Canadian Journal of Gastroenterology and Hepatology
Volume 2018 (2018), Article ID 5108781, 7 pages
https://doi.org/10.1155/2018/5108781

Research Article

Bacterial Infection and Predictors of Mortality in Patients with Autoimmune Liver Disease-Associated Acute-On-Chronic Liver Failure

Xuan Zhang,¹ Ping Chen,² Hainv Gao,² Shaorui Hao,¹ Meifang Yang,¹ Hong Zhao,¹ Jianhua Hu,¹ Weihang Ma,¹ and Lanjuan Li¹

¹State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
²Infectious disease department, Shulan (Hangzhou) Hospital, Hangzhou, China

Correspondence should be addressed to Lanjuan Li; ljli@zju.edu.cn

Received 28 September 2017; Revised 13 December 2017; Accepted 11 January 2018; Published 28 January 2018

Academic Editor: Yu-Chen Fan

Copyright © 2018 Xuan Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Objective. To date, few studies are available on autoimmune liver disease-associated acute-on-chronic liver failure (ACLF). The aim of this study is to investigate bacterial infection and predictors of mortality in these patients. Methods. We retrospectively studied patients with autoimmune liver disease from August 2012 to August 2017. Clinical data of the patients were retrieved for analysis. Results. There were 53 ACLF patients and 53 patients without ACLF in this study. The ACLF group had a higher prevalence of complications (). The 28-day and 90-day mortality rates were also obviously high in patients with ACLF (38.3% and 74.5%, resp.) (). No predictor was significantly associated with 28-day and 90-day transplant-free mortality. In 53ACLF patients, 40 (75.5%) patients showed bacterial infection. ACLF patients with bacterial infection showed high Child-Pugh score, MELD score, CLIF-SOFA score, 28-day mortality, and 90-day mortality (). Moreover, C-reactive protein (CRP) using 12.15 mg/L cut-off value proved to be more accurate than procalcitonin in identifying patients with infection. Conclusions. Autoimmune liver disease-associated ACLF showed more complications and high mortality. Bacterial infection patients displayed a more severe condition than those without infection. Elevated CRP is an accurate marker for diagnosing bacterial infection in autoimmune liver disease-associated ACLF patients.

1. Introduction

In recent years, acute-on-chronic liver failure (ACLF) as a specific clinical form of liver failure has attracted increasing attention. In fact, ACLF is considered a syndrome that occurs on the background of chronic liver disease, and previously diagnosed cirrhosis is not required, which is characterized by acute hepatic decompensation resulting in liver failure (jaundice and prolongation of the international normalized ratio [INR]) and one or more extrahepatic organ failures that are associated with increased mortality within a period of 28 days and up to three months from onset [1, 2]. Moreover, ACLF can rapidly progress, requiring an urgent need for assessment and referral for liver transplantation [3]. Therefore, recognition and intervention of the predictors of mortality in ACLF patients can prevent or reverse the process and improve the survival rate.

Several patients with ACLF have been recently reported [3–7]. Moreau et al. found that bacterial infection is the trigger of 33% ACLF and is the most commonly identifiable trigger of this syndrome [4]. Some studies considered hepatic encephalopathy, low-serum sodium, and high INR as predictors of poor outcome in ACLF patients [3, 5]. However, few studies about autoimmune liver disease-induced ACLF patients are available to date. Except for the known predictors, possible risk factors have also received less attention. Moreover, bacterial infection in the population is not largely known. The aim of this study is, therefore, to collect data about autoimmune liver disease-associated ACLF patients to investigate bacterial infection and predictors of mortality to reduce the mortality in this population.

2. Materials and Methods

2.1. Study Population and Data Collection

We retrospectively analyzed the data of all patients admitted at the infectious disease wards of the First Affiliated Hospital, College of Medicine, Zhejiang University, China, and diagnosed with autoimmune liver disease-associated ACLF from August 2012 to August 2017. Patients with autoimmune liver disease who satisfied the 13th Asia-Pacific Congress of Clinical Microbiology and Infection (APCCMI) Consensus Guidelines for diagnosis and treatment of liver failure [8], but not diagnostic criteria of the European Association for the Study of the Liver (EASL) [4], were as control group (i.e., no ACLF group). All of the patients in our study had oral care after they admitted to hospital. Patients showing the following were excluded: coinfections with other viruses, including hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, and human immunodeficiency virus; concomitant liver diseases, such as Wilson’s disease; coexisting liver cancer or extrahepatic malignancy; usage of hepatotoxic drugs. We used the composite of death or liver transplantation as our endpoint.

The research protocol was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University. The need for consent was waived because the study was retrospective and data were analyzed anonymously.

The following data were collected from hospital information system and medical documents: age, gender, diabetes, coexisting other autoimmune diseases, steroid exposure, laboratory findings, symptoms, the presence of bacterial infection at admission or during hospitalization, and mortality at 28 and 90 days. The chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score, Child-Pugh score, and model for end-stage liver disease (MELD) score were calculated from the collected data.

2.2. Definitions

Diagnostic criteria of primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC) were defined by American Association for the Study of Liver Diseases (AASLD) [9–11]. Diagnosis of AIH-PBC overlap syndrome referenced the standard which was proposed by Chazouillères et al. in 1998 [12].

Diagnostic criteria and grades of ACLF were defined according to EASL definition [4], as follows.

ACLF Grade 1. This group includes 3 subgroups: (1) patients with single kidney failure, (2) patients with single failure of the liver, coagulation, circulation, or respiration who had a serum creatinine level ranging from 1.5 to 1.9 mg/dL and/or mild to moderate hepatic encephalopathy, and (3) patients with single cerebral failure who had a serum creatinine level ranging from 1.5 and 1.9 mg/dL.

ACLF Grade 2. This group includes the patients with 2 organ failures.

ACLF Grade 3. This group includes the patients with 3 organ failures or more.

The patients as control group satisfied the following criteria specified by the 13th APCCMI Consensus Guidelines for diagnosis and treatment of liver failure [8] as follows.

Patients with chronic liver diseases have acute or subacute deterioration of liver function. ACLF usually exhibits the following symptoms: (a) fatigue with gastrointestinal tract symptoms; (b) rapidly deepening jaundice, with total bilirubin 10 times higher than the upper limit of normal or a daily increase ≥ 17.1 µmol/L; (c) hemorrhagic tendency with INR ≥ 1.5 or prothrombin activity ≤ 40% and other causes which have been excluded; (d) progressive reduction in liver size; and (e) hepatic encephalopathy occurrence.

Bacterial infection in parts of the body was defined as follows [13]. Bacterial pneumonia was defined as the association of clinical and radiological signs of lung infection observed in chest radiographs. Spontaneous bacterial peritonitis was diagnosed when ascites culture was positive or polymorphonuclear count was no less than 250 cells/μL in ascites, excluding other inflammations such as pancreatitis, peritoneal carcinosis, tuberculosis, and bloody ascites. Urinary tract infection was diagnosed using bacterial culture positive or urine leukocyte count >15 cells/high power field and >10⁶ bacteria/μL. Fever and cellulitis associated with leukocytosis were used to diagnose skin and soft tissue infection. Septicemia was defined as clinical signs of infection and two consecutive blood cultures yielding the same organism, when a blood culture yielding an organism was considered as bacteremia. Patients considered for bacterial infections but without positive culture or evidence of organ involvement were considered as undetermined infection.

2.3. Statistical Analyses

Statistical analysis was performed using SPSS version 18.0 (SPSS, Chicago, IL, USA). Categorical variables were expressed in percentages and frequencies. Continuous variables were expressed as means and standard deviation. Continuous variables were analyzed with independent-sample -test when they in line with the normal distribution otherwise Mann–Whitney test was used. The chi-square test was performed to analyze categorical variables. The 90-day mortality prediction was carried out with univariate and multivariate logistic regression. value < 0.05 was considered statistically significant.

3. Result

3.1. Characteristics of the Study Cohort

During the study period, 53 patients with autoimmune liver disease-associated ACLF who were admitted to the infectious disease ward of our hospital were included in this study. Fifty-three patients were included as control group. The clinical features and laboratory results of the ACLF patients and no ACLF patients are shown in Table 1. From these 53 ACLF patients, 30 patients (56.6%) showed PBC, 21 (39.6%) displayed AIH, 1 (1.9%) had PSC, and one (1.9%) patients had AIH-PBC overlap syndrome. The control group included 26 (49.1%) patients of PBC, 24 (45.3%) patients of AIH, and 3 (5.7%) cases of PSC. Compared to patients without ACLF, the ACLF group had a higher prevalence of complications (), such as hepatic encephalopathy (54.7% and 3.8%, ) and bacterial infection (75.5% and 50.9%, ). The 28-day and 90-day mortality rates were also obviously high in patients with ACLF ().

Table 1: Comparison of clinical features and laboratory results among the overall study collective.

Characteristics
No ACLF ()
ACLF ()
 value
ACLF
  value

Infection group ()
Noninfection group ()

Age
56.34 ± 11.64
58.23 ± 11.86
0.410
58.88 ± 13.18
56.23 ± 6.29
0.336

Female
46 (86.8%)
47 (88.7%)
0.767
34 (85.0%)
13 (100%)
0.317

Diabetes mellitus
9 (17.0%)
6 (11.3%)
0.403
5 (12.5%)
1 (7.7%)
0.635

Coexisting other autoimmune diseases
7 (13.2%)
7 (13.2%)
1.000
4 (10.0%)
3 (23.1%)
0.460

Steroid exposure
8 (15.1%)
11 (20.8%)
0.447
7 (17.5%)
4 (30.8%)
0.528

Complications

    Ascites
25 (47.2%)
41 (77.4%)
0.001
32 (80%)
9 (69.2%)
0.710

    Gastrointestinal bleeding
3 (5.7%)
12 (14.0%)
0.026
8 (20%)
4 (30.8%)
0.671

    Hepatic encephalopathy
2 (3.8%)
29 (54.7%)
≤0.001
21 (52.5%)
8 (61.5%)
0.570

    Hepatorenal syndrome
2 (3.8%)
16 (30.2%)
0.001
15 (37.5%)
1 (7.7%)
0.092

    Bacterial infection
27 (50.9%)
40 (75.5%)
0.005

Laboratory data

    Leukocyte counts (×10 9/L)
6.32 ± 3.93
10.43 ± 6.40
≤0.001
12.20 ± 6.34
4.97 ± 2.01
≤0.001

    Hemoglobin (g/L)
99.06 ± 21.09
89.32 ± 19.51
0.015
86.30 ± 19.91
98.62 ± 15.39
0.047

    Platelet (×10 9/L)
108.83 ± 65.32
87.25 ± 52.30
0.063
89.70 ± 56.43
79.69 ± 37.68
0.472

    CRP (mg/L)
19.25 ± 15.71
25.51 ± 19.05
0.071
30.49 ± 18.83
8.89 ± 5.93
≤0.001

    PCT (ng/ml)
0.43 ± 0.44
1.25 ± 1.65
0.007
1.44 ± 1.76
0.33 ± 0.14
0.136

    ALT (U/L)
227.06 ± 302.30
258.34 ± 331.79
0.613
177.15 ± 210.97
508.15 ± 492.74
0.034

    AST (U/L)
288.42 ± 352.18
310.58 ± 290.45
0.724
270.48 ± 244.16
434.00 ± 387.24
0.172

    AKP (U/L)
197.77 ± 105.19
1879.09 ± 104.54
0.361
176.05 ± 100.90
188.46 ± 118.91
0.714

    GGT (U/L)
185.15 ± 199.38
143.72 ± 165.20
0.247
161.15 ± 183.58
90.08 ± 67.81
0.045

    Total bilirubin (mg/dL)
20.44 ± 8.21
26.68 ± 8.20
0.005
26.16 ± 8.49
21.37 ± 6.21
0.067

    Albumin (g/L)
27.53 ± 5.98
26.71 ± 3.30
0.372
26.59 ± 3.61
26.97 ± 2.22
0.723

    Creatinine (mg/dL)
0.65 ± 0.19
1.22 ± 0.88
≤0.001
1.39 ± 0.91
0.72 ± 0.56
0.004

Fasting blood glucose (mmol/L)
4.68 ± 1.52
3.99 ± 1.99
0.119
3.80 ± 0.90
4.57 ± 3.74
0.471

    Serum sodium (mmol/L)
136.60 ± 5.12
133.81 ± 5.59
0.009
133.03 ± 5.88
136.23 ± 3.79
0.072

    INR
1.76 ± 0.29
3.04 ± 1.23
≤0.001
3.33 ± 1.54
2.95 ± 1.11
0.328

Child-Pugh score
9.53 ± 1.19
11.79 ± 1.46
≤0.001
11.06 ± 1.49
10.47 ± 1.85
0.055

MELD score
18.72 ± 3.15
29.60 ± 8.72
≤0.001
29.47 ± 7.06
27.37 ± 5.35
0.109

CLIF-SOFA score
7.43 ± 0.77
10.74 ± 2.22
≤0.001
11.03 ± 2.38
10.23 ± 1.54
0.266

ACLF grade

    Grade 1
42 (79.2%)
6 (11.3%)
0.186
4 (20.0%)
2 (15.4%)
0.678

    Grade 2
0
30 (56.6%)
≤0.001
22 (55.0%)
8 (61.5%)
0.003

    Grade 3
0
17 (32.1%)
≤0.001
14 (35.0%)
3 (23.1%)
0.008

28-day transplant-free mortality
4 (8.9%)
18 (38.3%)
0.001
15 (39.5%)
3 (33.3%)
0.733

90-day transplant-free mortality
6 (13.3%)
35 (74.5%)
≤0.001
27 (71.1%)
5 (55.6%)
0.618

CRP, C-reactive protein; PCT, procalcitonin; ALT, alanine transaminase; AST, aspartate aminotransferase; AKP, alkaline phosphatase; GGT, gamma glutamyl transpeptidase; INR, international normalized ratio; MELD, model for end-stage liver disease; CLIF-SOFA, chronic liver failure-sequential organ failure assessment.

3.2. Risk Factors Associated with 28-Day and 90-Day Mortality

In the study, 6 (11.3%) patients underwent liver transplantation. In the remaining 47 patients, 28-day mortality and 90-day mortality were 38.3% (18) and 74.5% (35), respectively. For the 28-day transplant-free mortality, in univariate analysis, gastrointestinal bleeding (), hepatic encephalopathy (), and CLIF-SOFA score () were significant factors (Table 2). However, in multivariate analysis, there was no predictor associated with increased mortality. In addition, for the 90-day transplant-free mortality, in univariate analysis, hepatic encephalopathy (), leukocyte counts (), hemoglobin (), aspartate aminotransferase (AST) (), serum creatinine (), serum sodium (), INR (), MELD score (), Child-Pugh score (), and CLIF-SOFA score () were significant factors (Table 3). In multivariate logistic regression analysis, no predictor was significantly associated with 90-day transplant-free mortality (Table 3).

Table 2: Significant univariate and multivariate logistic regression analyses of 28-day transplant-free mortality.

Variable
Univariate
Multivariate

OR
95% CI
value
OR
95% CI
value

Gastrointestinal bleeding
5.000
1.225–20.409
0.025
3.406
0.687–16.894
0.134

Hepatic encephalopathy
3.683
1.036–13.100
0.044
2.349
0.461–11.972
0.304

CLIF-SOFA score
1.362
1.023–1.812
0.034
1.093
0.741–1.613
0.653

CLIF-SOFA, chronic liver failure-sequential organ failure assessment.

Table 3: Significant univariate and multivariate logistic regression analyses of 90-day transplant-free mortality.

Variable
Univariate
Multivariate

OR
95% CI
value
OR
95% CI
value

Hepatic encephalopathy
8.800
2.024–38.253
0.004
36.714
0.085–15810.528
0.244

Leukocyte counts
1.160
1.003–1.342
0.046
1.328
0.962–1.832
0.085

Hemoglobin
0.964
0.930–1.000
0.048
0.912
0.808–1.029
0.135

AST
0.997
0.995–1.000
0.021
0.998
0.992–1.004
0.477

Creatinine
5.426
1.362–21.612
0.016
160.487
0.049–527959.376
0.219

INR
2.935
1.192–7.224
0.019
50.782
0.415–6206.850
0.109

MELD score
1.232
1.070–1.418
0.004
0.664
0.309–1.430
0.295

Child-Pugh score
2.003
1.169–3.430
0.011
0.595
0.114–2.457
0.473

CLIF-SOFA score
2.936
1.532–5.630
0.001
1.578
0.350–7.117
0.553

AST, aspartate aminotransferase; INR, international normalized ratio; MELD, model for end stage liver disease; CLIF-SOFA, chronic liver failure-sequential organ failure assessment.

3.3. Clinical Features of Bacterial Infection in Patients with Autoimmune Liver Disease-Associated ACLF

In our study, 40 (75.5%) patients had bacterial infection, and 14 (35.0%) patients were diagnosed with bacterial coinfection in the first 72 h of admission. The demographic and clinical characteristics of ACLF patients with and without bacterial infection are detailed in Table 1.

ACLF patients with bacterial infection showed high Child-Pugh score, MELD score, CLIF-SOFA score, 28- day mortality, and 90-day mortality. Meanwhile, no statistical significance was observed (). However, in laboratory findings, bacterial infection patients displayed high leukocyte counts and C-reactive protein (CRP) (). High serum levels of serum creatinine and gamma glutamyl transpeptidase (GGT), low levels of hemoglobin, and alanine transaminase (ALT) were also observed in bacterial infection patients () (Table 1).

In 40 ACLF patients with bacterial infection, the most common site of bacterial infection was in the respiratory tract (17, 42.5%), followed by the peritoneum, bloodstream, biliary tract, urinary tract, intestinal tract, skin and soft tissue, and undetermined site with percentage values of 22.5% (9), 7.5% (3), 7.5% (3), 5.0% (2), 5.0% (2), 2.5% (1), and 7.5% (3), respectively. The bacteriological evidence of infection was 7 cases (17.5%). The pathogens that caused bacterial infections were Escherichia coli in three cases, two of which produced extended spectrum β lactamase (ESBL); Klebsiella pneumoniae in two cases; Staphylococcus aureus in two cases, one of which involved methicillin-resistant S. aureus; and Enterococcus faecalis in one case.

3.4. Comparison of CRP and PCT in ACLF Patients with Bacterial Infection

CRP and PCT levels were obtained in 52 and 37 patients, respectively, among 53 patients. Thirty-seven patients had both biomarkers measured simultaneously. Using receiver operating characteristic analysis, area under curve (AUC) to diagnose bacterial infection was 0.948 (95% confidence interval [CI]: 0–1.000) for CRP () compared with 0.807 (95% CI: 0.668–0.947) for PCT () (Figure 1). For diagnosis of bacterial infection in CRP at a cut-off value of 12.15 mg/L, the sensitivity and specificity were 96.6% and 83.3%, respectively. For diagnosis of bacterial infection in PCT at a cut-off value of 0.57 ng/mL, the sensitivity and specificity were 72.4% and 100% respectively.

Figure 1: Using receiver operating characteristic analysis, comparison of C-reactive protein (CRP) and procalcitonin (PCT) in acute-on-chronic liver failure patients with bacterial infection.

4. Discussion

ACLF is a hotspot issues; however, it is lack of uniform diagnostic criteria. Different diagnostic criteria could lead to different patient prognosis. In our study, ACLF patients satisfied the EASL definition, and patients who met APCCMI definition but not EASL definition were included as control group. The 28-day transplantation-free mortality of autoimmune liver disease-associated ACLF was 38.3%, and 90-day transplantation-free mortality was 74.5%. Of note, a great number of critically ill patients were included in the ACLF group; ACLF grades 2 and 3 (56.6% and 36.1%, resp.) were dominant. Moreover, similar to the CANONIC study [4], the ACLF group had a higher prevalence of complications and higher 28-day and 90-day mortality rates.

Several studies were available about predictors of mortality in ACLF patients [5, 14–19]. Yu et al. [14] found that age, etiology, serum sodium, and ascites are independently associated with mortality. Cárdenas et al. [5] considered that the presence of hyponatremia is an independent predictive factor of survival in patients with ACLF. In Mücke’s study, infection-triggered ACLF was considered as an independent predictors associated with increased mortality [19]. In our study, no predictor was significantly associated with 28-day and 90-day transplant-free mortality. Small size of study population may cause the situation.

In this study, among the 53 patients with autoimmune liver disease-associated ACLF, 40 (75.5%) patients had bacterial infection. Bacterial infection in liver disease had been reported by previous documents, and the incidence was 24.4%–90% [13, 20–23]. However, study populations were different. Although bacterial infection in ACLF had been studied, autoimmune liver disease-associated ACLF received minimal attention.

In bacterial infection patients with ACLF, Child-Pugh score, MELD score, CLIF-SOFA score, 28-day mortality, and 90-day mortality were high in bacterial infection patients although no statistical significance was observed (). ACLF patients with bacterial infection showed a more severe condition than those without infection; this finding was consistent with that of previous study [13].

In recent years, serum CRP and PCT have been suggested for diagnosis and prediction of bacterial infection in chronic liver disease, with or without cirrhosis [13, 24–26]. Papp et al. [25] reported that CRP using a 10 mg/L cut-off value proved to be more accurate than PCT in identifying patients with infection (AUC: 0.93). In this study, we also revealed that CRP levels are more effective than PCT in the diagnosis of bacterial infection in autoimmune liver disease-associated ACLF. The optimal cut-off value of CRP for bacterial infection diagnosis is 12.15 mg/L (96.6% sensitivity and 83.3% specificity), with an AUC of 0.948, which is similar to previous report [25].

Several limitations were observed in this study. First, this work was a retrospective study at a single center. Some data collections were limited, and bacterial infection might be affected by specific circumstance of our institution. Second, some patients had been treated by antibacterial agents before admission, which might affect the accuracy of bacterial infection rate. Third, immunosuppressor except corticosteroid was not used in our study population. Thus, further studies are needed to investigate bacterial infection and predictors of mortality in autoimmune liver disease-associated ACLF patients using immunosuppressor.

5. Conclusions

In conclusion, autoimmune liver disease-associated ACLF displayed high mortality and had more complications. ACLF patients with bacterial infection showed a more severe condition than those without infection. CRP levels higher than 12.15 mg/L suggested bacterial infection in autoimmune liver disease-associated ACLF patients. No predictor was significantly associated with 28-day and 90-day transplant-free mortality. Further prospective and intervention studies on bacterial infection and predictors of mortality in autoimmune liver disease-associated ACLF patients with large sample numbers are thus needed.

Abbreviations

ACLF: | Acute-on-chronic liver failure
PBC: | Primary biliary cholangitis
AIH: | Autoimmune hepatitis
PSC: | Primary sclerosing cholangitis
CLIF-SOFA: | Chronic liver failure-sequential organ failure assessment
APPCCMI: | Asia-Pacific Congress of Clinical Microbiology and Infection
EASL: | European Association for the Study of the Liver
CRP: | C-reactive protein
PCT: | Procalcitonin
GGT: | Gamma glutamyl transpeptidase
ALT: | Alanine transaminase
INR: | International normalized ratio
MELD: | End-stage liver disease
AUC: | Area under curve
CI: | Confidence interval.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Xuan Zhang and Ping Chen contribute equally to the study.

Acknowledgments

This work was supported by the National Science and Technology Major Project (2017ZX10204401002002) and the Zhejiang Provincial Natural Science Foundation (LQ15H030004).

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