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.

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.

Extracorporeal membrane oxygenation rescue therapy in a case of portopulmonary hypertension during liver transplantation: a case report.

Portopulmonary hypertension has been reported in 2% to 9% of candidates for liver transplantation (OLT). If it is moderate to severe, it represents a contraindication to the procedure until pulmonary vasodilatative therapy has been optimized. We report the case of a 43-year-old man, scheduled for OLT due to alcoholic cirrhosis with hemosiderosis. His Model for End-Stage Liver Disease was 25 at that time. The preoperative evaluation showed a severe alteration of diffusion (pO2 68 mm Hg), without hepatopulmonary syndrome or portopulmonary hypertension (PPH) upon basal and dobutamine stress echocardiography. At the beginning of the OLT the hemodynamic profile showed mean pulmonary artery pressure (mPAP) 38 mm Hg, wedge pressure (WP) 19 mm Hg, cardiac output (CO) 9.1 L/min, pulmonary vascular resistance (PVR) 166 dyne s/cm(5), transpulmonary gradient (TPG) 19 mm Hg, which lead us to promptly initiate inhaled nitric oxide (iNO) and intravenous epoprostenol 2 to 5 ng/kg/min. Upon graft reperfusion the hemodynamic profile was: mPAP 47 mm Hg, WP 23 mm Hg, CO 14.2 L/min, PVR 135 dyne s/cm(5), TPG 24 mm Hg, and at the end of surgery, mPAP 39 mm Hg, WP 20 mm Hg, CO 10.6 L/min, PVR 123 dyne s/cm(5), TPG 19 mm Hg. On postoperative day (POD) 3, we observed severe worsening of PPH: mPAP 60 mm Hg, WP 10 mm Hg, CO 9.8 L/min, PVR 395 dyne s/cm(5), TPG 50 mm Hg even with maximal pulmonary vasodilatatory therapy (ambrisentan 5 mg, intravenous sildenafil 20 mg × 3 and epoprostenol 22 ng/kg/min, iNO). Severe acute respiratory distress syndrome (ARDS) was presents. Therefore we decided to begin veno-venous extracorporeal membrane oxygenation (v-v ECMO) to correct the hypoxic vasoconstriction. Subsequent weaning from inotropic support with iNO and epoprostenol was possible on POD 7 due to mPAP 42 mm Hg, WP 15 mm Hg, CO 7.9 L/min, PVR 273 dyne s/cm(5), and TPG 27 mm Hg. On POD 11 he was weaned from ECMO due to: mPAP 40 mm Hg, WP 16 mm Hg, CO 6.5 L/min, PVR 295 dyne s/cm(5) and TPG 24 mm Hg. The patient was extubated on POD 17. The cardiac catheterization 1 month after OLT showed: mPAP 28 mm Hg, WP 13 mm Hg, CO 5.4 L/min, PVR 220 dyne s/cm(5) and TPG 15 mm Hg. ECMO rescue therapy in this "extreme" case allowed us to correct hypoxemia responsible for worsening of pulmonary hypertension allowing time to reach the goal of vasodilatatory therapy.

Neurological complications of liver cirrhosis and orthotopic liver transplant.

Neurological complications are common in cirrhotic patients with end-stage liver failure. They comprise a wide array of etiologies, which may originate before, during, or after liver transplantation. The objective of this study was to describe the nature of the main neurological complications in patients with end-stage liver failure. Several toxins including ammonia, manganese, benzodiazepine-like substances, gamma-aminobutyric acid-like substances, and impaired dopaminergic neurotransmission are at the top of the list of candidates for hepatic encephalopathy, subclinical encephalopathy, and extrapyramidal signs before liver transplantation. Central pontine myelinolysis, cerebrovascular autoregulation impairment, and paradoxical cerebral embolism are probably responsible for the neurological complications during liver transplantation. Neurological complications represented by alterations of mental status, seizures, and focal motor deficits have been described after liver transplantation. These complications have been attributed to several pathogenetic factors, such as a poorly functioning graft, an intracranial hemorrhage, a cerebral infarction, an infection, or the toxicity of immunosuppressants.

[Gastroenterologists in ambulatory care. The experience in Turin in the year 2000]. / Poliambulatori specialisti di gastroenterologia. L'esperienza di Torino nell'anno 2000.

BACKGROUND: Digestive diseases (GI) have a major impact on public health in Italy. Hospital stay for digestive pathologies parallels that due to cardiovascular causes. Total mortality for GI causes is also very high. The management of GI pathologies is therefore a major task for the National Health System. To the experienced gastroenterologist it is clear that a large number of hospitalisation is linked to a lack of careful outpatient follow-up of diseases such as cirrhosis, ulcerative colitis and peptic ulcer. METHODS: One year of activity of our Gastro-entero-Hepatology outpatient service is examined. The management of the majority of GI diseases is organized in working teams of physicians and surgeons following cohorts of patients suffering of a specific disease. RESULTS: During the year 2000 not only a statistically significant higher number of patients has been examined (p<0.05), in comparison with 1994, but also the hospitalisation rate was lowered resulting in a very significative cost-containment. CONCLUSIONS: The specialization of outpatient activities into working teams offers advantages in terms of more appropriate medical care and cost reduction, partly due to a less frequent hospitalisation. The obvious counterpart was an increase of request of such form of follow-up from patients, resulting in longer delay to the access.

Effect of macrovescicular steatosis and other donor and recipient characteristics on the outcome of liver transplantation.

The influence of steatosis and of other donor and recipient characteristics in affecting liver performance post-orthotopic liver transplantation (OLT) was evaluated in 311 consecutive liver transplantations made in 278 patients. Donor variables considered were age, sex, blood group, cause of death, intensive care unit (ICU) days, need for vasopressors, hepatic enzymes and bilirubin, total and warm ischemia time, and macro- and microvescicular steatosis. Recipient variables considered were age, sex, blood group, biliary output, and post-OLT peak levels of hepatic enzymes. Patient and graft survival were the main outcome indicators. In the multivariate analysis, macrovescicular steatosis involving 25% or more of the hepatocytes was the only variable independently associated with shorter patient survival (p < 0.05). Five (62.5%) of the eight livers with macrovescicular steatosis involving 25% or more of the hepatocytes incurred in a delayed non-function (DNF) and one (12.5%) in a primary non-function (PRNF). The incidence of DNF and PRNF in the group with macrovescicular steatosis involving less than 25% of the liver cells was 1.6% (p < 0.001) and 2.3%, respectively. Microvescicular steatosis of any degree was not associated with a worse prognosis. Macrovescicular steatosis involving 25% or more of the hepatocytes identifies marginal livers, the use of which significantly increases the risk of graft non-function post-OLT.

Treatment of recurrent hepatitis C virus infection after liver transplantation.

Therapeutic strategies were designed based on experience from the treatment options of the last 10 years in the ordinary clinical setting. Interferon was the first treatment used. This monotherapy was discontinued with the arrival of ribavirin. Ribavirin monotherapy has also been shown to have a limited effect and in recent years the combination of interferon and ribavirin has become the first line therapy.

Hepatitis D viremia following orthotopic liver transplantation involves a typical HDV virion with a hepatitis B surface antigen envelope.

Patients receiving orthotopic liver transplantation (OLT) because of type D hepatitis frequently exhibit what appears to be an autonomous, or "isolated," hepatitis D virus (HDV) infection following the transplantation, with no evidence of hepatitis B virus (HBV) in the graft or in the serum. These observations have led to the hypothesis that HBV might not always be required for HDV infection, or that HDV could exist as a latent infection until rescued by HBV. Alternatively, an apparently autonomous HDV infection could be explained by coinfection of a small number of hepatocytes with both viruses following transplantation, with a very low level of HBV expression that supports low-level HDV propagation. Our results are consistent with the latter hypothesis. Sensitive polymerase chain reaction (PCR)-based analysis of HBV and HDV viremia in transplantation patients with HDV infection previously characterized as isolated showed that HDV viremia was not independent of HBV viremia. Additional analyses, including PCR amplification, buoyant density analysis in a CsCl gradient, and immunoprecipitation with monoclonal hepatitis B surface antigen antibodies (anti-HBs), indicated that the posttransplant HDV particle is typical: it contains full-length HDV RNA and an envelope of hepatitis B surface antigen (HBsAg) and is not different from that found during the acute and chronic stages of HDV superinfection or coinfection. Moreover, an experimental test of the first hypothesis in chimpanzees did not support the idea that HDV can persist for several weeks as an isolated, latent infection that can be rescued subsequently by HBV. The data indicate, therefore, that latent HDV infection is not a factor in OLT recipients. We conclude that the HDV virion in the posttransplantation setting is typical, and that HDV viremia following OLT requires the helper function of HBV infection.

Recurrent necroinflammatory disease of multiple organs and colon. Systemic presentation of inflammatory bowel disease or gut involvement during systemic disorder.

A 30-year-old man with a recurrent febrile illness resembling infection is described. Because he presented with an acute abdomen, he underwent a laparotomy, which showed the paraaortic and mesenteric lymph nodes to be changed into an abscess-like granulomatous tissue made up of necrotized granulocytes. During further flare-ups, the disease affected the spleen, skin, colon, peripheral nerve, and muscle. Histology on the biopsy materials of both the skin and colon, and on the surgically removed spleen showed the same invading pathologic tissue. Exhaustive investigation disclosed no pathogen, and the flare-ups responded repeatedly to high-dose steroids. This patient's picture has recently been defined as a syndrome of chronic granulomatosis based on several published cases. As a distinctive feature, in our patient the granulomas affected also the colon. For the present, and for another previously described similar case we analyzed the factors that might permit the differential diagnosis between the above-mentioned granulomatous syndrome and Crohn's colitis.

Effect of patient characteristics on hospital costs for cirrhosis: implications for the disease-related group (DRG) reimbursement system.

The Prospective Payment System uses Diagnosis-Related Groups (DRG) as a reimbursement system. DRG 202 is a disease-related group including liver cirrhosis as a whole. Patients referring to the inpatient unit complain of variable severity and complications of cirrhosis, possibly implying different expenditure of resources. Aim of the investigation was to identify factors affecting cost variability in patients with cirrhosis. A total of 73 consecutive, DRG 202-assigned, cirrhotic patients classified according to demographic and clinical variables were evaluated for length and costs of hospitalization calculated on a full-cost basis. Mean length of hospitalization was 10.2 +/- 7 days. Mean cost of hospitalization was Lit. 4.348.000 +/- 2.718.000. Medical, nursing, diagnostic, drug and general charges accounted for 13%, 29%, 37%, 5% and 16% of the cost, respectively. Child-Pugh score significantly correlated with drug consumption (p < 0.005), length (p < 0.01) and costs (p < 0.001) of hospitalization, but not with cost per day. Age, sex, admission status, referral reason, associated diseases and liver transplant susceptibility did not correlate with duration and costs of hospitalization. Disease severity significantly modifies costs of hospital admission in cirrhotic patients mostly on account of longer hospital stay. Surrogate indexes of disease severity, derived from ISTAT/DRG records, cannot identify patients consuming larger resources. In liver cirrhosis, the DRG system could be improved by introducing parameters, such as Child-Pugh score, directly taking into account disease severity.

Adenine arabinoside monophosphate coupled to lactosaminated human albumin administered for 4 weeks in patients with chronic type B hepatitis decreased viremia without producing significant side effects.

A conjugate of adenine arabinoside monophosphate (ara-AMP) with the liver-targeting molecule lactosaminated human serum albumin (L-HSA) was administered by intravenous infusion for 28 days to eight patients with chronic type B hepatitis. The daily dose varied among the patients, ranging from 34 mg/kg to 53 mg/kg (equal to 1.5 and 2.3 mg/kg ara-AMP, respectively). Pharmacokinetic analysis indicated that, at every dose tested, the conjugate was disposed of without accumulation. Viral DNA serum levels fell markedly during treatment; values rose again when treatment was ceased. The L-HSA-ara-AMP conjugate did not cause either the neurotoxic side effects of free ara-AMP or other adverse clinical reactions. It produced a significant increase both in serum alkaline phosphatase activity and platelet number, and a small but significant decrease in erythrocyte number. These laboratory parameters returned to normal levels within 2 months after treatment. The conjugate induced the production of small amounts of antibodies (approximately 20 pmol of conjugate bound by 1 mL of serum) in one patient only. In conclusion, the present results indicate that the L-HSA-ara-AMP conjugate can exert the antiviral activity of ara-AMP in chronic type B hepatitis patients without producing the neurotoxic side effects which hamper a 4-week period of treatment with the free drug.

Epithelioid haemangioendothelioma of the liver: report of a case submitted to orthotopic liver transplantation.

A case of hepatic epithelioid haemangio-endothelioma is described in a 42-year-old female who presented with abdominal pain and hepatomegaly. The radiographic finding showed multiple hepatic lesions in both lobes. Diagnosis was based on the liver biopsy. The tumour cells were immunoreactive with factor VIII related antigen and vimentine. A liver transplantation was performed. Although at the time of diagnosis there was no clinical evidence of metastasis, the intra-operatorive examination revealed multiple mesenteric and pulmonary neoplastic nodules. The patient is alive and well seven months after liver transplantation.

Liver targeting of adenine arabinoside monophosphate (ara-AMP) by coupling to lactosaminated human serum albumin.

Adenine arabinoside monophosphate (ara-AMP) is a potent antiviral agent against hepadnaviruses but its use in the treatment of chronic hepatitis B is hampered by severe neurotoxic side effects, which are dose dependent. In order to reduce these adverse reactions and to adopt the lysosomotropic approach to antiviral chemotherapy, ara-AMP was coupled to lactosaminated human serum albumin (L-HSA), a neoglycoprotein which specifically penetrates hepatocytes. In mice with Ectromelia virus hepatitis, ara-AMP coupled with L-HSA was selectively delivered to liver cells in which it was released in a pharmacologically active form. Moreover in woodchucks with WHV hepatitis and in patients with chronic HBV infection, coupled ara-AMP inhibited hepadnavirus replication at a dose (1.5 mg/kg/day) 3-6 times lower than the free drug. A clinical study using a 28-day period of treatment with conjugated ara-AMP at 1.5 mg/kg/day has now been started. In the first 6 patients the treatment has been completed. The conjugate inhibited virus growth without producing any side effects. L-HSA-ara-AMP conjugate must be given by intravenous infusion. New hepatotropic conjugates of ara-AMP have been recently prepared which could be administered by bolus intravenous injection or by intramuscular route. These complexes might assure a better compliance in patients with hepatitis B virus infection for a long lasting liver targeted antiviral treatment.