The authors declared that no competing interests exist.
Conceived and designed the experiments: KHL JWL CLC CCW. Performed the experiments: KHL CCW YWL CCY. Analyzed the data: KHL JWL SHW CCL CCW WFL. Contributed reagents/materials/analysis tools: KHL JWL THH TLL. Wrote the paper: KHL JWL CCW.
Liver transplantation is the only therapeutic modality for patients with acute-on chronic liver failure (ACLF). These patients are at high risk for bacterial infections while awaiting transplantation. The aim of this study was to elucidate whether an adequately treated bacterial infection influences the outcomes after transplantation in this patient population.
54 recipients (median age, 49.5 years [range, 22–60]) of adult-to-adult living donor liver transplant (LDLT) for ACLF were categorized as those with pretransplant infection (Group 1, n = 34) or without pretransplant infection (Group 2, n = 20) for retrospective analyses. With the exception of a higher male-female ratio (
These data suggested that an adequately treated pretransplant infection do not pose a significant risk for clinical outcomes including posttransplant fatality in recipients in adult-to-adult LDLT for ACLF.
Liver transplantation is the only curative modality for patients with relentless liver failure resulting from chronic hepatic decompensation or acute exacerbation of chronic liver disease. Among liver transplant recipients, a substantial number of patients have been of cases of acute-on-chronic liver failure (ACLF)
We retrospectively reviewed ACLF patients who underwent adult-to-adult living donor liver transplant (LDLT) at Kaohsiung Chang Gung Memorial Hospital between January 2001 and December 2009. This study was conducted with a waiver of patient consent approved the Institutional Review Board of Chang Gung Memorial Hospital (Document no. 101–0564B).
ACLF was defined as an acute hepatic insult manifesting as jaundice (serum bilirubin >5 mg/dl) and coagulopathy (international normalized ratio >1.5) complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease
A pretransplant infection referred to an infection occurred within 4 weeks prior to liver transplantation, which was diagnosed based on clinical and laboratory (e.g., blood, ascites, sputum, and urine) and/or imaging (e.g., chest X-ray, ultrasonography, and CT) findings. Pretransplant infections were categorized into bloodstream infection (BSI), pneumonia, spontaneous bacterial peritonitis (SBP), and urinary tract infection (UTI). Sepsis was defined as an infection with the presence of systemic inflammatory response syndrome in the affected patient, which was manifested by two or more of the following conditions: (i) temperature >38°C or <36°C, (ii) heart rate >90 beats/min, (iii) respiratory rate >20 breaths/min or PaCO2 <32 mmHg, and (iv) peripheral white cell count (WBC)> 12,000/ mm3, <4000/ mm3, or consisting of>10% immature (band-form) cell
All patients with a diagnosed bacterial infection were given antibiotic(s) on empirical basis, which was then adjusted based on recommendations made by an infectious-disease specialist if the infection clinically deteriorated, or was subsequently switched to other antimicrobial(s) as was indicated by the results of culture and susceptibility testing. A pretransplant bacterial infection was considered adequately treated and the affected patient was regarded as an eligible transplant recipient only when he or she fulfilled the criteria as follows: (i) disappearance of symptoms and signs suggestive of sepsis, and (ii) normalization or improvement of laboratory and/or imaging findings indicating bacterial infection.
Hepatectomy in donors and recipients and liver engrafting for recipients in LDLT were performed as described previously
All recipients were admitted to Liver Intensive Care Unit (LICU) for postoperative care, where laboratory data (mainly hemogram and blood chemistry) were closely monitored. Doppler ultrasound was performed daily to check the vascular flow in the graft for one week after liver transplant and then twice weekly until the patient was discharged. These patients were additionally evaluated by a dedicated infectious-disease specialist (Dr. JW Liu) on daily basis. Once bacterial infection was suspected, empirical antibiotic therapy immediately started.
Data of the included ACLF patients were retrieved from their medical records. Between different patient groups, comparison of categorical variables was carried out using the
Among a total of 408 patients received adult-to-adult LDLT during the study period, 54 (36 men and 18 women [median age = 49.5 years, range = 22–60 years]) were found to be of ACLF cases and were included for analyses. None of these patients was put on an artificial liver support system (ALSS) prior to liver transplant. The included ACLF patients were categorized as those with pretransplant infection (Group 1, n = 34) or those without pretransplant infection (Group 2, n = 20). With the exception of a higher male-female ratio (26∶8 vs. 10∶10,
Demographic, clinical or laboratory feature | Group 1 (with pre-transplant infection) N = 34 | Group 2 (without pre-transplant infection) N = 20 | |
Gender (Male: Female) | 26 : 8 | 10 : 10 | |
Age [year; median (range)] | 49 (30–60) | 50.5 (22–58) | 0.914 |
Child-Pugh score, median (range) | 12 (9–15) | 12 (8–15) | 0.701 |
MELD score, median (range) | 24 (16–39) | 24 (19–40) | 0.440 |
Serum total bilirubin [mmol/L; median (range)] | 12.05 (5.1–45.2) | 17.05 (5–64.4) | 0.993 |
Serum albumin [g/dL L; median (range)] | 2.6 (1.8–3.4) | 2.5 (1.7–3.6) | 0.535 |
Prothrombin time | |||
Second, median (range) | 17.25 (14.9–50) | 18.55 (15.1–50) | 0.286 |
INR, median (range) | 1.71 (1.5–5) | 1.84 (1.51–5) | 0.230 |
Pretransplant status | |||
ICU stay, n (%) | 10 (29.4) | 7 (35) | 0.672 |
ICU stay [day; median (range)] | 0 (0–25) | 0 (0–30) | 0.456 |
Hospital stay [day; median (range)] | 28 (2–85) | 14.5 (2–57) | |
Underlying liver disease, n (%) | 0.423 | ||
Hepatitis B | 23 (67.6) | 12 (60.0) | |
Hepatitis C | 3 (8.8) | 1 (5.0) | |
Alcoholic liver disease | 5 (14.7) | 2 (10.0) | |
Metabolic liver disease | 3 (8.8) | 5 (25.0) | |
Pretransplant hepatic encephalopathy n (%) | 0.335 | ||
Grade I & II | |||
Grade III & IV | 4 (40.0) | 5 (71.4) | |
6 (60.0) | 2 (28.6) | ||
Liver graft | |||
GRWR ≧0.8, n (%) | 29 (85.3) | 17 (85.0) | 0.977 |
Right lobe | 32 (94.1) | 19 (95.0) | 1.000 |
Outflow reconstruction | 22 (64.7) | 11 (55.0) | 0.480 |
Age of donor, median year (range) | 28 (18–47) | 28.5 (19–48) | 0.554 |
Intraoperative blood loss, mean (mL±SD) | 12006.1±15515.6 | 6040.8±9539.2 | 0.054 |
Transfused blood, mean (mL±SD) | 8738.7±11011.8 | 5000.39±6388.0 | 0.119 |
Abbreviations: SD = Standard deviation; MELD = Model for end-stage liver disease; INR = International normalized ratio; ICU = Intensive-care unit; GRWR: graft-to-recipient weight ratio.
Figure in bold font indicates a significant statistical difference.
A total of 42 pretransplant infection episodes were found in the 34 LDLT recipients. Among these patients, 26 (76.5%) experienced one episode of pretransplant infection, while the rest 8 each experienced 2. Major pretransplant infection entities in decreasing order were UTI (n = 14), SBP (n = 11), pneumonia (n = 7) and BSI (n = 6); pretransplant infection entities and the pathogens are summarized in
Infection entity and pathogen(s) | Episode |
Spontaneous bacterial peritonitis |
26.2 (11/42) |
Without bacteremia, % (n1/ |
19 (8/42) |
Culture-negative neutrocytic ascites, % (n2/n1) | 87.5 (7/8) |
|
12.5 (1/8) |
With secondary bacteremia, % (n1/ |
7.1 (3/42) |
100 (3/3) | |
Primary bloodstream infection, % (N/ |
14.3 (6/42) |
66.7 (4/6) | |
16.7 (1/6) | |
16.7 (1/6) | |
Pneumonia |
15.9 (7/44) |
Urinary tract infection, % (N/N) | 33.3 (14/42) |
Without bacteremia, % (n1/ |
31 (13/42) |
7.1 (1/14) | |
7.1 (1/14) | |
Gram-positive bacilli |
28.6 (4/14) |
Gram-negative bacilli |
28.6 (4/14) |
7.1 (1/14) | |
Pathogens not identified, % (n2/n1) | 28.6 (4/14) |
With bacteremia, % (n1/ |
2.4 (1/42) |
100 (1/1) | |
Cellulitis, % (N/ |
4.8 (2/42) |
Other infections |
4.8 (2/42) |
Episodes with the pathogen isolated, % (N/ |
47.6 (20/42) |
Concurrent spontaneous bacterial peritonitis and pneumonia were found in one recipient.
Isolates of Gram-positive bacillus and Gram-negative bacillus were identified as co-pathogens in one episode of urinary tract infection.
Isolates of
Including septic arthritis caused by
With the exception of a longer total hospital stay (89.0 days [range, 30–163] vs. 65.5 days [44–117],
Group 1 (with pretransplantinfection) N = 34 | Group 2 (withoutpretransplant infection) N = 20 | ||
Post-liver transplant | |||
Length of ICU stay, median day (range) | 21.5 (1–59) | 22.5 (14–62) | 0.851 |
Length of hospital stay, median day (range) | 52 (1–123) | 47 (28–94) | 0.667 |
Overall ICU stay, median day (range) | 24.5 (14–59) | 23.5 (14–62) | 0.667 |
Overall hospital Stay, median day (range) | 89 (30–163) | 65.5 (44–117) | |
Rejection (≦1 year after transplant), n (%) | 6 (17.6) | 4 (20) | 1 |
1-year graft survival, n (%) | 32 (94.1) | 18 (90) | 0.622 |
Patients with posttransplant infection, n (%) | 28 (82.3) | 16 (80) | 0.831 |
Episode of posttransplant infection | |||
Intra-abdominal infection |
20 | 13 | 0.477 |
Pneumonia | 10 | 5 | 0.727 |
Bloodstream infection | 4 | 1 | 0.318 |
Urinary tract infection | 4 | 2 | 1 |
1-year patient survival, n (%) | 32 (94.1) | 18 (90) | 0.622 |
Abbreviation: ICU = Intensive-care unit.
Figure in bold font indicates a significant statistical difference.
Including bacterial peritonitis, biliary tract infection, liver abscess and enterocolitis.
A total of 61 posttransplant infection episodes were found in an overall of 44 ACLF patients (28 [82.4%] in Group 1 vs. 16 [80%] in Group 2;
Infection category and pathogen(s) | Episode |
Bacterial peritonitis, % (N/ |
36.1 (22/61) |
Without bacteremia, % (n1/ |
34.4 (21/61) |
Culture-negative neutrocytic ascites, % (n2/n1) | 14.3 (3/21) |
28.6 (6/21) | |
Coagulase-negative |
23.8 (5/21) |
9.5 (2/21) | |
9.5 (2/21) | |
9.5 (2/21) | |
Other bacteria, % (n/N) |
19 (4/21) |
4.8 (1/21) | |
With secondary bacteremia, % (n1/ |
1.6 (1/61) |
Coagulase-negative |
100 (1/1) |
Primary bloodstream infection, % (N/ |
8.2 (5/61) |
Coagulase-negative staphylococci, % (n/N) | 40 (2/5) |
20 (1/5) | |
20 (1/5) | |
20 (1/5) | |
Pneumonia, % (N/ |
24.6 (15/61) |
20 (3/15) | |
Pathogens not identified, % (n1/N) | 80 (12/15) |
Urinary tract infection, % (N/ |
9.8 (6/61) |
Without bacteremia, % (n1/ |
8.2 (5/61) |
20 (1/5) | |
20 (1/5) | |
20 (1/5) | |
Pathogens not identified, % (n2/n1) |
60 (3/5) |
With bacteremia, % (n1/ |
1.6 (1/61) |
100 (1/1) | |
Biliary tract infection, (N/ |
8.2 (5/61) |
Liver abscess, (N/N) | 3.3 (2/61) |
Infectious colitis/enterocolitis, (N/ |
6.6 (4/61) |
Cellulitis, % (N/ |
1.6 (1/61) |
Surgical site infections, % (N/ |
1.6 (1/61) |
Episodes with pathogen(s) being isolated, % (N/ |
59 (36/61) |
Four episodes of bacterial peritonitis were simultaneously caused by 2 pathogens.
Including
One episode of urinary tract infection were simultaneously caused by 2 pathogens.
Including two episodes of urinary tract infection caused by Gram-positive coccus and one episode of clinically symptomatic pyuria; the pathogens were not identified on routine clinical-service based as the colony count was less than 105/mL.
||Three episodes of biliary tract infection found to be caused by isolates of viridans streptococci (n = 2),
Including pseudomembranous colitis due to
Polymicrobial infection caused by
No. recipients and pretransplant infection episodes | Posttransplant infection entities (episode) | |||
IAI |
BSI | pneumonia | UTI | |
Recipients with pretransplant UTI (n = 14) | ||||
Episodes of posttransplant infection (n = 16) | 7 | 2 | 5 | 2 |
Recipients with pretransplant SBP (n = 11) | ||||
Episodes of posttransplant infection(n = 13) | 7 | 1 | 4 | 1 |
Recipients with pretransplant pneumonia (n = 7) | ||||
Episodes of posttransplant infection (n = 7) | 4 | 0 | 3 | 0 |
Recipients with pretransplant primary BSI (n = 6) | ||||
Episodes of posttransplant infection (n = 7) | 4 | 1 | 1 | 1 |
Recipients with pretransplant cellulitis (n = 2) | ||||
Episodes of posttransplant infection (n = 3) | 2 | 0 | 0 | 1 |
Recipients with pretransplant septic arthritis (n = 1) | ||||
Episodes of posttransplant infection (n = 2) | 1 | 0 | 1 | 0 |
One patient might experienced one or more pretransplant and/or posttransplant infections.
Abbreviations: UTI = Urinary tract infection, SBP = Spontaneous bacterial peritonitis, BSI = Bloodstream infection.
Including bacterial peritonitis, biliary tract infection, liver abscess, and enterocolitis.
A total of the 49 pretransplant infection episodes developed in 34 (68%) of the overall 54 ACLF patients included in this series, and the most common pretransplant infection was UTI, as opposed to SBP that was reported to be the most frequently encountered pretransplant infection in patients with chronic liver failure
In the circumstances of shortage of organ donated by a deceased donor, liver graft donated by a living adult shortens the waiting time for patients for whom urgent liver transplant is indicated
In case a liver graft not being available in a timely fashion, a plasma-exchange-centered ALSS was reported to be helpful in bridging ACLF to liver transplantation
ACLF
Of note, frequently seen pathogens for hospital-acquired infections such as
Bacterial infections in general and bacteremia in particular have been reported to be the major causes of posttransplant mortality
Limitations of this study include potential biases inherent to the retrospective study and small sample size. Nevertheless, our data suggested that an adequately treated pretransplant infection do not pose a significant risk for clinical outcomes including posttransplant fatality in recipients in adult-to-adult LDLT for ACLF.