Prognostic value of C-reactive protein levels in patients with

cirrhosis

Vincent DI MARTINO (1,2), Caroline COUTRIS (1), Jean-Paul CERVONI (1), Stavros DRITSAS (1,2),

Delphine WEIL (1), Carine RICHOU (1), Claire VANLEMMENS (1), Thierry THEVENOT (1,2).

(1) Service d’Hépatologie et de soins intensifs digestifs, CHRU Jean Minjoz, 25030 Besançon Cedex,

France. (2) Université de Franche Comté, UFR-SMP, Besançon, France.

Running title: CRP and liver cirrhosis

Key words: Liver cirrhosis, C-reactive protein, inflammation, MELD score, prognosis.

Counts: Title: 72 characters. Summary: 260 words. Text: 2841 words. 29 references. 2 tables. 3

Figures.

Abbreviations: CRP: C-reactive Protein; MELD: Model for End-stage Liver Disease; AUROC: Area

Under Receiver Operating Characteristic Curve; HR: Hazard Ratio; SOFA: Sequential Organ Failure

Assessment; SIRS: Systemic Inflammatory Response Syndrome; ACCI: Age-adjusted Charlson

Comorbidity Index; ANOVA: Analysis of Variance; HIV: Human Immunodeficiency Virus; HCC:

Hepatocellular Carcinoma; HCV: Hepatitis C Virus; HBV: Hepatitis B Virus; NO: Nitric Oxide; OR: Odds

Ratio.

Conflict of Interest: Nothing to disclose.

Funding: This study was not supported by any pharmaceutical company or governmental agency.

Author contributions: Study Conception: VDM, JPC. Data collection: CC. Statistical analyses: VDM.

Manuscript Drafting: VDM, CC. Critical revision of the manuscript for important intellectual content:

JPC, TT, SD, DW.

Correspondence to: Prof. Vincent DI MARTINO, Service d’Hépatologie, CHRU jean Minjoz, 25030

Besançon Cedex, France. Tel: 33 3 81668421. Fax: 33 3 81668417. E-mail: vdimartino@chu-

besancon.fr.

This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as an‘Accepted Article’, doi: 10.1002/lt.24088

This article is protected by copyright. All rights reserved.

Di Martino V et al.- 2

ABSTRACT

Identifying cirrhosis with poor short-term prognosis remains crucial to improve the allocation of

liver grafts. The purpose of this study was to assess the prognostic value of a model combining the

variation of CRP levels within 15 days, the MELD score and the presence of comorbidities in

decompensated cirrhotic patients with Child-Pugh>B7 and to test the relevance of this model in

compensated cirrhotic patients. Data of cirrhotic patients without hepatocellular carcinoma,

extrahepatic malignancy, HIV infection, organ transplantation, seen between January 2010 and

December 2011 were collected. Multivariate analyses of predictors of 3-months mortality used Cox

models adjusted on the Age-ajusted Charlson Comorbidity Index (ACCI). The prognostic

performance (AUROCs) of the 3-variables model was compared to that of the MELD score. 241

patients met the inclusion criteria, including 109 patients with Child-Pugh>B7 hospitalized for

decompensation. In these severe patients, the 3-month mortality was independently predicted by

the MELD (HR=1.10, 95%CI:1.05-1.14, p<0.001), and CRP>32mg/L at baseline and day-15 (HR=2.21,

95%CI:1.03-4.76, p=0.042). This model was better than the MELD alone (AUROC, 0.789 vs.0.734,

p<0.05). In the whole cirrhotic population, the 3 month mortality was also predicted by high MELD

scores (HR=1.11, 95%CI:1.07-1.16,p<10-4) and CRP>10mg/L at baseline and day 15 (HR=2.89,

95%CI:1.29-6.48, p<0.001), but the AUROCs of the 3 variables model and of the MELD score alone

were no longer significantly different (0.89 vs. 0.88, NS). In conclusion, prognostic models

incorporating variations in CRP predict 3-month mortality in cirrhotic patients. Such models are

particularly relevant in patients with decompensated cirrhosis but provide limited increase of

prediction when compared to the MELD in the whole cirrhotic population.

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Di Martino V et al.- 3

The prognosis of cirrhotic patients remains difficult to assess despite its substantial improvement

over the last decades1,2, particularly due to the development of liver transplantation. The context of

organ shortage makes crucial to optimize organ allocation by giving priority to the sickest patients,

thus emphasizing the need for accurate short-term prognosis assessment. Currently, patients eligible

for liver transplantation are sorted according to their MELD score3, an indicator of liver function.

However, it has been shown that the short-term prognosis of patients with end-stage liver failure

largely depends on events that worsen temporarily or are superimposed to liver failure. These events

are better taken into account by general prognostic scores numbering organ failures (such as the

Acute Physiology and Chronic Health Evaluation (APACHE) and the Sequential Organ Failure

Assessment (SOFA) scores) than scores specifically dedicated to liver failure, such as the Child-Pugh

or MELD scores. A key event for prognosis seems to be the existence of a systemic inflammatory

response syndrome (SIRS)4,5

, which has been shown to increase mortality6,7

, complications of portal

hypertension, and encephalopathy8,9 in cirrhotic patients with or without renal failure. It therefore

seems appropriate to test prognostic models incorporating together parameters of liver function and

parameters reflecting SIRS. In a previous prospective study we suggested that CRP was an accurate

marker of SIRS and was able to predict 6-month mortality in patients with cirrhosis1. This study

included hospitalized cirrhotic patients with Child-Pugh score greater than B7 and suggested the

good prognostic value of a 3-variables model incorporating MELD score, assessment of extrahepatic

comorbidities, and variation of CRP levels within 15 days.

The aims of this study were therefore: 1) to provide a validation of this model in a new cohort of

patients; 2) to investigate whether CRP is still useful for predicting mortality in the general

population of cirrhotic patients, i.e., without clinical decompensation and with Child-Pugh A score; 3)

to investigate whether this model is able to predict 3-month mortality to make it more appropriate

for the context of liver transplantation.

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Di Martino V et al.- 4

PATIENTS AND METHODS

Study design

We conducted a prospective observational cohort study. The protocol for this study was approved by

the Besançon University Hospital Institutional Review Board (CPP Est-2).

Patients

All consecutive cirrhotic patients admitted between January 2010 and December 2011 in our

University Hospital were prospectively included if they fulfilled the following criteria: 1) cirrhosis

either histologically-proven or considered obvious by clinical, biochemical and morphological criteria;

2) no hepatocellular carcinoma, 3) no progressive extrahepatic malignancy, organ transplant or HIV

infection, 4) obtained consent. There were no exclusion criteria regarding age or Child-Pugh score.

Patients enrolled in our previous study were not eligible for the present study.

Data collection

Ninety-four variables were recorded at admission and during follow-up at day 15, and month six.

They concerned demographics (sex, age), cause and history of liver disease, relevant comorbidities as

assessed by the Age-adjusted Charlson comorbidity index (ACCI10), reason for admission (with a

specific distinction between planned hospitalizations (for routine paracentesis, endoscopy or other

diagnostic procedures) and unplanned hospitalization (in the event of decompensation) , clinical

status on admission including the SIRS criteria5, liver biochemistry, assessment of renal function,

culture of blood, urine, and ascitis (if any), and measurement of serum routine CRP and Procalcitonin.

Statistical analyses

Quantitative variables were expressed by their mean ± SE or median (with the 95% CI) in the event of

abnormal distribution. Comparisons of subgroups of patients regarding variations of CRP levels were

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Di Martino V et al.- 5

performed using the chi-square, Student t test and ANOVA. Correlations between CRP level and

MELD score were evaluated by the Spearman rank test.

Statistical analyses were performed separately in the whole study population and in the subset of

patients with Child-Pugh >B7 hospitalized for clinical decompensation. This latter population

constituted a validation cohort of results previously published.

For these two analyses, the primary outcome measure for prognosis was the 3-month mortality rate.

Patients were separated in three groups defined by the variation of CRP levels between baseline and

day 15 as defined previously, with relevant thresholds of CRP assessed by the Youden index. Group A

(validation cohort) or group A’ (whole population) were defined by persistently high CRP levels (at

baseline and day-15); Group B (validation cohort) or B’ (whole population) were defined by high CRP

levels at baseline with subsequent decrease below threshold at day-15; Group C (validation cohort)

or C’ (whole population) were defined by CRP levels below threshold at baseline. Patients’ group

according to CRP variation and other factors affecting prognosis were evaluated using the Kaplan-

Meier model and log-rank test for univariate analyses, and the proportional Hazard Regression (Cox)

Model for multivariate analysis. To include in the model the variation of CRP level within the first 15

days as a predictive factor of mortality, day 15 was considered as the starting point and patients who

died within the first 15 days were not included in the survival analysis. Patients transplanted during

follow-up were included and considered as alive with the liver transplant date marking the end of

follow-up. The performances of MELD, baseline CRP, and multivariate model for predicting short-

term mortality were compared using the comparison of the AUROCs. All statistical analyses were

performed using the NCSS package for Windows.

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RESULTS

Study population

Five hundred and five cirrhotic patients were admitted during the study period. Seventy-four patients

were excluded because they participated to the previous study; 138 patients had HCC, 7 patients

were HIV-infected, 7 patients were organ recipients and 16 patients had solid cancer or hematologic

malignancies. Twenty-two additional patients were excluded because of missing data. A total of 241

cirrhotic patients were thus finally included (Figure 1). Their characteristics are summarized in table

1. Briefly, there were 160 men (66.4%); the median age was 60 yrs (95%CI: 59-62 yrs); the cirrhosis

was related to alcohol for 140 patients (58.1%), to a metabolic syndrome for 40 patients (16.6%),

HCV or HBV for 28 patients (11.6%) and other disease (Wilson, hemochromatosis, autoimmune,

cryptogenic) for 33 patients (13.7%). Eighty-eight patients (36.5%) were Child-Pugh A, 64 patients

(26.5%) Child-Pugh B, and 89 patients (36.9%). Child-Pugh C Ninety-two patients (38.2%) were

hospitalized for endoscopic procedure or paracentesis (planned hospitalization) and 149 patients

(61.8%) for decompensation (unplanned hospitalization). The median MELD was 14.06 (95%CI:

11.42–15.72). The CRP value ranged from 1 to 372 mg/L (median 10 mg/l, 95%CI: 8-12). We

identified 69 overt bacterial infections (28.6%) including 20 spontaneous peritonitis (8.3%) and 18

bacteremia (7.5%). Among the 33 alcoholic patients with a Maddrey discriminant function>32 who

underwent transjugular liver biopsy, 23 patients had histologically-proven alcoholic hepatitis. It

represented 9.5% of the whole cohort and 21.1% of decompensated patients. Seventy-three patients

(30.3%) had SIRS as defined by the ACCP/SCCM consensus conference5. One hundred thirteen

patients (46.9%) had extrahepatic comorbidities, including 30 cardiac failures (12.4%), 18 respiratory

failures (7.4%), 15 renal failures unrelated to hepatorenal syndrome (6.2%). The median Age-ajusted

Charlson Comorbidity Index (ACCI)10

was 5 and ranged from 3 to 12. The subgroup of patients Child-

Pugh>B7 hospitalized for decompensation included 109 patients (45.27%).

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During a 14 months median follow-up (range: 15 days to 38 months), 76 patients (31.3%) died

including 38 deaths at month 3 and 51 deaths at month 6. Fifteen patients (6.2%) underwent liver

transplantation.

Determination of optimal cut-offs of CRP levels for predicting 3 month mortality

High baseline CRP levels were significantly associated with 3 month mortality (CRP=40.9±6.7 in

patients who died vs. 17.5±2.4 in others, p=0.0002). The AUROC was 0.783 (95%CI: 0.701-0.844).

Using the Youden index, the best discriminant value of CRP was 10mg/L (the upper normal range).

With this cut-off, the prediction of 3 month mortality was true for 62% of patients, the sensitivity was

89% and the negative predictive value was 97%. When considering the changes in CRP levels

between baseline and day 15 using this cut-off, 72 patients belonged to group A’, 21 to group B’ and

120 to Group C’.

In similar ROC curve analysis restricted to patients with decompensated cirrhosis and a Child-Pugh

score >B7 (validation cohort), the AUROC was 0.635 (95%CI: 0.509-0.734), and the best discriminant

value of CRP given by the Youden index was 32mg/L, which gave the following performance

indicators for predicting 3 month mortality: Sensitivity: 51%, specificity: 70%, NPV: 75%, well-

classified: 64%. When considering the changes in CRP levels between baseline and day 15 using this

cut-off, 19 patients belonged to group A, 20 to group B and 69 to Group C.

Predictors of 3 month mortality in decompensated cirrhotic patients

In univariate analyses restricted to Child-Pugh>B7 cirrhotic patients hospitalized for decompensation,

the 3-month mortality was significantly associated with the Child-Pugh C stage, a high MELD score,

the presence of SIRS, bacteriemia, overt bacterial infection and particularly spontaneous peritonitis.

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The survival rate was significantly lower in group A patients compared with others (p=0.020). At 3

months, it was 57.0% in group A vs. 70.0% in group B and 76.7% in group C; at 6 months, it was

50.7%, 65.0% and 66.0% in group A, B and C, respectively (Figure 2A). The 3 variables prognostic

model (including ACCI, MELD and group A as defined by CRP variations) was able to predict 3 month

mortality (AUROC=0.789; 95%CI: 0.679-0.875). Group A (HR=2.21; 95%CI: 1.03-4.76, p=0.042) and

MELD score (HR=1.10; 95%CI: 1.05-1.14, p<0.001) had independent influence on 3 month mortality.

There was no correlation between the CRP levels and MELD score (R² <0.001, p=NS).

Predictors of 3-month mortality in the general population

In univariate analysis, the 3 month mortality was significantly associated with group A' (OR=7.33;

95% CI: 3.18-16.89, p<10-4). The 3 month survival was 69.2% (95%CI: 58.3-80.2%) in group A’, 75.4%

(95%CI:56.6-94.2) in group B’, and 96.6% (95%CI: 93.4-99.9%) in group C’, (p<0.001; Figure 2B). Other

significant predictors were Child-Pugh >B7 (OR=23.26; 95%CI: 5.45-99.20, p<10-4), MELD>18

(OR=10.38; 95%CI: 4.47-24.10, p<10-4

), histologically proven alcoholic hepatitis (OR=2.67; 95%CI:

1.01-7.01, p=0.040), overt bacterial infection (OR=11.20; 95% CI: 5.04-24.90, p<10-4), positive blood

culture (OR=15.31; 95%CI: 5.29-44.26, p<10-4), pneumonia (OR=6.57; 95%CI:2.29-18.81; p< 0.001),

spontaneous peritonitis (OR=8.87; 95%CI: 3.37-23.36, p<10-4

), SIRS (OR=14.53; 95%CI: 5.36-39.36,

p<10-4) (and all SIRS criteria considered separately), cardiac failure (OR=3.30; 95%CI: 1.40-7.78,

p=0.004), and unplanned hospitalization (OR=30.12; 95%CI: 4.05-223.76, p<10-4

). The use of beta-

blockers had no significant impact on 3-month mortality.

Group A' patients were more often younger than 60yrs (42.7 vs. 26.7% p=0.012), had more often a

Child-Pugh score B or C (50.7 vs. 3.9% p<10-4), a MELD>18 (56.0 vs. 21.2%, p<10-4), a SIRS (72.7 vs.

16.5%, p<10-4), a bacterial infection (62.1 vs. 21.1%, p<10-4), positive blood cultures (88.2 vs. 29.1%,

p<10-4

), spontaneous peritonitis (85.0 vs. 28.5%, p<10-4

), alcoholic hepatitis (68.2 vs. 29.8%,

p=0.0003) and have been more often hospitalized for decompensation (49.6 vs. 6.4% p<10-4) than

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Di Martino V et al.- 9

others. There was no significant relationship between group A’ and sex, extrahepatic morbidities,

and etiology of cirrhosis. CRP and MELD were positively correlated (R²=0.056, p<0.001), conversely to

that observed in the subset of more severe patients.

Through Cox regression multivariate analysis adjusted on ACCI, the MELD score (HR=1.113, 95%CIHR:

1.07-1.16, p<10-4

), and the group A' according to the CRP variations (HR=2.894, 95% CIHR: 1.29-6.48,

p<0.001) were significant predictors of 3 month mortality (Table 2). The AUROC of the 3 variable

model was 0.895 (95%CI: 0.843-0.930).

Sensitivity analyses

Sensitivity analyses were performed to investigate whether group A’ was able to predict 6 month

mortality when excluding patients with histologically proven alcoholic hepatitis, or considering

separately patients with or without bacterial infection. When restricting survival analysis on patients

without alcoholic hepatitis and without infection, the 3 month survival was 85.2% in group A’ vs.

96.4% in other patients (p=0.003). Similar results were obtained when removing from analysis only

patients with alcoholic hepatitis or only patients with bacterial infection. In a sensitivity analysis

restricted to infected patients, the difference in 3 month survival was still significant between group

A’ patients vs. others (50.1% vs. 79.8%, p=0.028).

Performance of the 3 variables prognostic model vs. MELD score alone

In the general population, the prognostic performance of the 3 variables Cox model (incorporating

MELD, ACCI, and group A’ as performed in the previous study) was 0.895 (AUROC; 95%CI: 0.843-

0.930). When compared to the performance of the MELD score alone (AUROC: 0.876; 95% CI: 0.817-

0.916), the difference was not significant (p=0.18; Figure 3). In contrast, in the restricted population

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Di Martino V et al.- 10

(Child> B7 and unplanned hospitalization) the same model predicted significantly better than the

MELD score alone the 3-month mortality (AUROC: 0.789 vs. 0.734, p<0.05) (Figure 3).

Predictors of 6 month mortality

All the previous analyses have been performed for discriminating survivors vs. non-survivors at 6

months. The same predictors were identified, with similar cutoffs of CRP levels. The impact of

extrahepatic comorbidities was slightly stronger. (data not shown).

DISCUSSION

This study provided two relevant results. First, it confirmed that the variation of CRP level is a useful

tool for predicting short-term mortality in hospitalized cirrhotic patients with a Child-Pugh stage

greater than B7. In this population, the relevant cut-off of CRP was 32mg/L, close to that found in the

first set of patients1. We thus provided a convincing internal validation of the results previously

published. Second, we demonstrated that our prognostic model still works in patients with less

severe cirrhosis, as reflected by lower Child-Pugh scores and planned hospitalizations. In that

population, the relevant cut-off of CRP was 10mg/L, i.e., the upper normal value. However, the

increase in predicting 3 month mortality provided by our model appears to be marginal compared to

that already given by the MELD score alone.

Our study had the advantage of collecting prospectively numerous data in an unselected population,

thus avoiding selection bias. The sample size was adequate to allow multivariate analyses and to

compare the performance of different prognostic models. In addition, the assessment of

comorbidities was performed by the ACCI (quantitative index) rather than a qualitative indicator

(presence or absence of extrahepatic comorbidities), which enabled us to analyze more accurately

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Di Martino V et al.- 11

the prognostic consequences of comorbidities in cirrhotic patients. Such information is often missing

in the literature. Another advantage of this study is to have expanded the analysis of the prognostic

value of CRP to less severe cirrhotic patients, thus allowing us to generalize our findings to the

general cirrhotic population. We confirmed the deleterious impact of alcoholic hepatitis, bacterial

infection, and SIRS, as already described in the literature11–13

. Interestingly, the prognostic relevance

of CRP variations, although still significant, was much lower in the whole population than in the

population of severe cirrhotic patients. This was clearly illustrated when comparing the performance

of our 3 variables model and that of the MELD (figure 3). This finding was probably the consequence

of a higher variability of MELD in the whole population, thus increasing its power. We also found that

CRP and MELD were correlated in the whole population and were not in the subset of severe

cirrhotic patients. This makes our prognostic model particularly useful in the setting of end-stage

liver disease. In this context, systemic inflammation, a condition able to compromise survival, may be

frequent but poorly predicted by the variations of MELD. The measure of a simple and reproducible

marker of SIRS such as CRP seems thus interesting. Conversely, in patients with compensated

cirrhosis, the prognostic value of CRP variations is statistically significant but its clinical significance

probably remains limited.

SIRS is common in severe cirrhotic patients. It is the consequence of overt or occult bacterial

infections14 favored by an increased permeability of the gastrointestinal tract, a decrease in serum

concentrations of fibronectin, complement and opsonins and an impairment of phagocytic function

and chemotaxis of neutrophils15. The activation of the inflammatory response is promoted by the

bacterial translocation of gram-negative bacilli and gram-positive cocci from the gastrointestinal tract

to the mesenteric lymph nodes and/or other extra-intestinal sites16. Bacterial translocation is the

consequence of bacterial growth17,18, structural19 and functional changes (exsudative enteropathy)20

of the mucosa and a deficiency of mucosal T lymphocytes21

and immunoglobulin A22

. Bacterial

translocation may increase the production of NO in the splanchnic circulation aggravating portal

hypertension and abnormal liver flow23,24

. It also activates peritoneal macrophages which produce

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Di Martino V et al.- 12

pro-inflammatory cytokines (IL2, IL12, TNF alpha). Such pro-inflammatory response is exacerbated by

interleukin-625. In cirrhotics with ascites, Albillos et al. found that high concentrations of

lipopolysaccaride binding protein stimulate the secretion of Tumor Necrosis Factor-alpha and

interleukin-626. The clinical diagnosis of SIRS may be difficult in the event of cirrhosis: hypersplenism

can hide hyperleucocytosis or worsen leukopenia, subclinical encephalopathy may lead to an

increase in respiratory rate and induce hypocapnia, tachycardia is frequently associated with

hyperkinetic syndrome but can conversely be hidden by beta-blockers. CRP is synthesized in the

acute phase of inflammation in response to IL6 and its concentration is not modified by liver

impairment27. It seems to be a good marker of SIRS, which is easily available, inexpensive, and more

accurate than clinical parameters of SIRS for identifying systemic inflammation in cirrhotic patients.

We have shown that a simple measurement of CRP at baseline and at day 15 provided a powerful

tool for predicting short-term mortality in hospitalised cirrhotic patients. Interestingly, high baseline

CRP levels could remain elevated over time despite the resolution of bacterial infection in some

patients. This suggests that systemic inflammation may become persistent and acts as an

autonomous disease. In the event of bacterial infection, the value of serial CRP measures for

predicting mortality of cirrhotic patients was underlined by other authors: prognosis was significantly

better in patients who quickly recovered from bacterial infection and experienced reduction in the

CRP levels28, as also observed in our series. Our findings are also in keeping with those of a

multicenter study recently published29

, which found that high CRP levels, as well as

hyperleukocytosis, were strong predictors of death in cirrhotic patients. However, this study did not

investigate the relevance of serial measures of CRP, and its strong prognostic value out of the context

of sepsis.

The applicability of our findings to the context of liver transplantation seems good. It may allow to

better sort patients with intermediate MELD scores in the waiting list. Although it requires a 15-days

follow-up to become available, our model helps avoiding the prioritization of infected patients to

liver transplantation, contrary to what a single measure of CRP would produce.

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Di Martino V et al.- 13

In conclusion, CRP level, and particularly its variation, is a true prognostic marker in cirrhotic patients,

particularly powerful in the event of advanced liver failure. It allows identifying cirrhotic patients with

poor short-term prognosis. A model combining MELD and CRP variations may sort the candidates for

liver transplantation better than the MELD score alone. Such model warrants external validations.

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Di Martino V et al.- 15

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Di Martino V et al.- 16

Table 1: Patients characteristics

Whole population

(n = 241)

Pugh>B7, unplanned

hospitalization

(n = 109)

Age (years)

Sex (Males)

Etiology of cirrhosis

- Alcohol

- Virus

- Metabolic

- Other

Histologically-proven alcoholic hepatitis

Extrahepatic comorbidities

ACCI

MELD

Bacterial Infection

Spontaneous peritonitis

Pneumonia

Bacteremia

SIRS

- SIRS according to heart rate

- SIRS according to breath rate or pCO2

- SIRS according to leukocytes count

- SIRS according to body temperature

-

Baseline CRP (mg/L)

PCT (ng/ml)

Planned hospitalization

Beta-blockers

Child-Pugh A

Child-Pugh B

Child-Pugh C

60 (59-62)

160 (66.4%)

140 (58.1%)

28 (11.6%)

40 (16.6%)

33 (13.7%)

23 (9.5%)

113 (46.9%)

5.4 (5.2-5.7)

15.4 (14.3-16.5)

69 (28.6%)

20 (8.3%)

16 (6.6%)

18 (7.5%)

73 (30.3%)

69 (28.6%)

206 (85.5%)

76 (31.5%)

18 (7.5%)

21.2 (16.6-25.8)

0.69 (0.29-1.09)

92 (38.2%)

135 (56.0%)

88 (36.5%)

64 (26.5%)

89 (36.9%)

59 (57-61)

83 (76.1%)

79 (72.5%)

9 (8.2%)

9 (8.2%)

12 (11.0%)

23 (21.1%)

49 (44.9%)

5.3 (5-5.6)

21.5 (20-23.1)

57 (52.3%)

20 (18.3%)

16 (14.7%)

15 (13.8%)

55 (50.4%)

41 (37.6%)

100 (91.7%)

41 (37.6%)

14 (12.8%)

35.2 (26.2-44.2)

0.72 (0.27-1.17)

-

70 (64.2%)

-

26 (23.8%)

83 (76.1%)

ACCI: Age-Adjusted Charlson Comorbidity Index. MELD: Model for End-Stage Liver Disease. SIRS:

Systemic Inflamatory Response Syndrome. CRP: C-Reactive Protein. PCT: Procalcitonin.

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Table 2: multivariate analysis of factors associated with 3-month mortality in the whole

population.

Cox model. 33 events. 208 patients. R²=0.22

Variables HR 95% CI (HR) p % variance

(pseudoR2)

ACCI

MELD

CRP group A’

1.085

1.113

2.894

0.90-1.31

1.07-1.16

1.29-6.48

0.39

<0.0001

<0.001

0.8

24.2

7.0

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FIGURES LEGEND

Figure 1: Flowchart of cirrhotic patients included in our study

Figure 2: Survival according to variation of CRP levels between baseline and day 15. 2A in the

validation cohort (Child-Pugh>B7 and unplanned hospitalization, N = 109). 2B In the general

population (N=217), survival was significantly lower in groups A and A' as defined by a persistently

elevated CRP level.

Figure 3: Prediction of the 3-month mortality: comparison of MELD score and 3 variables model.

In the whole population of inpatients with cirrhosis, the MELD score accurately predicts 3 month

mortality (AUROC=0.876) whereas a Cox model (1) including MELD, Age-adjusted Charlson

comorbidity index (ACCI) and the variation of CRP levels between baseline and day 15 provided

marginal and non-significant improvement for the same prediction (AUROC=0.895). In severe

patients (as defined by Pugh >B7 and unplanned hospitalization for clinical decompensation), the

MELD score has lower variability and its power for predicting 3 month mortality decreases

(AUROC=0.734). In that population, a 3 variables Cox model (MELD, ACCI, CRP variation within 15

days, (2)) provides significant improvement for predicting 3-month mortality (AUROC=0.789, p<0.05).

(1) Index= Exp(0.08207*(ACCI) + 1.06274*(groupA', i.e., CRP>10mg/L at baseline and day-15) +

0.10699*(MELD)

(2) Index=Exp(0.49429*ACCI + 0.79383*(groupA, i.e., CRP≥32mg/L at baseline and day-15)+

0.09322*MELD)

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Figure 1

Inpatients with cirrhosis 1/1/2010-31/12/2011

N=505

N=263

242 Excluded First cohort N=74

HCC N=138 Transplanted N=7 HIV positive N=7

Extrahepatic malignancies N=16

22 Excluded for missing data

Whole Study population N=241

Pugh>B7 and clinical

decompensation N=109

Pugh≤ B7 or compensated

cirrhosis N=132

Validation cohort of the

3-variable model

Assessment of the prognostic value of CRP changes in

cirrhotic patients

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0

10

20

30

40

50

60

70

80

90

100

0 3 6

months

Group A

Group B

Group C

P=0.020

Figure 2A

0

10

20

30

40

50

60

70

80

90

100

0 3 6

months

Group C’

Group B’

Group A’

P<0.0001

Figure 2B

% surviving

% surviving

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0.00

0.25

0.50

0.75

1.00

0.00 0.25 0.50 0.75 1.00

1-Specificity

Sens

itivi

ty

3 variables model. AUROC=0.789 (0.679-0.875)

MELD. AUROC=0.734 (0.618-0.820)

Validation cohort (Pugh>B7; clinical decompensation)

Whole population

Figure 3

0.00

0.25

0.50

0.75

1.00

0.00 0.25 0.50 0.75 1.00

1-Specificity

Sens

itivi

ty

3 variables model. AUROC=0.895 (0.843-0.930)

MELD. AUROC=0.876 (0.817-0.916)

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