Community-Acquired Pneumonia in Patients

With Liver Cirrhosis

Clinical Features, Outcomes, and Usefulness of Severity Scores
Diego Viasus, MD, Carolina Garcia-Vidal, MD, PhD, Jose Castellote, MD, PhD, Jordi Adamuz, RN,
Ricard Verdaguer, MD, Jordi Dorca, MD, PhD, Frederic Manresa, MD, PhD, Francesc Gudiol, MD, PhD,
and Jordi Carratalà, MD, PhD

found in patients without cirrhosis. The severity of hepatic dysfunction

Abstract: We performed an observational analysis of a prospective plays an important role in the development of adverse events. Cirrhosis-
cohort of nonimmunocompromised hospitalized adults with community- specific scores may be useful for predicting and stratifying cirrhotic
acquired pneumonia (CAP) to determine the epidemiology, clinical fea- patients with CAP who have a high risk of severe disease.
tures, and outcomes of patients with liver cirrhosis. We also analyzed
the prognostic value of several severity scores. Of 3420 CAP episodes, (Medicine 2011;90: 110Y118)
90 occurred in patients with liver cirrhosis. The median value of the
Model for End-Stage Liver Disease (MELD) was 14 (range, 6Y36). On Abbreviations: AUC = area under the curve, CAP = community-
the Child-Pugh (CP) score, 56% of patients were defined as grade B and acquired pneumonia, CI = confidence interval, CP = Child-Pugh
22% as grade C. Patients with liver cirrhosis were younger (61.8 vs. score, CURB-65 = confusion, urea, respiratory rate, blood pressure,
66.8 yr; p = 0.001) than patients without cirrhosis, more frequently pre- and age Q65 years, HIV = human immunodeficiency virus, ICU =
sented impaired consciousness at admission (33% vs. 14%; p G 0.001) intensive care unit, LR = likelihood ratio, MELD = Model for End-
and septic shock (13% vs. 6%; p = 0.011), and were more commonly Stage Liver Disease, OR = odds ratio, PSI = Pneumonia Severity
classified in high-risk Pneumonia Severity Index (PSI) classes (classes Index, ROC = receiver operating characteristic, SBP = spontaneous
IVYV) (74% vs. 58%; p = 0.002). Streptococcus pneumoniae (47% vs. bacterial peritonitis.
33%; p = 0.009) and Pseudomonas aeruginosa (4.4% vs. 0.9%; p =
0.001) were more frequently documented in patients with cirrhosis.
Bacteremia was also more common in these patients (22% vs. 13%; p =
0.023). Areas under the curve (AUCs) from disease-specific scores
(MELD, CP, PSI, and CURB-65 Econfusion, urea, respiratory rate, blood
INTRODUCTION
pressure, and age Q65 yr^) were comparable in predicting severe disease
(30-d mortality and intensive care unit EICU^ admission). A new score L iver cirrhosis is one of the most common causes of mortality
worldwide,29,31 and patients with cirrhosis frequently require
hospital admission for medical complications. Bacterial in-
based on MELD, multilobar pneumonia, and septic shock at admission
(MELD-CAP) had an AUC of 0.945 (95% confidence interval ECI^, fections are recognized as a significant cause of morbidity and
0.872Y0.983) for predicting severe disease and was significantly differ- mortality in this population;7,11,46 the most commonly reported
ent from other scores. Early (5.6% vs. 2.1%; p = 0.048) and overall bacterial infections are spontaneous bacterial peritonitis (SBP),
(14.4% vs. 7.4%; p G 0.024) mortality rates were higher in cirrhotic urinary tract infections, pneumonia, bacteremia, and skin and
patients than in patients without cirrhosis. Factors associated with soft tissue infections.3,5,42 Prospective studies have found that
mortality were impaired consciousness, multilobar pneumonia, ascites, 13%Y20% of bacterial infections in patients with cirrhosis are
acute renal failure, bacteremia, ICU admission, and MELD score. Among caused by pneumonia.3,5,20 Although several studies have shown
the severity scores, MELD-CAP was the only score associated with se- that the clinical features and prognosis of infections may be
vere disease (odds ratio EOR^, 1.33; 95% CI, 1.09Y1.52) and mortality different in patients with and without liver cirrhosis,4,6,14,23 to
(OR, 1.21; 95% CI, 1.03Y1.42). our knowledge no study has specifically evaluated community-
In conclusion, CAP in patients with liver cirrhosis presents a dis- acquired pneumonia (CAP) in this setting. As a result, the es-
tinctive clinical picture and is associated with higher mortality than is sential information needed to understand the clinical features,
etiologies, and outcomes of CAP in patients with liver cirrhosis
is still lacking.
Cirrhosis-specific scores, such as the Child-Pugh score
From Departments of Infectious Diseases (DV, CG, JA, FG, J. Carratalà), (CP) and the Model for End-Stage Liver Disease (MELD),
Hepatology and Liver Transplant (J. Castellote), Microbiology (RV), and have been reported to be good predictors of short- and long-
Respiratory Medicine (JD, FM), Hospital Universitari de Bellvitge, Institut
d’Investigació Biomèdica de Bellvitge (IDIBELL), University of Barcelona.
term mortality in cirrhotic patients, even in patients with in-
L’Hospitalet de Llobregat, Barcelona, Spain. fections.15,27,28,47 Consequently, disease severity prediction in
The authors are supported by research grant REIPI RD06/0008 from the patients with liver cirrhosis may need to be based on specific
Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, parameters rather than those used in the general population.
Spanish Network for the Research in Infectious Diseases; Fondo de
Investigación Sanitaria de la Seguridad Social (grant 07/0864);
However, studies that compare cirrhosis-specific scores with
and Institut d’Investigació Biomèdica de Bellvitge (Dr. Viasus). disease-specific or general scores are scarce.1,10,51 Significantly,
Reprints: Dr. Diego Viasus, Department of Infectious Diseases, Hospital no study has evaluated the usefulness of CAP-specific severity
Universitari de Bellvitge, Feixa Llarga s/n, 08907, L’Hospitalet de scoresVPneumonia Severity Index (PSI) and CURB-65 (confu-
Llobregat, Barcelona, Spain (e-mail: dfviasusp)unal.edu.co).
Copyright * 2011 by Lippincott Williams & Wilkins
sion, urea, respiratory rate, blood pressure, and age Q65 yr)Vand
ISSN: 0025-7974 cirrhosis-specific scores for predicting outcomes in patients with
DOI: 10.1097/MD.0b013e318210504c liver cirrhosis and CAP.

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Medicine & Volume 90, Number 2, March 2011 Pneumonia in Patients With Cirrhosis

We conducted the current study to determine the epidemi- ous 5 years or influenza vaccine in the previous year. Previous
ology, clinical features, and outcomes of patients with liver cir- antibiotic therapy was defined as the use of any antibiotic for
rhosis in a large prospective cohort of hospitalized adults with more than 48 hours during the previous 3 months. Chronic heart
CAP who were not severely immunosuppressed. We also aimed disease was defined as systolic or diastolic ventricular dys-
to examine the value of disease-specific scores in predicting function documented by history, and chest radiograph, echo-
severe disease (30-d mortality and/or intensive care unit EICU^ cardiogram, or left ventriculogram. The diagnosis of septic shock
admission). was based on a systolic blood pressure of less than 90 mm Hg
and peripheral hypoperfusion with the need for vasopressors.
Impaired consciousness was considered as disorientation with
PATIENTS AND METHODS respect to person, place, or time that was not known to be
chronic, stupor, or coma. Empirical antibiotic therapy was de-
Setting, Patients, and Study Design
fined as antibiotics received on the first day of therapy for
The study was conducted at a 900-bed university hospital pneumonia. Initial inappropriate therapy was defined as the
for adults. All nonseverely immunosuppressed patients ad- absence of antimicrobial agents directed at a specific type of
mitted to the hospital with pneumonia via the emergency de- organism or administration of an antibiotic to which the organ-
partment from February 13, 1995, through December 31, 2008, ism was resistant, according to susceptibility test criteria for
were prospectively recruited and followed. Patients with neu- lower respiratory tract pathogens.
tropenia, solid organ transplantation, chemotherapy, acquired Complications were defined as any untoward circum-
immunodeficiency syndrome (AIDS) or current corticosteroid stances occurring during hospitalization. In patients with
therapy (Q20 mg prednisone/d or equivalent) at admission were cirrhosis, acute renal failure at admission or during hospitali-
excluded. zation was diagnosed when the serum creatinine level rose
above 133 Kmol/L (1.5 mg/dL) or increased more than 50%
Clinical Assessment, Antibiotic Therapy, and in patients with preexisting renal impairment.35 Hepatorenal
Follow-Up syndrome was defined according to the criteria proposed by the
Patients were seen daily during the hospital stay by 1 or International Ascites Club.2 Presence or absence of ascites was
more of the investigators, who recorded clinical data in a based on physical examination or imaging findings. Spontaneous
computer-assisted protocol. Data were collected on demo- bacterial peritonitis was defined as a polymorphonuclear count
graphic characteristics, comorbidities, causative organisms, in ascitic fluid greater than or equal to 250/mm3, in the absence
antibiotic susceptibilities, biochemical analysis, empirical an- of an intraabdominal source of infection.44
tibiotic therapy, and outcomes, including mortality. A long- The composite outcome of 30-day mortality or ICU ad-
term follow-up visit took place 1 month after discharge. To mission was used to evaluate severe disease. Early case-fatality
stratify patients according to risk, we used CAP-specific rate and overall case-fatality rate were defined as death from
scores (PSI and CURB-65) and cirrhosis-specific scores (CP any cause within 48 hours and 30 days of hospitalization,
score and MELD), as described elsewhere.21,27,41,45 MELD respectively.
scores were calculated using the online calculator available at
http://www.mayoclinic.org/meld/mayomodel8.html.
Microbiologic Studies and Etiologic Diagnosis
Antibiotic therapy was initiated in the emergency depart-
ment in accordance with the hospital guidelines, which recom- Pathogens in blood, normally sterile fluids, sputum, and
mend the administration of a A-lactam (ceftriaxone sodium or other samples were investigated using standard microbiologic
amoxicillin/clavulanate potassium) with or without macrolide procedures. The Streptococcus pneumoniae antigen in urine was
or levofloxacin. Combination therapy was recommended for detected using a rapid immunochromatographic assay (NOW
patients with clinical suspicion of a Legionella species or an Assay, Binax Inc., Portland, ME). L. pneumophila serogroup 1
atypical pathogen, or in the absence of a demonstrative finding antigen in urine was detected by an immunochromatographic
on sputum Gram stain results. Levofloxacin was recommended method (NOW Legionella Urinary Antigen Test, Binax Inc.) or
for patients with a urine antigen test result that was positive enzyme-linked immunosorbent assay (ELISA-Bartels, Bartels,
for Legionella pneumophila serogroup 1. Combined amoxicillin/ Trinity Biotech, Wicklow, Ireland). Standard serologic methods
clavulanate was recommended for patients with clinical sus- were used to determine antibodies against atypical agents. Anti-
picion of aspiration pneumonia, in order to provide adequate microbial susceptibility was tested by the microdilution method,
antianaerobic coverage, as described elsewhere.32 following the Clinical and Laboratory Standard Institute methods
and criteria.12,13

Definitions
Diagnosis of liver cirrhosis was made by histology and/or Statistical Analysis
by clinical, laboratory, and imaging criteria, as described else- We analyzed the results using a commercially available
where.39 CAP was defined as an acute illness associated with 1 statistical software package (SPSS, v. 15.0, SPSS Inc., Chicago,
or more of the following signs and symptoms: new cough with IL). To detect significant differences between groups, we used
or without sputum production, pleuritic chest pain, dyspnea, the chi-square test or the Fisher exact test for categorical vari-
fever or hypothermia, altered breath sounds on auscultation, ables and the t test or the Mann-Whitney test for continuous
leukocytosis, plus the presence of a new infiltrate on a chest variables, as appropriate. We used linear trend analysis to ac-
radiograph. count for multiple comparisons. We used a multivariate analysis
Current smoker was recorded when a patient had smoked to evaluate associations between disease-specific scores and
more than 10 cigarettes per day for at least 1 year preceding the mortality and severe disease. The relative risks were expressed
study. Alcohol abuse was considered if alcohol intake was 93 as odds ratios (ORs) and 95% confidence intervals (CIs). Like-
standard drinks per day. Vaccinated patients included all indi- wise, receiver operating characteristic (ROC) curves were gen-
viduals who had received pneumococcal vaccine in the previ- erated, and areas under the curve (AUCs) were compared to

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Viasus et al Medicine & Volume 90, Number 2, March 2011

evaluate the predictive value of the scores. The following grad- moderate; 0.80Y0.89 = good; 0.90Y1.00 = excellent. Statistical
ing is widely accepted for interpreting the discriminatory value significance was established at > = 0.05. All reported p values
of AUCs: 0.50Y0.59 = zero; 0.60Y0.69 = poor; 0.70Y0.79 = are 2-tailed.

TABLE 1. Characteristics of Community-Acquired Pneumonia by Epidemiologic Group

Patients With Liver Cirrhosis Patients Without Liver Cirrhosis

Characteristic* (n = 90) No. (%)† (n = 3330) No. (%)† P
Demographic data
Age (yr), mean T SD 61.8 T 13 66.8 T 16.9 G.001
Male sex 72 (80.0) 2272 (68.3) .01
Current smoker 37 (41.6) 864 (26.2) .001
Alcohol abuse 32 (35.6) 591 (17.9) G.001
Influenza vaccine (season) 31 (41.9) 1456 (48.2) .28
Pneumococcal vaccine, 5 yr 14 (18.9) 458 (15.4) .40
Previous antibiotic therapy 28 (33.7) 572 (18) G.001
Comorbid conditions 53 (58.9) 2282 (68.5) .05
COPD 20 (22.2) 909 (27.3) .28
Chronic heart disease 13 (14.4) 845 (25.4) .01
Diabetes mellitus 25 (27.8) 670 (20.1) .07
Chronic renal failure 4 (4.4) 205 (6.2) .50
Other‡ 11 (12.2) 635 (19.1) .10
Clinical features
Fever (Q38.0 -C) 44 (49.4) 1821 (55.3) .27
Tachycardia (Q100 beatsImin-1) 36 (51.4) 1330 (49.9) .79
Tachypnea (Q30 breathsImin-1) 34 (43) 1320 (43.9) .87
Impaired consciousness 30 (33.3) 460 (13.9) G.001
Septic shock at presentation 12 (13.5) 200 (6) .01
Chills 40 (44.4) 1555 (46.9) .64
Purulent sputum 51 (64.6) 1601 (62.7) .73
Pleuritic chest pain 32 (35.6) 1425 (43) .15
Signs of consolidation 73 (82) 2696 (81.8) .98
Laboratory and radiographic findings
Respiratory failure
(PaO2/FiO2 G300 or PaO2 G60 mm Hg ) 41 (56.9) 1891 (69.8) .01
Leukocytosis (leukocytes Q12 109/L) 37 (41.1) 1996 (60.1) G.001
Serum creatinine (mmol/L), mean T SD 109.6 T 62.5 119.8 T 91.5 .24
Hypoalbuminemia (albumin G30 g/L) 67 (75.3) 1351 (44.7) G.001
Hyponatremia (sodium G130 mEq/L) 16 (18.0) 146 (6.8) G.001
Multilobar pneumonia 27 (30.3) 1080 (32.8) .62
Pleural effusion 14 (15.6) 571 (17.2) .67
Empyema 3 (3.3) 137 (4.1) 1
Bacteremia 19 (21.8) 400 (13) .01
Pneumococcal bacteremia 15 (17.2) 331 (10.8) .05
CAP-specific scores
PSI score, mean T SD 117.4 T 36.7 101.1 T 34.4 G.001
PSI risk classes§ .002
High risk 67 (74.4) 1915 (57.7)
CURB-65 groups .69
Group 2 23 (30.3) 499 (32.1)
Group 3 20 (26.3) 456 (29.3)
Abbreviations: COPD = chronic obstructive pulmonary disease; SD = standard deviation.
*See definitions in Methods section.
†Data are given as numbers (percentage from available data) except where otherwise indicated.
‡‘‘Other’’ includes cancer, cerebrovascular disease, and/or dementia.
§Patients were stratified into the following risk classes according to PSI score: low risk (e90 points, classes I, II, and III) and high risk (990 points,
classes IV and V).

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Medicine & Volume 90, Number 2, March 2011 Pneumonia in Patients With Cirrhosis

RESULTS liver cirrhosis the causative agents were S. pneumoniae in 331,

H. influenzae in 21, viridans streptococci in 12, P. aeruginosa
Patient Characteristics in 8, Klebsiella pneumoniae in 3, and other pathogens in 25.
During the study period, 3420 consecutive episodes of CAP No differences were found regarding resistance to peni-
in nonseverely immunosuppressed patients were recorded, of cillin (11.1% vs. 8.4%; p = 0.49), ciprofloxacin (0% vs. 1.4%;
which 90 (2.6%) occurred in patients with liver cirrhosis. The p = 0.99), or erythromycin (15.4% vs. 14.7%; p = 0.99) in
most common cause of liver cirrhosis was alcoholism (38.9%), S. pneumoniae isolates. Although 7 patients with liver cir-
followed by chronic viral hepatitis C (27.8%), mixed (chronic rhosis had received norfloxacin or levofloxacin in the previous
viral hepatitis and alcoholism) (12.2%), cryptogenic (5.5%) and 3 months, no quinolone resistance was found in S. pneumoniae.
chronic viral hepatitis B (3.3%). Ten patients (11.1%) did not
have etiology of cirrhosis at the time of CAP diagnosis. The Clinical Outcomes
median value for MELD was 14 (range, 6Y36), and for MELD- The susceptibility test for pathogen isolates indicated that
sodium was 19 (range, 7Y37). As for CP score, 56.6% of cases most patients had received adequate initial empirical antibiotic
were grade B and 21.7% were grade C. therapy. There was a trend toward a greater need for mechanical
We compared the characteristics of patients with and ventilation in patients with cirrhosis (Table 3). However, similar
without liver cirrhosis (Table 1). Patients with liver cirrhosis percentages of patients in the 2 groups developed in-hospital
were younger, more often male, current smokers, and heavy complications or required ICU admission. In addition, no dif-
alcohol consumers. Regarding comorbidity, chronic heart dis- ferences were found in the median length of hospital stay for
ease was less frequent in patients with cirrhosis. Patients with patients between groups.
liver cirrhosis were more commonly classified in high-risk PSI With respect to cirrhosis-related complications, the preva-
classes (IVYV). Impaired consciousness and septic shock at lence of acute renal failure at admission or during hospitalization
presentation were more frequent in patients with liver cirrhosis, was 15.7%. No patients developed hepatorenal syndrome. Fur-
but respiratory failure was less frequent in these patients. Lab- thermore, 2 of 18 patients with ascites had SBP and no pathogen
oratory data demonstrated that CAP patients with liver cirrhosis was isolated. There were no episodes of esophagogastric variceal
were significantly more likely to have hypoalbuminemia and bleeding in patients with cirrhosis during hospitalization.
hyponatremia, but less likely to have leukocytosis. The early and overall case-fatality rates were higher in
patients with liver cirrhosis than in those without. Causes of
Causative Organisms and Antibiotic death were respiratory failure (2 of 13 patients in the liver cir-
Susceptibilities rhosis group and 140 of 247 patients in the group without liver
An etiologic diagnosis for CAP was more frequently es- cirrhosis), shock/multiorgan failure (9 of 13 and 55 of 247
tablished in patients with liver cirrhosis than patients without patients, respectively), and gastrointestinal bleeding (2 of 13
cirrhosis (73.3% vs. 58.5%; p = 0.005). Table 2 shows the and 5 of 247 patients, respectively). Other mortality causes in
distribution of causative organisms in both groups. Overall, patients without liver cirrhosis were acute coronary syndrome,
S. pneumoniae was the most frequent causative pathogen, nosocomial infections, sudden death, and stroke. Similarly, mor-
followed by Haemophilus influenzae, aspiration pneumonia, tality in pneumococcal pneumonia (19.0% vs. 6.6%; p = 0.002)
and L. pneumophila. However, patients with liver cirrhosis and bacteremic pneumococcal pneumonia (46.7% vs. 11.8%;
presented more infections attributable to S. pneumoniae and p G 0.001) were higher in patients with liver cirrhosis. Like-
Pseudomonas aeruginosa. There were no significant differences wise, current smokers and heavy alcohol drinkers had higher
regarding other pathogens between the groups. mortality if they had liver cirrhosis (10.8% vs. 3.9%; p = 0.06
Bacteremia was more frequent in patients with liver cir- and 18.8% vs. 4.2%; p = 0.003, respectively). Two of 4 patients
rhosis than in those without (21.8% vs. 13%; p = 0.01). Of with P. aeruginosa pneumonia died. No significant difference in
the 19 patients with liver cirrhosis, bacteremia was caused mortality was found when comparing patients with liver cirrhosis
by S. pneumoniae in 15, P. aeruginosa in 2, H. influenzae in 1, caused by alcoholism and patients with liver cirrhosis due to
and Streptococcus anginosus in 1. In the 400 patients without chronic viral hepatitis (8.6% vs. 13.8%; p = 0.69). Clinical

TABLE 2. Etiology of CAP by Epidemiologic Group

Patients With Liver Patients Without Liver

Etiology Cirrhosis (n = 90) No. (%) Cirrhosis (n = 3330) No. (%) P
Streptococcus pneumoniae 42 (46.7) 1099 (33.0) .007
Legionella pneumophila 4 (4.4) 203 (6.1) .65
Haemophilus influenzae 6 (6.7) 186 (5.6) .66
Aspiration pneumonia 4 (4.4) 247 (7.4) .41
Gram-negative bacilli 4 (4.4) 56 (1.7) .07
Pseudomonas aeruginosa 4 (4.4) 30 (0.9) .01
Atypical agents 5 (5.6) 144 (4.3) .57
Other organisms* 6 (6.7) 116 (3.5) .10
No pathogen identified 24 (26.7) 1378 (41.5) .005
*Other causative organisms were Staphylococcus aureus (n = 3), Moraxella catarrhalis (n = 1), Aspergillus fumigatus (n = 1), and Streptococcus
species (n = 1) in patients with liver cirrhosis, and M. catarrhalis (n = 30), Streptococcus species (n = 26), respiratory viruses (n = 36), Staphylococcus
aureus (n = 16), Neisseria meningitides (n = 4), Streptococcus pyogenes (n = 2), and other organisms (n = 6) in patients without liver cirrhosis.

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Viasus et al Medicine & Volume 90, Number 2, March 2011

TABLE 3. Antibiotic Therapy and Outcome of CAP by Epidemiologic Group

Patients With Liver Patients Without Liver

Therapy and Outcome Cirrhosis (n = 90) Cirrhosis (n = 3330) P
Initial antibiotic therapy .94
Monotherapy 59 (67.8) 2217 (68.2)
Combination therapy 28 (32.2) 1035 (31.8)
Inappropriate antibiotic therapy 2 (3.0) 135 (7.2) .31
In-hospital complications 28 (31.1) 946 (29.1) .67
ICU admission 10 (11.1) 291 (8.8) .44
Need for mechanical ventilation 9 (10) 183 (5.6) .07
Length of hospital stay (days), median (IQR) 8 (6Y15) 8 (6Y12) .54
Length of intravenous therapy (days), median (IQR) 5 (3Y9) 4 (2Y7) .05
Early case-fatality rate, e48 hr 5 (5.6) 71 (2.1) .04
Overall case-fatality rate, e30 d 13 (14.4) 247 (7.4) .01
Abbreviations: ICU = intensive care unit, IQR = interquartile range.

characteristics and disease-specific scores of the patients with generated ROC curves for MELD, CP score, PSI, and CURB-65
cirrhosis who died and those who survived are shown in Table 4. and found an AUC of 0.832 (95% CI, 0.736Y0.904), 0.761
(95% CI, 0.655Y0.848), 0.741 (95% CI, 0.638Y0.827), and
0.783 (95% CI, 0.673Y0.869), respectively, for predicting se-
Value of Disease-Specific Scores in Patients With vere disease. The optimal cutoff point of 920 for MELD had a
Liver Cirrhosis sensitivity of 0.647 and a specificity of 0.955 for predicting
Bacteremia and mortality rates increased with the severity severe disease. Likewise, using cutoff points of Q30, Q22, and
of the liver disease (5.6%, 20.5%, 33.3% and 0%, 8.5%, 38.9% Q15 for MELD, 100%, 76.9%, and 36.6% of cirrhotic patients,
in CP groups A, B, and C, chi-square test for trend p = 0.038 respectively, had severe disease. Meanwhile, 23.9% of high-risk
and p G 0.001, respectively). High prevalence of bacteremia PSI classes had severe disease (8.1% in class IV and 43.3% in
and mortality was also significantly associated with high MELD class V).
scores (data not shown). Conversely, the prevalence of these Among disease-specific scores, the MELD score emerged
events did not differ significantly between low-risk and high-risk as the only independent predictor of severe disease in the mul-
PSI classes (14.3% vs. 24.2%; p = 0.54 and 4.3% vs. 17.9%; p = tivariate analysis (OR, 1.22; 95% CI, 1.04Y1.42; p = 0.01).
0.17, respectively). In a further analysis, among clinical findings measured at ad-
Eighteen (20%) patients with CAP and liver cirrhosis de- mission, multilobar pneumonia (Q2 lobes involved) and septic
veloped severe disease (30-d mortality or ICU admission). We shock at presentation were significantly associated with MELD

TABLE 4. Factors Associated With Mortality in Patients With CAP and Liver Cirrhosis: Univariate Analysis

Patients With Liver Patients With Liver

Characteristic Cirrhosis Alive (n=77)* Cirrhosis Death (n=13)* P OR (95% CI)
Age (yr), mean T SD 61.8 T 12.8 58.4 T 14.4 .38
Male sex 61 (79.2) 11 (84.6) 1
Current smoker 33 (42.9) 4 (33.3) .75
Alcohol abuse 26 (33.8) 6 (46.2) .53
Impaired consciousness 22 (28.6) 8 (66.7) .01 4.82 (3.67Y6.32)
Septic shock at presentation 8 (10.4) 4 (30.8) .07
Multilobar pneumonia 19 (25) 8 (61.5) .01 2.74 (2.11Y3.55)
Bacteriemia 10 (13,5) 9 (69.2) G.001 2.94 (2.17Y3.99)
Acute renal failure 8 (10.4) 6 (50) .003 8.62 (2.24Y33.19)
Ascites 11 (14.3) 7 (58.3) .005 8.40 (2.25Y31.23)
ICU admission 5 (6.5) 5 (38.5) .005 6.96 (5.17Y9.35)
PSI, high-risk class† 55 (71.4) 12 (92.3) .17
CURB-65, groups 2Y3 34 (53.1) 9 (75) .21
CP score, groups B-C 54 (75) 11 (100) .11
MELD score, high-risk class‡ 7 (9.6) 7 (58.3) G.001 13.2 (3.29Y52.8)
*Data are given as numbers (percentage from available data).
†High-risk class for PSI score (990 points, classes IV and V).
‡High-risk class for MELD (21Y40 points).

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Medicine & Volume 90, Number 2, March 2011 Pneumonia in Patients With Cirrhosis

p = 0.005) and mortality (OR, 1.21; 95% CI, 1.03Y1.42; p =

0.02). Comparisons of low-risk and high-risk groups and the
diagnostic accuracy of the best operating point in ROC curves
for predicting severe disease of scores are shown in Table 5.

DISCUSSION
In the current study we evaluated the epidemiology, clin-
ical features, outcomes, and performance of severity scores in
patients with CAP and liver cirrhosis. The main findings were
1) cirrhotic patients had distinct clinical features and more
severe CAP at admission compared with other patients; 2)
S. pneumoniae and P. aeruginosa were more frequent in patients
with liver cirrhosis than in those without; 3) bacteremia was also
more frequent in patients with liver cirrhosis; 4) mortality rates
were significantly higher in patients with cirrhosis; and 5) cir-
rhosis-specific scores were useful in predicting and stratifying
severe disease (30-d mortality or ICU admission).
The prevalence of liver cirrhosis in patients with CAP
varies according to the definition of chronic liver disease used.
In the Patient Outcomes Research Team (PORT) study, Fine
et al21 documented liver cirrhosis or chronic liver disease such
as chronic active hepatitis in 2.2% of inpatients. Using the
Charlson comorbidity index, Mortensen et al37 found a preva-
FIGURE 1. Comparison between ROC curves of scores for lence of 1.86% for mild chronic liver disease and 0.6% for
predicting severe disease in cirrhotic patients with moderate/severe chronic liver disease in older patients. Other
community-acquired pneumonia. CAP = community-acquired studies have reported a prevalence of chronic liver disease of
pneumonia, CP = Child-Pugh score, MELD = Model for End-Stage
Liver Disease, PSI = Pneumonia Severity Index.
8%.43,48 In the current study, we analyzed only patients with
evidence of liver cirrhosis, who accounted for 2.6% of all cases
in the series. CAP has been reported to be among the most
common bacterial infections in patients with cirrhosis, and, in
for predicting severe disease in the bivariate logistic regression. fact, approximately 13%Y20% of bacterial infections in patients
We therefore examined the presence (1) or absence (0) of with cirrhosis are caused by pneumonia.3,5,20
multilobar pneumonia and septic shock as predictors of severe We compared the clinical picture of CAP at admission in
disease. The new score was calibrated using A from logistic patients with and without liver cirrhosis. Although CAP occurs
regression (MELD-CAP = EMELD + Ehypotension*12^ + on a regular basis in both groups, with fever, expectoration,
Emultilobar pneumonia*8^^). The ROC curve from this new pleuritic pain, and signs of consolidation, we found differences
model (MELD-CAP) produced an AUC of 0.945 (95% CI, between the groups in demographic data and other clinical fea-
0.872Y0.983) (Figure 1). Significant differences were observed tures. Although generally younger than patients without cir-
compared with the AUC for other disease-specific scores (p e rhosis, patients with cirrhosis presented more severe CAP, as
0.02), except for MELD (p = 0.06). Using the optimal cutoff evidenced by higher PSI values. Among the acute clinical vari-
point of 922, the new model had a sensitivity of 0.882 and a ables contained in the PSI, patients with cirrhosis had more
specificity of 0.850 for predicting severe disease. No patients prevalence of septic shock, impaired consciousness, and hy-
with MELD-CAP score G19 died or required ICU admission. ponatremia, but lower levels of respiratory failure. Cirrhotic
Among all disease-specific scores, MELD-CAP was the only patients had less chronic heart disease, and a tendency toward
score related with severe disease (OR, 1.33; 95% CI, 1.09Y1.52; higher levels of diabetes mellitus. Previous studies offer little

TABLE 5. Scores in Cirrhotic Patients With CAP: Risk Groups and Diagnostic Accuracy for Severe Disease

Risk Group* Diagnostic Accuracy†

Low Risk Severe High Risk Severe
Score Disease/Total Low Risk (%) Disease/Total High Risk (%) Sensitivity/Specificity LR+/LRj
MELD-CAP 2/59 (3.4) 15/25 (60) 0.882/0.851 5.91/0.14
MELD 6/71 (8.5) 11/14 (78.6) 0.647/0.955 14.6/0.37
CP 1/18 (5.6) 15/65 (23.1) 0.500/0.985 33.5/0.51
PSI 2/23 (8.7) 16/67 (23.9) 0.722/0.778 3.25/0.36
CURB-65 3/33 (9.1) 14/43 (32.6) 0.647/0.847 4.24/0.42
Abbreviations: LR = likelihood ratio.
*Low-risk and high-risk groups, respectively: MELD-CAP (6Y22, 23Y60 points), MELD (6Y20, 21Y40), CP (A, BYC groups), PSI (IYIII, IVYV
classes), and CURB-65 (0Y1, 2Y3 groups).
†Based on best operating point in ROC curve: MELD-CAP 922, MELD 920, CP 911, PSI 9131, and CURB-65 92.

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Viasus et al Medicine & Volume 90, Number 2, March 2011

information on the epidemiologic data and clinical presentation Polysaccharide pneumococcal vaccination may prevent in-
of CAP in this context. Fernández et al19 and Fasolato et al17 vasive pneumococcal disease in adults and improve outcomes
found pneumonia to be an important cause of septic shock and in patients with CAP.26,38 In the present study, only 18.9% of
acute renal failure, respectively, in patients with liver cirrhosis. patients with liver cirrhosis had previously received pneumo-
Similarly, in a recent study, human immunodeficiency virus coccal vaccine, despite the fact that the United States Advisory
(HIV)-positive patients with liver cirrhosis and CAP showed Committee on Immunization Practices recommends vaccination
more frequent mental status alterations and lower oxygen satu- for all patients with cirrhosis.40 These findings concur with
ration than HIV-positive patients without cirrhosis.33 those of another study showing that current vaccination rates
In the current study, a microbial etiology was more fre- among target persons remain low.25 Wider use of the vaccine
quently established in patients with liver cirrhosis. S. pneumoniae may help prevent invasive pneumococcal pneumonia and may
was the most common causative organism in both pneumonia lower mortality in patients with cirrhosis and CAP. There is
groups, although its prevalence was significantly higher in concern about the protective efficacy of pneumococcal vaccine
patients with cirrhosis. Pneumococcal bacteremia was also more in patients with liver cirrhosis. Studies show that immunoglob-
common in this group. Our findings concur with those of pre- ulin levels increase significantly in patients with cirrhosis but
vious reports that found liver cirrhosis to be a predisposing that they fall over time; in contrast, healthy persons receiving
factor to pneumococcal disease.9,30,43 It is noteworthy that we pneumococcal vaccine maintain heightened antibody levels for
found a higher prevalence of P. aeruginosa in patients with several years.40 Vaccine efficacy in patients with cirrhosis has
liver cirrhosis; in fact, P. aeruginosa has also been reported as a not so far been assessed in large prospective studies.
causative organism in cellulitis in patients with cirrhosis.14 To our knowledge, the present study is the first to assess
With respect to cirrhosis-related complications, 15.7% of the accuracy of CAP-specific (PSI and CURB-65) and liver-
the patients in the current study with CAP and cirrhosis devel- specific (CP and MELD) prognostic scores in cirrhotic patients
oped acute renal failure, but none developed hepatorenal syn- with CAP. The disease-specific scores traditionally used to pre-
drome. Acute renal failure was mainly present in patients with dict poor outcome in CAP have been used to guide clinicians
high values of MELD, and was a risk factor for mortality in regarding the need for hospital admission and have consis-
univariate analysis. The renal failure rate in the current study tently proved to be good predictors of mortality.21,45 However,
was lower than that reported in cirrhotic patients with SBP21 and the ability of these tools to identify patients with severe dis-
in unpublished data from our Hepatology and Liver Transplant ease in the current population is limited. We note that MELD
Department in patients with SBP (48.7%). However, our data score was a good predictor of death and ICU admission in
corroborate the results of the prospective studies by Fasolato patients with cirrhosis and CAP. Although no significant dif-
et al17 and Terra et al,47 who reported acute renal failure in ferences were observed between AUCs from MELD, CP, PSI,
approximately 20% and 29%, respectively, of cirrhotic patients and CURB-65 scores, MELD was more useful in stratifying
with CAP. Fasolato et al17 also found that only biliary or gas- patients in low- and high-risk groups. Therefore, the severity of
trointestinal tract infections, SBP, and urinary tract infections liver dysfunction in patients with cirrhosis is an important
precipitated the progressive form of renal failure. We found no point to consider when attempting to classify CAP patients in
other cirrhotic-related complications, such as esophageal var- appropriate risk groups. The mean MELD score in our cohort
iceal bleeding or nosocomial SBP, in our cohort of patients. (15.1 T 6.7) was similar to that reported by Fasolato et al17 in
Early and overall mortality rates were higher in patients their patients with pneumonia (16.6 T 1.6), but was lower than
with cirrhosis than in those without cirrhosis, and increased those reported in studies of patients with SBP.39 Similarly,
with the severity of liver dysfunction. We also found higher AUCs obtained from all disease-specific scores were close to
mortality in pneumococcal pneumonia and in invasive pneu- those obtained in other studies for predicting mortality or
mococcal pneumonia in patients with cirrhosis. This finding is severe disease in patients with cirrhosis or in patients with
in agreement with a previous study18 that recorded a mortality CAP.39,45,47 The advantages of MELD are that it uses only ob-
rate in patients with liver cirrhosis and invasive pneumococcal jective variables and that it has been validated in a large num-
pneumonia of 34%. However, the specific factors responsible ber and variety of samples. The disadvantages are its reliance
for the increased mortality have not been clearly elucidated. In on laboratory investigation, the need for instruments for the
the univariate analysis in the current study, factors associated calculations, and the marked variations in the scores of tests
with mortality in patients with liver cirrhosis and CAP were performed at different centers.50
impaired consciousness, multilobar pneumonia, ascites, acute Previously, Durand et al15 suggested that adjustments of
renal failure, bacteremia, ICU admission, and high-risk MELD MELD score and/or the addition of other variables are required
score. We were unable to perform a multivariate logistic re- to address some specific issues and that more studies are needed
gression analysis due to the small sample size of patients who to create adapted MELD score derivates. Likewise, another
died. Most of these factors have been described as prognostic study showed that extrahepatic organ dysfunction significantly
factors in previous studies involving patients with CAP or impacts short-term survival in cirrhotic patients with acute de-
patients with cirrhosis. Bacteremia, CP score, and MELD score compensation.10 We therefore supplemented MELD with 2
have been found to be risk factors for mortality in cirrhotic variables associated with poor prognosis in patients with pneu-
patients with infections.8,11,28,47 In a noteworthy case-control monia and routinely assessed on admissionVmultilobar pneu-
study, Graudal et al24 reported that bacteremia in cirrhotic monia and septic shock, which significantly improved the
patients is a severe prognostic sign, not because of its influence predictive value of MELD. The new MELD-CAP score also had
on survival but because of its occurrence late in the course of an excellent discriminatory ability. The AUC of MELD-CAP
cirrhosis. In the current study, bacteremia was also more fre- differed significantly from those of other scores in predicting
quent in patients with advanced liver dysfunction. Likewise, severe disease. Cirrhotic patients with CAP with MELD-CAP
studies in patients with CAP have found that chronic liver values Q28 had a high incidence of severe disease (970%). We
disease is a comorbid condition that is independently associ- note that no patients with scores below 19 died or required ICU
ated with bacteremia,16,43 ICU admission,48 treatment failure,34 treatment, identifying 68% of patients without severe disease.
and mortality.21,36 The MELD-CAP score was also superior to other scores in

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Medicine & Volume 90, Number 2, March 2011 Pneumonia in Patients With Cirrhosis

predicting mortality. Therefore, these scales may be valuable for outcome in spontaneous bacterial peritonitis. Scand J Infect Dis.
the identification of low-risk and high-risk patients with liver 2007;39:697Y702.
cirrhosis and CAP at hospital admission, which is crucial for 9. Choi SH, Park HG, Jun JB, Lee SO, Choi SH, Woo JH, Kim YS.
stratifying places of care, investigation strategies, and thera- Clinical characteristics and outcomes of pneumococcal bacteremia in
peutic measures. adult patients with liver cirrhosis. Diagn Microbiol Infect Dis.
The strengths of the current study include the prospec- 2009;63:160Y164.
tive nature, the large cohort of consecutive hospitalized patients 10. Cholongitas E, Senzolo M, Patch D, Shaw S, Hui C, Burroughs AK.
with CAP, and the comprehensive data collection. Nevertheless, Review article: scoring systems for assessing prognosis in critically ill
there are several limitations that should be acknowledged. The adult cirrhotics. Aliment Pharmacol Ther. 2006;24:453Y464.
study was performed at a single institution, and because of the
11. Christou L, Pappas G, Falagas ME. Bacterial infection-related morbidity
small number of cirrhotic patients with adverse outcomes, it and mortality in cirrhosis. Am J Gastroenterol. 2007;102:1510Y1517.
was impossible to perform a multivariate analysis to establish
independent factors related with mortality. 12. Clinical and Laboratory Standard Institute (CLSI). Methods for dilution
Hepatic cirrhosis is one of the most common causes of antimicrobial susceptibility test for bacteria that growth aerobically;
approved standard. 5th ed. Document M7-A5; supplemental tables
acquired immunodeficiency. Patients with liver cirrhosis have
M100-S10. Wayne, PA: National Committee for Clinical Laboratory
significant immunologic alterations (abnormal cytokine levels
Standards; 2000.
and down-regulation on HLA-DR expression in response to
infections, decrease in activation of macrophages, alterations 13. Clinical and Laboratory Standard Institute (CLSI). Performance
in recruitment and bactericidal activity of polymorphonuclear standards for antimicrobial susceptibility testing: eleventh
leukocytes, and low complement levels) and circulatory altera- informational supplement. Document M100-S11. Wayne, PA: National
Committee for Clinical Laboratory Standards; 2001.
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dilatation).11,46,49 As a consequence of those defects, patients 14. Corredoira JM, Ariza J, Pallares R, Carratala J, Viladrich PF, Rufi G,
with cirrhosis may be more predisposed to multiorgan failure Verdaguer R, Gudiol F. Gram-negative bacillary cellulitis in patients
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hepatic dysfunction plays an important role in the develop- NAC-CALIDAD (Proyecto Integrado de Investigacion de la Sociedad
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cially MELD and the new MELD-CAP, may help to identify Respiratorias de Vias Bajas) Study Group. A prediction rule for
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