A simplified regimen of targeted antifungal prophylaxis in liver transplant recipients: A single-center experience.

BACKGROUND: Invasive fungal infection (IFI) is a severe complication of liver transplantation burdened by high mortality. Guidelines recommend targeted rather than universal antifungal prophylaxis based on tiers of risk. METHODS: We aimed to evaluate IFI incidence, risk factors, and outcome after implementation of a simplified two-tiered targeted prophylaxis regimen based on a single broad-spectrum antifungal drug (amphotericin B). Patients presenting 1 or more risk factors according to literature were administered prophylaxis. Prospectively collected data on all adult patients transplanted in Turin from January 2011 to December 2015 were reviewed. RESULTS: Patients re-transplanted before postoperative day 7 were considered once, yielding a study cohort of 581 cases. Prophylaxis was administered to 299 (51.4%) patients; adherence to protocol was 94.1%. Sixteen patients developed 18 IFIs for an overall rate of 2.8%. All IFI cases were in targeted prophylaxis group; none of the non-prophylaxis group developed IFI. Most cases (81.3%) presented within 30 days after transplantation during prophylaxis; predominant pathogens were molds (94.4%). Only 1 case of candidemia was observed. One-year mortality in IFI patients was 33.3% vs 6.4% in patients without IFI (P = .001); IFI attributable mortality was 6.3%. At multivariate analysis, significant risk factors for IFI were renal replacement therapy (OR = 8.1) and re-operation (OR = 5.2). CONCLUSIONS: The implementation of a simplified targeted prophylaxis regimen appeared to be safe and applicable and was associated with low IFI incidence and mortality. Association of IFI with re-operation and renal replacement therapy calls for further studies to identify optimal prophylaxis in this subset of patients.

Simultaneous Liver-Kidney Transplantation in Adults: A Single-center Experience Comparing Results With Isolated Liver Transplantation.

BACKGROUND: After introduction of the Model for End-Stage Liver Disease (MELD) score in 2002, a worldwide increasing number of simultaneous liver-kidney transplantations (SLKTx) has been observed. However, organ shortage puts into question the allocation of 2 grafts to 1 recipient. This retrospective, single-center study compared SLKTx results with isolated liver transplantation (LTx). METHODS: Between 1995 and 2013, 37 SLKTx were performed in adult recipients. Every SLKTx was matched by donor age (±5 years) and transplantation date with 2 LTx (n = 74). Pretransplant, intraoperative, and post-transplant variables were collected; liver graft and patient survivals were calculated. RESULTS: As expected, donor age was similar in the 2 groups (median, 39.7 years), whereas serum creatinine level, glomerular filtration rate, and MELD and D-MELD (donor age*MELD) scores were significantly higher in the SLKTx group. SLKTx had longer waiting list time (P = .0034) as well as higher surgical difficulty, testified by more blood transfusions (P = .0083), increased use of classic caval reconstruction (P = .0024), and more frequent need of abdominal packing for bleeding control (P = .0003). In addition, duration of hospital stay (P < .0001), second-look surgery (P = .0082), post-transplant dialysis (P < .0001), and post-transplant infections (P = .04) were significantly greater in SLKTx group. Acute rejection episodes involving the liver were significantly less in SLKTx than in LTx (14% vs 41%; P = .0045). Liver graft and patient survival at 10 years after transplantation was similar in the 2 groups (liver graft: SLKTx, 80% vs LTx, 77% [P = .85]; patient: SLKTx, 86% vs LTx, 79% [P = .56]). CONCLUSIONS: Despite being technically challenging, SLKTx provided excellent long-term results and was shown to be an effective use of liver grafts.

Minimization of anti-hepatitis B surface antigen immunoglobulins for prophylaxis of hepatitis B viral recurrence in the first month after liver transplantation: the meaning of HBsAg quantitative level at the time of transplant.

BACKGROUND: Hepatitis B virus recurrence after liver transplantation (LT) has practically disappeared with a prophylaxis combining anti-hepatitis B surface antigen Immunoglobulins (HBIg) and antiviral drugs. Recently, cost-saving requirements pushed us to move from a fixed schedule of 50,000 IU intravenous HBIg in the first month after LT to an "on demand" administration guided by close monitoring of HBV surface antigen (HBsAg) and anti-HBV surface Antigen antibody (HBsAb) with a serological target of HBsAg negative and HBsAb>300 mIU/mL. In this context, we investigated the meaning of HBsAg quantitative determination at LT in predicting the need of HBIg in the first month after LT. METHODS: From February 2012 to July 2013, we performed 35 LTs in HBsAg-positive patients, 18 of whom had hepatitis Delta virus coinfection (Delta-positive). Anti-HBV prophylaxis was based on nucleos(t)ide analogues from day 1 post-LT and intravenous HBIg (10,000 IU intraoperatively and, in the following days, 5,000 IU and 2,500 IU pulses to reach and maintain the serological target). RESULTS: The HBsAg quantitative level at LT was significantly higher in Delta-positive recipients. Complete negativization of HBsAg and HBsAb serum level>300 mIU/mL was achieved on day 3 in Delta-positive and on day 2 in Delta-negative. A positive linear correlation between HBsAg quantitative level at LT and HBIg administered in the first month after LT was observed (RHO=.788), with a total of 32,500 IU HBIg used in HDV-positive and 22,000 IU in HDV-negative recipients (P=.0016). Compared to the old schedule, we saved a median of 14,750 IU in HDV-positive and 28,000 IU in Delta-negative. No HBV recurrence was observed in a median follow-up of 10.5 months. CONCLUSIONS: Delta-positive patients need higher doses of HBIg to reach the serological target after LT because they have greater HBsAg quantitative levels at LT. In future studies, pre-LT HBsAg quantitative determination will be helpful to predict the actual need of HBIg early after LT.

Invasive Candida infections in low risk liver transplant patients given no antifungal prophylaxis in the post-operative period.

BACKGROUND: In recent years the incidence of invasive fungal infections (IFIs) in post liver transplant (LT) has reduced to about 5%, however the majority of IFIs develops early in the post-transplant course. Candida species are the most frequent causative pathogens followed by Aspergillus species. Mortality for invasive candidiasis is still 40-50%. For this reason universal prophylaxis is still considered useful and is adopted by different LT centers, although it is not justified by available data. The aim of study is to evaluate Candida infection incidence and mortality in low risk patients and therefore not subjected to antifungal prophylaxis in the immediate post-LT. METHODS: The patient is defined low risk if without any risk factor for IFIs as reported in literature and according to our center protocol described below. We analyzed retrospectively the records (with 90 days follow-up) of all adult patients underwent to LT at our center in 2011-2012. RESULTS: At our center between 2011 and 2012, 247 LT in 232 adult patients were performed: 137 patients (59%) received prophylaxis with Amphotericin B lipid complex or liposomal Amphotericin B, 95 patients (41%) didn't receive any prophylaxis. In these latter patients was observed only one case of Candida oesophagitis at the second month post-LT. The incidence of invasive candidiasis was 0%, and there wasn't mortality ascribed to Candida infection. CONCLUSIONS: It is possible to identify low risk patients for IFIs post-LT and the no prophylaxis policy in the early LT course appears safe and feasible.

Liver transplantation for hepatocellular carcinoma within Milan Criteria in patients with Model for End-Stage Liver Disease score below 15: the impact of the etiology of cirrhosis on long-term survival.

BACKGROUND: Liver transplantation (OLT) is the gold standard therapy for patients with cirrhosis complicated by hepatocellular carcinoma (HCC) within Milan Criteria (MC). We evaluated the impact of the etiology of the underlying liver disease on long-term outcomes of patients undergoing OLT for HCC within MC having a Model for End-stage Liver Disease (MELD) score < 15. METHODS: From November 2002 to December 2009, we performed 203 primary OLTs from brain-dead donors in recipients with HCC and cirrhosis with biochemical MELD scores below 15. We excluded 31 patients outside MC on the explant pathology of the native liver. The remaining 172 were divided into 3 groups according to the etiology of the underlying cirrhosis: hepatitis C virus-positive (HCV+; n = 78; 45%), hepatitis B virus-positive (HBV+; n = 65; 38%) and other indications (n = 29; 17%). The groups were compared for donor and recipient features, donor-recipient match, and transplant variables. The study endpoint was long-term patient survival. RESULTS: The groups were similar, except for a greater prevalence of hepatitis B core antibody-positive grafts in the HBV+ group and less frequent HCC bridging procedures in the other indications group. After a median follow-up of 72 months, HCC recurrence was observed in 8 (4.7%) patients (6 HCV+, 2 other indications), 5 of whom died. Overall 5-year patient survival of 82%, revealed significant differences among groups: 98.3% in HBV+, 67.1% in HCV+, and 85.8% in other indications (HBV+ vs other indications: P = .01; HBV+ vs HCV+: P = .0001; HCV+ vs other indications: P = NS). In the HCV+ group, recurrent HCV hepatitis was the most frequent cause of death. Upon multivariate analysis, HBV positivity in the recipient was an independent predictor of better patient survival (hazard ratio = 0.10, 95% confidence interval 0.02-0.64, P = .013). CONCLUSIONS: Etiology of the underlying cirrhosis significantly influenced the long-term survival after OLT of patients with HCC within MC and MELD < 15. It should be taken into account in estimation of survival benefit.

Outcomes of liver transplantation in simultaneously hepatitis B surface antigen and hepatitis C virus RNA positive recipients: the deleterious effect of donor hepatitis B core antibody positivity.

BACKGROUND: Recent data from Italian studies have shown excellent results of liver transplantation (LT) in hepatitis B virus (HBV)-infected patients with grafts from hepatitis B core antibody (HBcAb)-positive donors, whereas such grafts in hepatitis C virus (HCV)-infected recipients have displayed poorer outcomes. We investigated the results of LT with HBcAb-positive grafts in patients with ongoing HBV and HCV coinfections. METHODS: From August 1999 to December 2009, we performed 27 adult primary LTs from deceased heart-beating donors into recipients showing hepatitis B surface antigen (HBsAg)- and HCV-RNA-positivity simultaneously: 12 patients received a graft from an HBsAg-negative HBcAb-positive donor (core+D group) and 15 from an HBcAb-negative donor (core-D group). Immunosuppression included a calcineurin inhibitor, antimetabolite and steroids which were suspended at 6 months. Anti-HBV prophylaxis was always perfomed with anti-HBs immunoglobulins and nucleos(t)idic analogues. RESULTS: The groups were similar regarding variables of donor, recipient, donor-recipient match, LT procedure, and acute rejection treatment. Median follow-up for surviving grafts was 67 months (range, 16-141). Among all patients, HCV-RNA remained positive after LT. The prevalence of histologically proven recurrent HCV hepatitis was similar in the 2 groups: 83% core+D vs 73% core-D. No recurrent HBV hepatitis occurred during the follow-up. Graft survival at 5 years was significantly lower in the core+D group (core+D 48% vs core-D 87%; P = .018), in which a significantly higher prevalence of graft loss was caused by HCV recurrence (core+D 5/12, 42% vs core-D 1/15, 7%; P = .03). All of the 5 core+D patients who lost their grafts due to HCV recurrence did not receive anti-HCV therapy (4 owing to an aggressive disease and 1 because of patient refusal). CONCLUSIONS: Outcomes of LT in patients with ongoing HBV and HCV coinfection are adversely affected by donor HBcAb positivity, an effect that is mainly mediated by the dismal course of HCV recurrence after LT.

Outcomes of liver transplantation from hepatitis B core antibody-positive donors in viral cirrhosis patients: the prevailing negative effect of recipient hepatitis C virus infection.

BACKGROUND: Liver transplantation (LT) with grafts from hepatitis B core antibody (HBcAb)-positive donors has been the object of recent studies, suggesting different outcomes depending on the etiology of viral cirrhosis in the recipient. METHODS: From November 2002 to December 2009, we transplanted 124 livers from hepatitis B surface antigen (HBsAg)-negative HBcAb-positive deceased heart-beating donors to adult recipients with viral cirrhosis, classified as: HBsAg positive (group 1; n = 63); hepatitis C virus (HCV) RNA positive (group 2; n = 52); and simultaneously HBsAg and HCV-RNA positive (group 3; n = 9). Immunosuppression included a calcineurin inhibitor, mycophenolate, and steroids (tapered to suspension in 6 months). In all groups, anti-HBV prophylaxis was performed with anti-HBs immunoglobulins and nucleos(t)idic analogues. RESULTS: The groups were similar regarding donor, recipient, donor-recipient match, transplant procedure, variables, and treatment of acute rejection, except for younger recipient age in group 1 (P = .009), lower recipient body mass index in group 3 (P = .03), and longer cold ischemia time in group 2 (P = .003). Median follow-up for surviving grafts was 63 (range, 16-102) months. No case of recurrent or de novo hepatitis B occurred. The prevalence of histologically proven recurrent HCV hepatitis was similar in groups 2 and 3 (65% vs 78%). Graft survival at 5 years was 86% in group 1, 35% in group 2, and 31% in group 3 (P < .0001 for group 1 vs 2; P < .01 for group 1 vs 3). On multivariate analysis, independent predictors of worse graft survival were HCV infection in the recipient (HR 8.08, 95% CI 3.36-17.97; P < .0001) and MELD at LT ≥25 (HR 3.72, 95% CI 1.12-12.37; P = .032). CONCLUSIONS: The presence of HCV infection in the recipient is the factor which most negatively influenced the outcome of LT using grafts from HBcAb-positive donors. Allocation of such grafts should consider the type of viral cirrhosis among LT candidates.

Randomized clinical trial of radiofrequency-assisted versus clamp-crushing liver resection.

BACKGROUND: Surgical resection remains the treatment of choice for primary and secondary liver cancer. Complications are mainly related to blood loss. Radiofrequency-assisted liver resection (RF-R) has been proposed for parenchymal division as an alternative to clamp crushing in order to reduce blood loss. METHODS: Fifty patients (median age 62 (range 30-82) years) undergoing hepatectomy were randomized to RF-R (24 patients) or the clamp-crushing method (26). In the RF-R group the resection plane was precoagulated by multiple insertion of a planar triple-cooled radiofrequency ablation needle, and then the parenchyma was sectioned using a scalpel. RESULTS: The two groups were well matched in terms of age, sex, liver disease and type of resection. There were no deaths. Eight in the RF-R group developed complications (abscess in six, biliary fistula in three and biliary stenosis in one) compared with none of those who had resection by the crush method (P < 0.001). Two patients with cirrhosis in each group developed decompensation. Blood transfusion was required in eight of 24 patients in the RF-R group and 13 of 26 in the clamp-crushing group (P = 0.079). CONCLUSION: RF-R allows parenchymal resection in a clean surgical field but is associated with a higher rate of postoperative complications than the clamp-crushing technique.

Assessing mortality risk in very low birthweight infants: a comparison of CRIB, CRIB-II, and SNAPPE-II.

BACKGROUND: Illness severity scores are increasingly used for risk adjustment in clinical research and quality assessment. Recently, a simplified version of the score for neonatal acute physiology (SNAPPE-II) and a revised clinical risk index for babies (CRIB-II) score have been published. AIM: To compare the discriminatory ability and goodness of fit of CRIB, CRIB-II, and SNAPPE-II in a cohort of neonates < 1500 g birth weight (VLBWI). METHODS: Data from 720 VLBWI, admitted to 12 neonatal units in Lombardy (Northern Italy) participating in a regional network, were analysed. The discriminatory ability of the scores was assessed measuring the area under the receiver operating characteristic curve (AUC). Outcome measure was in-hospital death. RESULTS: CRIB and CRIB-II showed greater discrimination than SNAPPE-II (AUC 0.90 and 0.91 v 0.84, p < 0.0004), partly because of the poor quality of some of the data required for the SNAPPE-II calculation-for example, urine output-but also because of the relative weight given to some items. In addition to each score, several variables significantly influenced survival in logistic regression models. Antenatal steroid prophylaxis, singleton birth, absence of congenital anomalies, and gestational age were independent predictors of survival for all scores, in addition to caesarean section and not being small for gestation (for SNAPPE-II) and a five minute Apgar score of > or = 7 (for SNAPPE-II and CRIB). CONCLUSIONS: CRIB and CRIB-II had greater discriminatory ability than SNAPPE-II. Risk adjustment using all scores is imperfect, and other perinatal factors significantly influence VLBWI survival. CRIB-II seems to be less confounded by these factors.