefore, ascitic fluid PMN count 250 cells/mm3 to be a good bedside
third-generation cephalosporins, which target both gram-neg- screening tool.70 Preliminary application of molecular analysis
ative and gram-positive bacteria, are preferred prophylactic to identify bacterial DNA has yielded promising results that
strategies. In patients with advanced cirrhosis, 1 g of intrave- may replace culture techniques in the future.71,72
nous (IV) ceftriaxone for 7 days after bleeding was found to be Bacterascites and secondary peritonitis are unique condi-
more effective in preventing bacterial infections than oral nor- tions of SBP that require specific guidelines for identification
floxacin.51 Prospective randomized trials and a recent Cochrane and therapy. It is identified by a positive ascitic fluid culture
Database review found antibiotic prophylaxis to significantly and an ascitic PMN 250 cells/mm3. The differentiation be-
reduce rates of infection, rebleeding, and mortality.5254 Based tween SBP and secondary peritonitis, ie, bacterial peritonitis
upon the endotoxin-induced sinusoidal pressure hypothe- caused by perforation or acute inflammation of organs, can be
sis,49 antibiotic decontamination may lower the risk of rebleed- quite difficult. Secondary peritonitis, though only accounting
ing via reduction of endotoxin levels and subsequent portal for 4.5% of all peritonitis cases in cirrhosis,73 should be sus-
pressure. Nonselective beta blockers, commonly used to lower pected in any of the following situations: (1) lack of a response
portal hypertension and prevent initial variceal hemorrhage, to antibiotic therapy; (2) 2 or more organisms isolated (partic-
can also serve to decrease bacterial translocation during an ularly anaerobes or fungi; (3) the presence of at least 2 of the
acute hemorrhage. A recent meta-analysis55 found evidence that following in ascitic fluid: glucose 50 mg/dL, protein 1
beta blockers increase gut motility and reduce translocation, g/dL, lactic dehydrogenase greater than normal serum lev-
thereby reducing the incidence of infection. A study by Che- els.63 With intestinal perforation, secondary peritonitis may
larescu et al56 in the postsurgical setting found propranolol to also be suspected if chorioembryonic antigen 5 ng/mL or
reduce infections from 42% to 15%. However, the use of beta alkaline phosphatase 240 U/L.74 After diagnosis of a cause
blockers in patients with refractory ascites may limit the com- of secondary peritonitis with a radiological study such as
pensatory increase in cardiac output and increase vulnerability magnetic resonance imaging or computed tomography scan,
to complications such as septic shock and renal failure.57,58 patients should receive antibiotic therapy and undergo sur-
Prokinetic agents may also reduce dysmotility and bacterial gical evaluation.63,66,73,75 Because it is often a monobacterial
translocation. Prophylaxis with norfloxacin and cisapride was infection with an associated white blood cell response, SBP is
found to significantly reduce the rate of SBP compared with defined as culture positive. However, a variant of it called
norfloxacin alone.59 There is some evidence to suggest that the culture-negative neutrocytic ascites can be encountered and
use of probiotics promotes the growth of gram-positive bacteria has similar clinical outcomes (Figure 4).66,74,76 79
at the expense of gram-negative bacteria,60 but it has yet to been The current standard for treatment of SBP is with a minimal
shown to benefit patients with cirrhosis.61,62 Given the increas- dose of 2 g of intravenous cefotaxime every 12 hours for 5
ingly negative implication of gram-positive bacteria in infec- days.80,81 In those with clinical improvement, a repeat of para-
tions, replacing gram-negative bacterial populations may be of centesis is not necessary to assess for resolution of SBP. Equally
little use. effective alternative therapies include cephalosporins (ceftriax-
one, ceftazidime, ceftizoxime), amoxicillin-clavulanic acid, and
Spontaneous Bacterial Peritonitis: Diagnosis, quinolones (ciprofloxacin, ofloxacin, levofloxacin) for beta-lac-
Treatment, and Prevention tam hypersensitive patients.31,63,82 When clinical signs of infec-
The prevalence of SBP in patients with cirrhosis and tion have improved, replacing IV cephalosporin with oral cip-
ascites admitted to the hospital ranges between 10% and 30%; rofloxacin to complete the course of therapy may be more
approximately half of cases are present at the time of hospital- cost-effective.83 Patients taking quinolones as prophylaxis
ization and half develop during the hospitalization.63 The in- should be aware of treatment failure because of antibiotic
hospital mortality rate from SBP is approximately 32%.64 The resistance or enterococcal infection. If clinical improvement
majority of these infections are caused by E. coli, Klebsiella spp., and a sufficient drop in neutrophil count in ascites (25% of
other Enterobacteriaceae, P. aeruginosa, enterococci, and strep- initial value) are not observed by day 3 of treatment, a switch of
tococci (Table 1).65 The current recommendation is to perform antibiotic therapy should be considered while the patient is
a diagnostic paracentesis in all patients with ascites at the time evaluated for secondary peritonitis.
of hospital admission and in those who manifest symptoms of Renal impairment develops in approximately 1 third of all SBP
peritoneal infection, systemic signs of infection, hepatic en- patients and is a strong predictor of mortality during hospitaliza-
cephalopathy, or rapid impairment in renal function while tion.27 The activation of the cytokine cascade and NO production
hospitalized.63,66 The diagnosis cutoff of SBP is a polymorpho- 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 Common clinical syndrome Special comments
Bacteria
E. coli, Klebsiella spp., and other SBP, bacteremia, UTI Increased resistance in patients taking
gram-negative enteric bacteria prophylactic quinolones and in nosocomial
infections
Vibrio vulnificus Soft tissue infection, bacteremia Increased incidence in cirrhosis, particularly
hemochromatosis
50%60% mortality in septic form138
24% for localized wound infection139
Vibrio cholera (non-o1) Diarrhea, septicemia Increased incidence and morbidity in
advanced cirrhosis (mortality 24%)11
Vibrio parahemolyticus Diarrhea, septicemia Increased morbidity
Aeromonas spp. Soft tissue infection, bacteremia Increased incidence and morbidity in cirrhosis
Yersinia spp. Septicemia, hepatosplenic abscesses, peritonitis Increased incidence in cirrhosis and iron
overload state
Listeria monocytogenes Septicemia, meningitis, peritonitis Increased incidence in cirrhosis, particularly
hemochromatosis
Plesiomonas shigelloides Septicemia, meningitis, soft tissue infection Increased incidence in cirrhosis and iron
overload state
Clostridium spp. Septicemia, soft tissue infection, peritonitis Increased incidence and morbidity of C.
perfringens in cirrhosis (mortality
54%65%)11
Clostridium difficile Antibiotic-associated diarrhea and colitis Increased incidence (may be related to the
common use of antibiotics and PPI in
patients with cirrhosis)122
Increased mortality (14%)121
Staphylococcus aureus Soft tissue infection, septicemia, endocarditis Increased incidence in cirrhosis, particularly
hospitalized patients
Increased MRSA nasal carriage
Streptococcus pneumoniae Septicemia, pneumonia, meningitis Increased incidence and morbidity
Pneumococcal vaccine is recommended in
patients with cirrhosis (vaccine efficacy has
been validated in alcoholic cirrhosis)
Streptococcus group B Septicemia, peritonitis, skin and soft tissue Increased incidence
infection
Enterococcus spp. SBP, septicemia, UTI, biliary tract infection, Increased incidence and morbidity
endocarditis Mortality rate approximately 25% (up to 50%
in endocarditis form)114
Mycobacterium tuberculosis (TB) Pulmonary TB, extrapulmonary TB, esp. Higher incidence, more virulent, and more
peritonitis, disseminated TB extra-pulmonary forms in cirrhosis compare
to non-cirrhosis
Risk for multi-drug resistance TB
Fungi
Cryptococcus neoformans Peritonitis, meningitis, disseminated Increased incidence in advanced cirrhosis
cryptococcosis Mortality rate up to 70%132
Fungi
Candida spp. Biliary tract infection, septicemia 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 80%.63 For patients who fail treatment, hospital mortality
SBP diagnosis followed by 1 g/kg body weight on day 3) in ranges from 50% to 80%.89 The rapid deterioration of liver
conjunction with cefotaxime was found to reduce the incidence of function in SBP patients makes for generally poor long-term
renal impairment from 33% to 10% and mortality from 29% to prognosis after an episode of SBP. Franca et al90 found the
10%.28 Albumin increases mean arterial volume, binds TNF- and 1-year survival rate to be 28.5%. The recent shift in microbial
NO to counteract the inflammatory response of infection, and etiology of SBP toward cefotaxime-resistant strains may com-
removes toxins from circulation.84 86 These infusions are most plicate survival by delaying infection resolution.
effective in patients with baseline creatinine 1.0 mg/dL and total Patients recovering from an episode of SBP should be given
bilirubin 4.0 mg/dL.28,87 A recent pilot study by Cartier et al88 antibiotic prophylaxis. In those without antibiotic prophylaxis,
suggests polygeline (Gelafundin 4%; B Braun Medical AG, Crissier, the rate of recurrence of SBP is 43% at 6 months, 69% at 1 year,
Switzerland), a cheaper plasma expander, as a reasonable alterna- and 74% at 2 years after the initial episode.91 Gins et al92 found
tive to albumin. that 400 mg per day oral norfloxacin reduced recurrence of SBP
When treated effectively, recovery from SBP is seen in ap- from 68% to 20%. The use of 500 mg ciprofloxacin per day,
proximately 90% of patients and 30-day survival is in at least rather than the 750 mg once per week dosage previously sug-
732 BONNEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9

Figure 4. Ascites infection


algorithm.

gested,93 is known to be effective.94 Intermittent dosing of residual volume as an explanation, however, this finding was
prophylactic antibiotics may select resistant flora, therefore not supported in a subsequent study.99 Treatment of UTI with
daily dosing is preferred. For patients intolerant to quinolones, quinolones is effective in approximately 95% of cases.99
daily double-strength oral trimethoprim/sulfamethoxazole is
an effective alternative.95,96 The current time scale for long-term Pneumonia
prophylaxis is indefinite. Pneumonia is the third leading cause of infections in
Patients with advanced cirrhosis and low protein ascites may be patients with cirrhosis.1,50 Pulmonary clearance of pneumococci
candidates for primary prophylaxis against SBP.97 In a randomized was significantly decreased in a rat model of cirrhosis, most
controlled trial,98 patients with low protein ascites levels (1.5 likely as a result of decreased complement levels.103 Communi-
g/dL) with advanced liver failure or impaired renal function who ty-acquired pneumonia (CAP) is most often caused by S. pneu-
received norfloxacin prophylaxis had a significantly decreased moniae and H. influenza.104 S. aureus, M. pneumoniae, M. catarrha-
probability of SBP, hepatorenal syndrome, and mortality. lis, C. pneumoniae, Klebsiella spp., and Legionella spp. have also been
implicated as causes of CAP. The risk of bacteremia in CAP is
Other Infections in Cirrhosis increased in patients with cirrhosis.105 Further, procedures such
as tracheal intubation and esophageal tamponade put patients
Urinary Tract Infection with cirrhosis at risk of hospital-acquired pneumonia.106 In the
UTI occurs in approximately 15% to 20% of hospitalized presence of comorbidities such as cirrhosis, treatment is ideal
patients with cirrhosis; it is twice as frequent in patients with with IV beta-lactam plus macrolide or IV antipneumococcal
cirrhosis compared with matched controls.3,99 Women have a 4 quinolones.104 Pneumococcal vaccination is recommended in
times higher rate of bacteriuria than men.99 Gram-negative patients with cirrhosis.104,107
bacilli, such as E. coli and Klebsiella spp., are the primary causative
agents. Notably, bacteriuria is not associated with an increased Soft Tissue Infections
risk of sepsis, SBP, or other infections often seen in patients Chronic edema and increased bacterial translocation
with cirrhosis.99 Although more frequent among those with predispose patients with cirrhosis to soft tissue infections,
cirrhosis, UTI does not consistently correlate with the severity which constitute approximately 11% of infections.108 Both
of liver disease and is more strongly associated with gender and gram-positive (S. aureus, group A Streptococci) and gram-negative
diabetes.99 101 The high incidence of UTI in cirrhosis remains bacteria (Klebsiella spp., Aeromonas spp., V. vulnificus) are common
unexplained. Bercoff et al102 cite the increased bladder postvoid causes of soft tissue infections. Cellulitis is the most frequently
September 2011 IMMUNE DYSFUNCTION AND INFECTION IN CIRRHOSIS 733

observed skin infection in patients with cirrhosis and has a and gram-positive pathogens. Approximately 37% to 64% of
recurrence rate of 20%.109 Necrotizing fasciitis, a rare but severe bacterial infections, either nosocomial or in the context of
form of soft tissue infection, is predominantly caused by gram- antibiotic intervention in an outpatient setting, have been
negative bacilli.110 Unlike the general population, necrotizing found to be multidrug-resistant.3,123,124 Gram-negative isolates
fasciitis in those with cirrhosis rarely develops from an obvious in SBP, such as E. coli and K. pneumoniae, are being encountered
portal of entry in the extremities, thereby suggesting a potential with increasing rates of resistance.125 Gram-positive pathogens
pathway of bacterial translocation and bacteremia leading to are increasingly common in patients with cirrhosis.125 Methi-
soft tissue infections.110,111 Broad spectrum antibiotic treatment cillin-resistant S. aureus has been noted to account for 24.8% of
is necessary for proper management of soft tissue infections, nosocomial SBP.125 E. faecalis and E. faecium have been isolated
and surgical intervention for deep infections may be needed. in nearly 10% to 24% of infections in the setting of cirrhosis and
are associated with 25% mortality rate.3,125,126 Approximately a
Endocarditis third of enterococcal bacteremia cases demonstrate vancomycin
Approximately 10% of infectious endocarditis (IE) cases resistance and are associated with twice the mortality rate of
have cirrhosis as an underlying condition.112 IE is a concern for nonresistant strains.127,128
hospitalized patients with cirrhosis because of the increased risk of
bacteremia associated with invasive procedures (transjugular intra- Fungal Infections
hepatic portosystemic shunt, upper endoscopy, etc). Valve disor- Cirrhosis increases susceptibility to Cryptococcus neofor-
ders are present in approximately 60% of patients with cirrhosis mans, an encapsulated fungus that is typically associated with
who have IE.112 Gram-positive bacteria such S. aureus, -hemolytic human immunodeficiency virusinfected patients.129,130 Liver
streptococci (S. agalactiae, S. pyogenes), and enterococci (E. faecalis, E. cirrhosis is an underlying condition in approximately a third of
faecium) are the most commonly isolated organisms.112,113 Depend- non human immunodeficiency virus cryptococcaemia cases
ing on the organism, a minimum of 4 weeks of antibiotic therapy and is a stronger independent predictor of 30-day mortality
is recommended.114 Patients with advanced liver cirrhosis have than in those with acquired immunodeficiency syndrome.131
high surgical mortality rates;115 therefore surgical management of Though uncommon, C. neoformans may infect ascites and cause
IE is reserved for selected patients who do not respond to medical spontaneous cryptococcal peritonitis. Unlike SBP, spontaneous
therapy. cryptococcal peritonitis presents itself with an elevation in
lymphocyte count and, because of late detection, has a very high
Tuberculosis mortality rate (70%).132 The pathogenesis of cryptococcal peri-
The incidence and virulence of Mycobacterium tuberculosis tonitis may be via direct percutaneous inoculation during para-
infections are increased in patients with cirrhosis.116 In a cohort of centesis, GI bleeding, or bacterial translocation.130,133 Candida
tuberculosis (TB) patients with liver cirrhosis in Denmark, the infections can also be encountered particularly in patients with
30-day case fatality rate was 27.3% and the 1-year case fatality rate primary sclerosing cholangitis (PSC). Candida species have been
was 47.7%.116 TB patients with liver cirrhosis show extrapulmonary identified in 44% of bile samples in PSC patients, particularly
involvement,117 such as TB peritonitis, more frequently. Compared those with dominant strictures.134,135 A high prevalence of bil-
with SBP, TB peritonitis is present in less advanced cirrhosis and iary candidiasis exists, however, the effect of antifungal thera-
is characterized by lower white blood cell count in ascites, higher pies on treatment outcomes for recurrent cholangitis remains
proportion of mononuclear leukocytes, higher protein concentra- unknown.
tion, and higher levels of adenosine deaminase activity in ascites.118
Though adenosine deaminase level analysis is useful in the detec- Specific Liver DiseaseRelated Infections
tion of TB peritonitis in patients without cirrhosis, the presence of Iron overload state impairs cell-mediated response and
cirrhosis reduces its sensitivity to 30%.119 Laparoscopic biopsies enhances growth of various pathogens such as E. coli, Vibrio spp.,
provide definitive diagnosis of TB peritonitis by revealing multiple and Listeria monocytogenes.136 Recent evidence suggests that de-
whitish nodules scattered over the peritoneum.118,120 Patients with creased levels of hepcidin, an iron-regulator hormone with
TB and cirrhosis respond well to anti-TB therapy, however they antimicrobial activity, serve as the link between liver disease and
face a greater risk of hepatotoxicity.117 these infections.137 Patients with hemochromatosis face a 30-
fold greater risk of acquiring V. vulnificus, a bacterium acquired
Clostridium difficile through ingestion of contaminated raw oysters.138 V. vulnificus
Clostridium difficile is an increasingly prevalent hospital- septicemia has a 50% to 60% case mortality rate in patients with
acquired infection that affects patients with cirrhosis. A recent liver disease and 7% to 22% mortality for localized wound
study of over 80,000 patients with cirrhosis found patients with infection.138,139 Yersinia enterocolitica and Yersinia pseudotuberculo-
C. difficile-associated disease to have higher mortality and longer sis, 2 gram-negative bacilli transmitted zoonotically, infect via
length of stay than those without infection.121 Antibiotics and systemic or portal vein bacteremia to cause hepatic abscesses
proton pump inhibitors were independently associated with C. with up to a 56% mortality rate.140 142
difficile infection. Thus it is recommended that antibiotic pro- PSC is a risk factor for ascending cholangitis, which is
phylaxis be limited to patients at highest risk of developing SBP associated with up to a 16% mortality rate.143,144 Generally,
and that proton pump inhibitors be used selectively.122 ascending cholangitis is relatively uncommon unless the biliary
tree has been manipulated by endoscopic retrograde cholangio-
Drug-Resistant Infections pancreotography. The most common infections after endo-
Nosocomial infections account for a significant propor- scopic retrograde cholangiopancreotography are caused by
tion of infections in patients with cirrhosis and an increasing gram-negative bacteria such as E. coli, Klebsiella spp., and Entero-
number of these infections are caused by antibiotic-resistant bacter spp.143,144 However, if cholangitis occurs without any in-
734 BONNEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9

tervention, the presence of stones, dominant strictures, or chol- 2. Arvaniti V, DAmico G, Fede G, et al. Infections in patients with
angiocarcinoma should be considered. In a study of explanted cirrhosis increase mortality 4-fold and should be used in deter-
livers with PSC, bacteria were isolated in approximately 60% of mining prognosis. Gastroenterology 1256;2010:1246 1256,
cases.145 The most common bacteria isolated were alpha-hemo- e1241 e1245.
lytic streptococci, enterococci, and staphylococci. Though the 3. Fernndez J, Navasa M, Gmez J, et al. Bacterial infections in
cirrhosis: epidemiological changes with invasive procedures and
etiology of PSC is largely unknown, bacterial infection of the
norfloxacin prophylaxis. Hepatology 2002;35:140 148.
bile ducts with dominant stenoses has been implicated in the 4. Borzio M, Salerno F, Piantoni L, et al. Bacterial infection in
progression of the disease.146 patients with advanced cirrhosis: a multicentre prospective
study. Dig Liver Dis 2001;33:41 48.
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Summary rats with cirrhosis to mesenteric lymph nodes partially explains
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