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Cirrhotic Patients Are at Risk for Health CareAssociated Bacterial

*Division of Gastroenterology, Department of Clinical Medicine, Department of Infectious Diseases and Tropical Medicine, Sapienza University of Rome, Rome, Italy

BACKGROUND & AIMS: Bacterial infections are a frequent and serious burden among patients with cirrhosis because they can further deteriorate liver function. We assessed
the epidemiology, risk factors, and clinical consequences of
bacterial infections in hospitalized cirrhotic patients. METHODS: In a cohort of hospitalized cirrhotic patients (n 150)
referred to a tertiary care setting, all episodes of bacterial infections
were recorded prospectively. Infections were classified as community-acquired (CA), health careassociated (HCA), or hospital-acquired (HA). Site of infection, characteristics of bacteria, and prevalence of antibiotic resistance were reported; consequences for liver
function and patient survival were evaluated. RESULTS: Fiftyfour infections were observed among 50 patients (12 CA, 22
HCA, and 20 HA). Bacterial resistance was more frequent
among patients with HCA or HA infections (64% of isolates).
Mortality was 37% from HA, 36% from HCA, and 0% from CA
infections. Independent predictors of infection included a previous infection within the past 12 months (P .0001; 95%
confidence interval [CI], 2.210.6), model of end-stage liver
disease score 15 (P .01; 95% CI, 1.3 6.1), and protein
malnutrition (P .04; 95% CI, 1.510). Infectious episodes
worsened liver function in 62% of patients. Patients with infection more frequently developed ascites, hepatic encephalopathy,
hyponatremia, hepatorenal syndrome, or septic shock. Child
class C (P .006; 95% CI, 1.6723.7), sepsis (P .005; 95% CI,
1.721.4), and protein malnutrition (P .001; 95% CI, 2.8
38.5) increased mortality among patients in the hospital.
CONCLUSIONS: In hospitalized cirrhotic patients, the
most frequent infections are HCA and HA; these infections
are frequently resistant to antibiotics. As infections worsen,
liver function deteriorates and mortality increases. Cirrhotic patients should be monitored closely for infections.
Keywords: Sepsis; Survival; Multidrug Resistance; Nutritional

acterial infections are a frequent and severe complication

in cirrhotic patients.1 Episodes of infection are reported in
40% of hospitalized cirrhotic patients.2 Infections are associated
with a longer hospital stay and a higher risk of death; infectionrelated mortality rate, in fact, ranges between 15% and 19%.2,3
Most of the infections in cirrhotic patients are caused by enteric
bacteria.4 This suggests that the defense mechanisms of these
patients fail to prevent the microorganisms present in the
intestinal lumen from reaching the systemic circulation. Sepsis
favors acute decompensation of cirrhosis and may lead to
hepatic encephalopathy, renal insufficiency, shock, and acute
on chronic liver failure.1

The possible risk factors for infections have been scarcely

evaluated in chronic liver disease and a recent review indicated
that a ChildPugh C score can be considered the only independent predictor.5 In most of the studies, bacterial infections in
cirrhotic patients are caused, in large prevalence (70% 80%), by
gram-negative cocci. In the past decade, however, infections
induced by gram-positive bacilli have increased, owing to longterm antibiotic prophylaxis with quinolones recommended for
those patients with previous spontaneous bacterial peritonitis
(SBP) episodes,6,7 which prevents infections caused by gramnegative bacilli but not those caused by gram-positive cocci. It
recently has been proposed that infections occurring in patients
who have had previous recent contact with the health care
system can be classified as health careassociated (HCA) and
may have a worse prognosis.8 Patients with advanced liver
disease frequently need to be hospitalized and therefore may be
included in this risk category. No information is available about
the prevalence and consequences of HCA infections in cirrhotic
The current study consists of a prospective investigation
aimed at determining, in a large cohort of hospitalized cirrhotic
patients, the following: (1) the prevalence and etiology of community-acquired (CA), HCA, and hospital-acquired (HA) bacterial infections; (2) the risk factors associated with the development of bacterial infections; (3) the short-term clinical
consequences of infection; and (4) patient survival 6 months
after hospital discharge.

Patients and Methods

From October 2008 to June 2009, we consecutively
enrolled all cirrhotic patients hospitalized at our University
Hospital (a tertiary referral center). Diagnosis of cirrhosis was
based on liver biopsy, when available, or on obvious clinical,
biochemical, or ultrasonographic and endoscopic features. Exclusion criteria were a concomitant human immunodeficiency
virus infection, high-dose corticosteroid treatment, and immunosuppressive therapy. The study was approved by the local
Abbreviations used in this paper: CA, community-acquired; CI, condence interval; HA, hospital-acquired; HCA, health careassociated;
HCC, hepatocellular carcinoma; HRS, hepatorenal syndrome; MDR,
multidrug resistant; OR, odds ratio; SBP, spontaneous bacterial peritonitis; SIRS, systemic inammatory response syndrome.
2010 by the AGA Institute



Ethical Committee Review Board, and written informed consent was signed by all the participants.

Clinical Evaluation and Management

Demographic, clinical, and biochemical parameters
were recorded for each patient in a preformed digitalized dataset. At admission, previous relevant clinical data, such as origin
of liver disease, history of alcohol abuse, ascites, encephalopathy, gastrointestinal bleeding, acute or chronic renal failure,
and coexistence of other diseases, were recorded. Previous hospitalizations (within 6 mo), episodes of infections diagnosed
within the past 12 months, and therapy administered during
the past 4 weeks also was noted. The main cause of hospitalization was identified and basal clinical and biochemical parameters were assessed to define the severity of liver disease,
renal function, and electrolyte imbalance. Mean arterial pressure, heart rate, respiratory rate, and body temperature were
measured and the presence of systemic inflammatory response
syndrome (SIRS) was investigated.9 The severity of liver disease
was assessed using the ChildPugh score10 and the model of
end-stage liver disease (MELD) score.11 Hepatorenal syndrome
(HRS) was diagnosed according to international criteria.12 The
nutritional status was assessed in all the patients by anthropometric measurements.13 Complications of cirrhosis were treated
according to recent guidelines.14 Antibiotic prophylaxis was
administered in patients with previous SBP or recent gastrointestinal bleeding.15,16 Overt hepatic encephalopathy was diagnosed according to the West Haven criteria17 and treated only
when the symptoms were clinically evident.

Diagnosis and Management of Infection

Bacterial infections were actively looked for in all patients based on the following assessment: (1) medical history
reporting symptoms of infection; (2) physical examination focused on symptoms and signs suggestive of infection; (3) laboratory tests including erythrocyte sedimentation rate, C-reactive protein level, polymorphonucleater cell count, hepatic and
renal function tests, and urinary sediment; (4) analysis of the
ascitic fluid when present; (5) chest radiograph; and (6) abdominal ultrasound. When a bacterial infection was suspected, further investigations (cultures of blood, urine, sputum, ascitic
fluid, or purulent secretions) were performed.
SBP was defined as a polymorphonucleater cell count greater
than 250/mm3 in the ascitic fluid a positive culture; pneumonia was defined as the presence of radiologic evidence of
consolidation plus at least 2 of the following criteria: fever
higher than 38C or hypothermia less than 35C, dyspnea,
cough and purulent sputum, pleuritic chest pain, or signs of
consolidation on physical examination. Urinary tract infections,
biliary tract infections, cellulitis, and gastroenteritis were all
diagnosed according to congruent symptoms and biochemical
and imaging parameters following standard criteria.18 The evidence of a positive blood culture without a recognized site of
infection was defined as spontaneous bacteremia.

Study Design, Follow-Up Evaluation, and

A complete patient assessment was performed at hospital admission and at discharge. If a diagnosis of infection was
made during hospitalization, the patient assessment was repeated at that time. Main outcomes were modifications of the


liver function, development of kidney dysfunction, development of hepatic encephalopathy, gastrointestinal bleeding, ascites, hyponatremia, length of hospital stay, and in-hospital
survival. Patients were re-evaluated as outpatients at 1, 3, and 6
months or until death or liver transplant. The study was closed
when the last patient enrolled had completed at least the
6-month follow-up evaluation.

Infections were classified as follows.
Infections were classified as HA if the diagnosis of infection
was made after more than 48 hours of hospital stay.
Infections were classified as HCA if the diagnosis was made
within 48 hours of hospitalization in patients with any of the
following criteria: (1) had attended a hospital or a hemodialysis
clinic, or had received intravenous chemotherapy during the 30
days before infection; or (2) were hospitalized for at least 2 days,
or had undergone surgery during the 180 days before infection;
or (3) had resided in a nursing home or a long-term care
Infections were classified as CA if the diagnosis of infection
was made within 48 hours of hospitalization and the patient
did not fulfill the criteria for HCA infection8 (ie, had no recent
contact with the health care system and was not hospitalized in
the past 6 months).
Patients with infections were treated immediately with empiric large-spectrum antibiotics, based on the site of infection
and according to standard guidelines and local epidemiology.
The antibiotic treatment then was modified according to the
results of cultures (if available) and in case of treatment failure.
All patients with infection underwent a consultation by an
infectious diseases specialist with expertise in nosocomial infections.
Patients were considered to have SIRS when they fulfilled the
criteria established by the most recent international guidelines.
Sepsis was diagnosed in the presence of SIRS and a known or
highly suspected infection. Septic shock was defined as sepsis
with hypotension refractory to intravascular volume loading,
associated with perfusion abnormalities that required the use of
The definition of a multidrug resistant (MDR) pathogen was
used to describe a methicillin-resistant Staphylococcus aureus, an
Acinetobacter baumannii, an extended-spectrum -lactamases
producing gram-negative strain, or any bacterial isolate resistant to at least 3 classes of antimicrobial agents.19,20 Protein
malnutrition was diagnosed when the midarm muscle circumference was below the fifth percentile of the referral standard.13

Statistical Analysis
Each patient was considered only once during the first
To evaluate liver function modifications induced by the
infection, the tests performed at the time of diagnosis were
compared either with recent previous results (when available) or
with the liver function test at the first outpatient control after
discharge (1 month), when the infection had completely resolved.
All the values are reported as means standard deviations;
P values less than .05 were considered significant. Data were
analyzed as continuous or categoric by using the Student t test
for parametric data and the MannWhitney U test or the Wil-

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coxon test for nonparametric data; the chi-square test was used
for the comparison of dichotomous data. The logistic regression analysis was used to identify possible predictors of infection and in-hospital mortality. Univariate analysis (log rank)
was used to identify prognostic factors of survival, and the
variables selected by this analysis were included in a multivariate analysis according to a Cox regression model. The software
used for the analysis was NCSS (Number Cruncher Statistical
System, Kaysville, UT) 2007.

Four patients were excluded, 1 for high-dose steroid
therapy and 3 because of a recurrence of cirrhosis after liver
transplantation. A total of 150 patients was enrolled: 48 women
and 102 men, with a mean age of 64 13 years. The origin of
cirrhosis was hepatitis C in 51% of cases, alcohol abuse in 19%,
cryptogenetic in 15%, autoimmune in 5%, hepatitis B in 4%, and
both hepatitis B and C in 3.3% of patients. Child class was A in
30%, B in 39%, and C in 31% of patients. The mean MELD score
at admission was 13.5 (range, 5 40). The main reasons for
hospital admission were as follows: ascites in 37 patients (25%),
elective procedures in 33 (22%), suspected infection in 21 (14%),
encephalopathy in 20 (13%), gastrointestinal bleeding in 12
(8%), renal failure in 5 (3%), and other reasons in the remaining
22 patients (15%). Forty-nine patients had clinical evidence of
ascites at the time of hospitalization, and 82 were known to
have esophageal varices (48 small and 34 large varices). Fiftytwo patients reported a previous documented infection in the
past 12 months (19 urinary tract infections, 13 pneumonia, 4
spontaneous bacteremia, 4 biliary tract infections, 3 gastrointestinal, 3 skin infections, 2 SBP, and 6 in other sites). Seventeen
patients received antibiotics in the preceding 30 days, 9 because
of a recent infectious episode and 8 because of prophylaxis with
Thirteen patients had been treated previously with transjugular intrahepatic portosystemic shunt. Twenty-six cases had a
diagnosis of hepatocellular carcinoma (HCC), 18 were within the
Milan criteria,21 and 8 exceeded the Milan criteria (3 of these
patients also had portal thrombosis). The 26 patients with HCC
were hospitalized either for diagnostic purposes (3 cases), to receive locoregional treatment (21 cases), or for other complications
of cirrhosis (2 patients).
A total of 54 episodes of bacterial infection were recorded in
50 patients (33%); 4 patients presented more than one episode
of infection during hospitalization. Demographic, clinical, and
biochemical characteristics of the patients with and without
infection are shown in Table 1.
The degree of liver impairment was significantly more severe
in the patients with infection. The patients who developed an
infection had significantly lower albumin levels (P .001),
higher bilirubin levels (P .002), higher creatinine levels (P
.001), and lower sodium levels (P .008) than those who did

Bacterial Infections, Systemic Inflammatory

Response Syndrome, and Sepsis
Among the 54 episodes of infection, 12 were CA, 22
were HCA, and 20 were HA. The infections most commonly
recorded were urinary tract infections (37%), pneumonia (22%),



and spontaneous bacteremia (13%). Table 2 shows the frequency of the different sites of infection in the 3 epidemiologic
groups. Twenty-six infections were documented microbiologically. Gram-negative organisms, particularly Escherichia coli, were
isolated more frequently (62%) than gram-positive ones (38%),
but gram-positive bacteria were prevalent in HA infections (64%
of isolates). Blood cultures were positive in 12 episodes of
infection: 3 urinary infections, 4 cases of cholangitis, 2 cases of
pneumonia, 1 case of SBP, and 2 cases of spontaneous bacteremia.
As shown in Table 2, 16 patients had an infection caused by
MDR bacteria. Six of the 16 patients (37.5%) with MDR pathogens died during their hospital stay (3 HRS, 2 septic shock, 1
variceal bleeding). Among the 17 patients undergoing antibiotic
therapy in the preceding 30 days, MDR pathogens were isolated
more frequently (5 of 7 infectious episodes; P .002).
SIRS was diagnosed in 43 patients and sepsis was diagnosed
in 31 patients. The type of infection more often leading to
sepsis was pneumonia. SIRS unrelated to infection mostly occurred in those patients undergoing invasive treatments.

Risk Factors for the Development of Infection

The variables examined as possible risk factors for the
development of infection or sepsis are reported in Table 3. At
multivariate analysis, a history of previous infection in the past
12 months, a MELD score of 15 or greater, and a diagnosis of
protein malnutrition were independent predictors for infections and sepsis (Table 4).
Potential risk factors that could be involved in the development of HA infections also were evaluated. The number of
invasive procedures during hospitalization was significantly
higher (P .02) in patients who developed HA infections (Table
5). We also found that HA infections were associated with
hospitalization in rooms in which there was a need to place
additional beds (P .0002) (Table 5).

Clinical Features
A worsening of liver function frequently was observed
in patients with infection, especially in those with sepsis. The
ChildPugh score deteriorated in 62% of cases with infection
(mean increase in Child score, 1.9 0.8; range, 12) and
in 71% of patients with sepsis (mean increase in Child
score, 2.5 0.7; range, 1 4), whereas the MELD score in
the same patients showed a mean increase of 3.8 2.7
(range, 1 4) in patients with infection and of 4.9 2.7
(range, 112) in those with sepsis. The parameters that deteriorated more often were as follows: bilirubin (4.4 12
mg/dL), albumin (0.34 0.9 g/dL), creatinine (0.6
1.8 mg/dL), and serum sodium (3.3 6.1 mEq/L) levels,
respectively. Moreover, episodes of ascites, hepatic encephalopathy, hyponatremia, HRS, and septic shock were more
frequent in patients with infection as compared with those
who were not infected (Table 6).

Overall in-hospital mortality was 12%; 14 patients
with and 4 patients without infection died (28% vs 4%; P
.00007). The mortality rate was higher in the patients with
sepsis (12 of 31; 38%) than in those with infection but no
sepsis (2 of 19, 10%; P .00000).




Table 1. Demographic, Clinical, and Biochemical Characteristics of Patients Included in the Study Classified According to the
Presence of Infection During Their Hospitalization
Age, y
Active alcohol abusers, n (%)
Origin of liver disease
Alcohol, n (%)
HCV-related, n (%)
HBV-related, n (%)
Other, n (%)
Main cause of admission
Elective procedure, n (%)
Ascites, n (%)
Suspected infection, n (%)
Encephalopathy, n (%)
Gastrointestinal bleeding, n (%)
Renal failure, n (%)
Other, n (%)
HCC, n (%)
MELD score
ChildPugh score
Mean arterial pressure, mm Hg
Heart rate, beats/min
Respiratory rate, breaths/min
Temperature, 37.5C
White blood cells, cell/mm3
Hemoglobin level, g/dL
Platelets, num/mm3 103
Alanine aminotransferase level, IU/L
Serum bilirubin level, mg/dL
Serum albumin level, mg/dL
International normalized ratio
Serum creatinine level, mg/dL
Blood urea nitrogen level, mg/dL
Serum sodium level, mmol/L
Serum potassium level, mmol/L
Sedimentation rate, mm/h

Patients without infections

(n 100)

Patients with infections

(n 50)

P value

63 13
21 (21)

65 13
14 (28)


19 (19)
56 (56)
6 (6)
19 (19)

10 (20)
21 (42)
5 (10)
14 (28)


31 (31)
30 (30)
0 (0)
11 (11)
9 (9)
2 (2)
17 (17)
20 (20)
11.8 4.5
7.6 2.0
88 11
75 13
15 2
6 (6)
5297 2754
11.6 2.3
120 95
57 62
3.1 5.6
3.3 0.6
1.5 1.3
0.91 0.44
23.2 18.2
135.7 5.1
4.4 0.7
21 19

2 (4)
7 (14)
21 (42)
9 (18)
3 (6)
3 (6)
5 (10)
7 (14)
17.1 7.4
8.7 2.1
84 20
82 14
18 4
37 (74)
9229 5973
10.9 3.6
123 88
58 79
7.6 12.0
2.7 0.7
1.5 0.4
1.57 1.58
37.9 30.5
130.0 19.6
4.2 0.2
37 26


HCV, hepatitis C virus; HBV, hepatitis B virus.

Patient mortality was related to the epidemiology of infection: patients with HA infections, in fact, had a mortality
rate (37%) similar to that of patients with HCA infections
(36%), whereas none of the patients with CA infections died
(P .046).
Univariate analysis showed that sepsis (P .00000), bacterial
infections (P .00002), MELD score of 15 or greater (P .03),
Child class C (P .00004), protein malnutrition (P .000001),
development of antibiotic resistance (P .00009), and hyponatremia (P .002) were related significantly to mortality.
Multivariate analysis selected Child class C (P .006; odds ratio
[OR], 6.3; 95% confidence interval [CI], 1.6723.7), sepsis (P
.0056; OR, 6.01; 95% CI, 1.721.46), and protein malnutrition
(P .0004; OR, 10.44; 95% CI, 2.8 38.5) as independent predictors of in-hospital death. Causes of in-hospital death in
patients with infections were HRS (6 patients), septic shock (5
patients), hemorrhagic shock (2 patients), severe arrhythmia
causing cardiovascular arrest (1 patient). All of the 4 patients
who died without infection died of end-stage liver failure, and
3 of them also had a diagnosis of advanced HCC.

The overall mortality in the following 6 months also was

evaluated. The mortality rate at 3 months was 34% versus 6%,
and at 6 months was 50% versus 11% in patients with infection
as compared with those without infection (Supplementary Figure 1). The main causes of death after hospital discharge were
end-stage liver failure (7 patients), variceal bleeding (4 patients),
renal failure (4 patients), septic shock (2 patients), and myocardial infarction (1 patient); 5 patients underwent liver transplantation.

Cirrhosis presently may be considered one of the most
common immunodeficiency-acquired conditions and previous
studies reported an infection rate of 40% to 50% among hospitalized cirrhotic patients, with consequent significant morbidity
and mortality rates.2,5 In the present study, we found the following: (1) the large majority of bacterial infections in hospitalized cirrhotic patients are HCA or HA; (2) the high prevalence of these epidemiologic categories contributes to a higher

November 2010


Table 2. Characteristics of the 54 Episodes of Infections

According to the Epidemiology Classification
(n 12)
Sites of infection
Urinary tract infections, n (%)
Pneumonia, n (%)
Spontaneous bacteriemia, n (%)
Spontaneous bacterial
peritonitis, n (%)
Biliary tract infections, n (%)
Other infections, n (%) (eg,
skin, gastrointestinal,
lymphangitis, bursitis)
Microbiologically documented
Isolated pathogens
Staphylococcus aureus
Enterococcus faecalis
Enterobacteriaceae (E coli,
Klebsiella, Proteus)

(n 22)

Table 4. Variables Independently Associated With Infection

and Sepsis at Multivariate Analysis

(n 20)
Previous infections
(past 12 months)

4 (33)
3 (25)
1 (8)
1 (8)

4 (18)
5 (23)
4 (18)
2 (9)

9 (45)
4 (20)
2 (10)
1 (5)

1 (8)
2 (16)

2 (9)
4 (18)

1 (5)
2 (10)

4 (33)

11 (50)

11 (55)

MELD score, 15

Protein malnutrition







2 (16)

9 (41)

5 (23)

prevalence of antibiotic-resistant strains and a worse outcome;

(3) in addition to the severity of the liver disease, protein
malnutrition is an important independent risk factor for the
development of infections in cirrhosis; and (4) infection and
sepsis induce liver deterioration and increase the risk of hepatic
encephalopathy, renal failure, hyponatremia, and mortality in
cirrhotic patients.
In our experience, the most common sites of infection were
the urinary (35%) and the lower respiratory (22%) tracts. These
latter infections were those more frequently leading to a sepsis
syndrome. In all the patients hospitalized with clinical evidence
of ascites (49 cases), the peritoneal fluid was analyzed for
neutrophil cell count and bacterial culture, and 4 (8%) patients




OR, 4.7
95% CI, 2.210.6
P .000
OR, 2.8
95% CI, 1.3 6.1
P .001
OR, 4
95% CI, 1.510
P .004

OR, 3.4
95% CI, 1.3 8.1
P .007
OR, 4.4
95% CI, 1.8 10
P .001
OR, 4
95% CI, 1.510
P .004

had a diagnosis of SBP, a rate similar to that reported previously in other Italian studies.3
Enteric gram-negative cocci were the microorganisms more
frequently isolated, whereas gram-positive ones were more frequent in the HA infection group. It has recently been proposed
that antibiotic resistances are increasing in hospitalized cirrhotic patients and this has been attributed to the larger diffusion of quinolone prophylaxis for SBP.6 In the present study we
found a consistent (64%) number of MDR pathogens among
the isolates. This high prevalence was probably related to the
great number of HCA and HA infections that were diagnosed in
our series, because the patients with advanced liver disease
frequently are in need of hospital care. Previous studies, performed on noncirrhotic patients, showed that HA and HCA
infections are caused more frequently by antibiotic-resistant
bacteria and are associated with a more severe clinical course
than CA infections.8,22 A different empiric treatment for this
new epidemiologic category has been suggested. The present
prospective and observational study reports data on HCA infections in cirrhotic patients. We confirm that, as in other
categories, in cirrhotic patients HCA infections also are similar
to HA infections with regard to the prevalence of antibioticresistant pathogens, severe clinical course, and unfavorable outcome (in-hospital mortality in our series was 37% in HCA, 36%
in HA, and none of the patients with CA infections died). In a
recent meta-analysis, only the severity of liver disease has been

Table 3. Variables Associated With Infection at Univariate

Analysis in the Patients Included in the Study

Previous hospitalizations
(past 6 months), n (%)
Previous infections (past
12 months), n (%)
ChildPugh class C, n (%)
MELD score, 15, n (%)
Protein malnutrition, n (%)
Transjugular intrahepatic
portosystemic shunt,
n (%)
Recent gastrointestinal
bleeding (7 d), n (%)
Antibiotic therapy in the
preceding 30 days
Diabetes, n (%)

Table 5. Prevalence of Factors That May Be Involved in the

Development of HA Infections

Patients without

Patients with


37 (37)

33 (66)



26 (26)

26 (52)


24 (24)
25 (25)
19 (19)
5 (5)

22 (44)
25 (50)
26 (52)
12 (24)


Patients undergoing
invasive procedures,
n (%)
Invasive procedures,
number per patienta
Patients hospitalized in a
room with an
additional bed, n (%)

6 (6)

4 (8)


9 (9)

8 (16)


16 (32)


29 (29)


Patients without Patients with

infections (16)


66 (74)

14 (75)


1.77 1.1

2.4 1.7


19 (19)

10 (62)


procedures were as follows: paracentesis, dialysis, urinary

catheter, endoscopic variceal ligation, sclerotherapy, endoscopic retrograde cholangiopancreatography, percutaneous transhepatic
cholangiography, locoregional treatments of HCC, and placement of a
transjugular intrahepatic portosystemic shunt.




Table 6. Clinical Complications in 150 Cirrhotic Patients With and Without Infections and With and Without Sepsis During
Their Hospitalization

HRS type 1, n (%)

HRS type 2, n (%)
Hepatic encephalopathy, n (%)
Ascites, n (%)
Variceal bleeding, n (%)
Hyponatremia, n (%)
Shock, n (%)
In-hospital mortality, n (%)

Patients with
infection (50)

infection (100)

P value

Patients with
sepsis (31)

Patients without
sepsis (119)

P value

7 (14)
4 (8)
19 (38)
33 (66)
7 (14)
19 (38)
6 (12)
14 (28)

2 (2)
15 (15)
51 (51)
6 (6)
14 (14)
4 (4)


5 (16)
4 (13)
11 (35)
23 (74)
5 (16)
13 (42)
6 (19)
12 (38)

2 (1.6)
2 (1.6)
23 (19)
61 (51)
8 (6.7)
8 (6.7)
6 (5)


rewarded as a reliable risk factor for infections and sepsis.5

When the factors associated with both these conditions were
examined, we could confirm that the severity of the liver disease
(indicated by a MELD score of 15) is a good predictor, but we
also found that additional parameters (a previous episode of
infection in the past 12 months and protein malnutrition) may
allow identification of a subgroup of cirrhotic patients at high
risk of infection. All these parameters are easy to identify at
hospital admission through the clinical history, simple anthropometric measurements, and biochemical data.
Malnutrition is known to be a negative prognostic factor for
in-hospital morbidity and mortality in cirrhotic patients23 and
increases the rate of infection in liver recipients.24
As previously reported, the consequences of infection/sepsis
in cirrhotic patients are highly detrimental.3 The liver function
deteriorated in about two thirds of the patients who developed
an infection: these patients showed a worsening of the main
indicators of hepatic function (bilirubin and albumin) and a
higher risk of encephalopathy, ascites, renal dysfunction, hyponatremia, and hemodynamic shock.
The mechanism through which infections induce a further
deterioration of liver function in cirrhotic patients has not been
investigated extensively as yet. Infections, and especially sepsis,
are accompanied by a downright cytokine storming, mostly
interleukin-6 and tumor necrosis factor-. These latter are the
major hepatic triggers for the production of acute-phase proteins.25 It is conceivable that a cirrhotic liver facing an infection
or an increased endotoxin blood level may be overwhelmed by
an increased demand of acute-phase reaction protein,26 and this
may lead to an exhaustion of the hepatocytes reserve function.
It is worth noting that the in-hospital mortality rate was
higher in those patients who had an episode of infection during
hospitalization. Moreover, survival was worse in this group even
for those who were discharged from the hospital. The main
causes of death in this setting were liver failure, variceal bleeding, and renal failure: the episode of infection by deteriorating
liver function seems to accelerate the natural history of the
In conclusion, the results of our study show that the majority of infections in hospitalized cirrhotic patients are HCA.
Severe liver disease, malnutrition, and infection in the past 12
months are parameters that identify patients at higher risk.
Because infection and sepsis are highly detrimental in hospitalized patients with cirrhosis and frequently are caused by resistant pathogens the identification of the criteria to select a

high-risk group may help in planning a different empiric antibiotic approach in this category.

Supplementary Material
Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at, and at doi:10.1016/
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Reprint requests
Address requests for reprints to: Professor Manuela Merli, MD,
Gastroenterologia II, Dipartimento di Medicina Clinica, Sapienza
Universit di Roma, Viale dellUniversit 37, 00185 Rome, Italy.
e-mail:; fax: (39) 064453319.
The authors thank Mrs Maria Teresa Barbieri for assistance with the
English revision.
Conicts of interest
The authors disclose no conicts.
Supported by a research grant C26FO9BMAN from Sapienza University of Rome.

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Supplementary Figure 1. Survival in 150 hospitalized cirrhotic patients according to the presence of infection. Curves were estimated
using the KaplanMeier method. A period of 6-months follow-up was
examined. Patients with diagnosis of infection at the time of enrollment
showed a higher rate of mortality (P .0001).