Nancy Rolando

Fungal infection : a common, unrecognised complication of acute liver failure

The true incidence and clinical relevance of fungal infection was ascertained in a prospective study of 50 consecutive patients with acute liver failure. Fungal infection was present in 16 (32%) patients (15 candida, one aspergillus) and in seven was considered the major cause of death. All six untreated died, while five of ten patients treated with anti-fungal therapy survived. The diagnosis was made on positive cultures from at least one significant site or on histological evidence of tissue invasion. All 16 had concomitant bacterial infection and shared features suggestive of a clinical syndrome: deterioration in coma grade after initial improvement; pyrexia unresponsive to antibiotics; established renal failure; and a markedly elevated white cell count. Fungal infection is a common, serious complication of acute liver failure and therapy is indicated for those with positive cultures. A prophylactic trial would be justified in those surviving 5 days, especially, with established renal failure.

Immunosuppression and Donor Age With Respect to Severity of HCV Recurrence After Liver Transplantation

In HCV cirrhotic patients after liver transplantation, survival and recurrence of HCV appears to be worsening in recent years. Donor age has been suggested as a cause. However, it is not clear if early and/or late mortality is affected and whether donor age is a key factor, as opposed to changes in immunosuppression. The aim of this study was to assess impact of donor age and other factors with respect to the severity of HCV recurrence posttransplant. A consecutive series of 193 HCV cirrhotic patients were transplanted with cadaveric donors, median age 41.5 years (13–73) and median follow‐up of 38 months (1–155). Donor age and other factors were examined in a univariate/multivariate model for early/late survival, as well as fibrosis (grade 4 or more, Ishak score) with regular biopsies, 370 in total, from 1 year onwards. Results of the study indicated that donor age influenced only short‐term (3 months) survival, with no significant effect on survival after 3 months. Known HCC independently adversely affected survival, as did the absence of maintenance azathioprine. Severe fibrosis (stage ≥ 4) in 51 patients was related to neither donor age nor year of transplantation, but it was independently associated with combined biochemical/histological hepatitis flare (OR 2.9, 95% CI 1.76‐4.9) whereas maintenance steroids were protective (OR 0.4, 95% CI 0.23‐0.83). In conclusion, in this cohort donor age did not influence late mortality in HCV transplanted cirrhotic patients or development of severe fibrosis, which was related to absence of maintenance steroids and a hepatitis flare. Maintenance azathioprine gave survival advantage. (Liver Transpl 2005;11:386–395.)

Cytomegalovirus Replication Kinetics in Solid Organ Transplant Recipients Managed by Preemptive Therapy

After allotransplantation, cytomegalovirus (CMV) may be transmitted from the donor organ, giving rise to primary infection in a CMV negative recipient or reinfection in one who is CMV positive. In addition, latent CMV may reactivate in a CMV positive recipient. In this study, serial blood samples from 689 kidney or liver transplant recipients were tested for CMV DNA by quantitative PCR. CMV was managed using preemptive antiviral therapy and no patient received antiviral prophylaxis. Dynamic and quantitative measures of viremia and treatment were assessed. Median peak viral load, duration of viremia and duration of treatment were highest during primary infection, followed by reinfection then reactivation. In patients who experienced a second episode of viremia, the viral replication rate was significantly slower than in the first episode. Our data provide a clear demonstration of the immune control of CMV in immunosuppressed patients and emphasize the effectiveness of the preemptive approach for prevention of CMV syndrome and end organ disease. Overall, our findings provide quantitative biomarkers which can be used in pharmacodynamic assessments of the ability of novel CMV vaccines or antiviral drugs to reduce or even interrupt such transmission.

Clinical Characteristics Affecting The Outcome Of Liver Retransplantation

BACKGROUND The outcome of retransplantation remains unsatisfactory when compared with primary transplantation of the liver. The aim of the present study was to determine which preoperative clinical and laboratory risk variables are implicated in the poorer outcome. METHODS The preoperative status of 70 retransplanted patients was compared with a group of 303 time-matched recipients receiving their first graft. RESULTS Survival at 1 year was reduced in the retransplant versus the primary transplant group (50% vs. 80%, P<0.001). Preoperatively older age, high United Network of Organ Sharing score, inpatient status, elevated bilirubin, and creatinine levels were associated with increased mortality after a second transplant. Preoperatively, the retransplant group had higher encephalopathy grades, were more likely to be inpatients, and had higher serum creatinine, bilirubin, and white cell levels than the primary recipients (P<0.05 in all cases). The median length of inpatient stay was longer after the second transplant (25 vs. 19 days, P<0.001). CONCLUSIONS These factors assist in the stratification of patients awaiting retransplantation; however, the outcome of this procedure is only likely to be improved with an earlier identification of the patients who require it, along with an increased priority in organ allocation.

Long-term mycophenolate mofetil monotherapy in combination with calcineurin inhibitors for chronic renal dysfunction after liver transplantation.

Background. Calcineurin inhibitors (CNIs) are the first-line immunosuppressive agents administered after liver transplantation, but they cause renal impairment. Two recent randomized trials report cellular rejection and liver graft loss when mycophenolate mofetil (MMF) monotherapy was used as a renal-sparing agent. Our experience with MMF in the same setting but with longer follow-up is described. Methods. In 45 patients with serum creatinine more than 120 &mgr;mol/L or creatinine clearance less than 50 mL/min, 2 g MMF per day was administered (median 29 months, 1–49 months) either as monotherapy (with all other immunosuppression withdrawn in 1 month) in 16 patients (group I) or in combination with low-dose CNI (trough tacrolimus ≤5 ng/mL, cyclosporin A ≤50 ng/mL) in 29 patients (18 patients without [group II] and 11 patients with [group III] previous refractory rejection [rejection after two episodes of treated rejection]). Results. In group I (median interval receiving MMF, 33 months), only one patient (6%) experienced cellular rejection, and serum creatinine normalized in five of eight patients long term. In group II (median follow-up 26.5 months), none of 18 experienced rejection, and serum creatinine normalized in 6 of 10 long term. In group III (median follow-up 34 months), 5 of 11 patients (45%) experienced further rejection, one was not steroid responsive, and serum creatinine normalized in four of eight patients long term. There was no graft loss or death as a result of rejection. Conclusions. Our cohort with prolonged follow-up showed significant improvement in renal function with both MMF monotherapy and in combination with low-dose CNI with minimal rejection (five of six steroid responsive) and no graft loss. MMF substitution is a therapeutic strategy that deserves more extensive use in liver transplantation.

Infectious sequelae after endoscopic sclerotherapy of oesophageal varices: role of antibiotic prophylaxis

In order to determine the incidence of infection following sclerotherapy and the role of antimicrobial prophylaxis, a prospective randomized control study was performed comparing i.v. imipenem/cilastatin, with an infusion of dextrose-saline as a control group. One hundred patients with bleeding esophageal varices were included. All episodes of infection were documented during admission to the unit. Ninety-seven patients were evaluable. Post-sclerotherapy bacteremia developed in six (5.6%) of 107 sclerotherapy sessions in the control group and one (1.1%) of the 88 sclerotherapy sessions in the imipenem/cilastatin group (P < or = 0.1, NS): six of these seven post-sclerotherapy bacteremias occurred after emergency sclerotherapy. Infection within 7 days of the procedure was documented after 43 (22.1%) of the 195 sclerotherapy sessions, 18 (20.5%) in the imipenem/cilastatin group and 25 (23.4%) in the control group (P = NS). These infections were significantly more common after emergency sclerotherapy, 40 (34.8%) of 115 sessions, than after elective sclerotherapy, three (3.8%) of 80 sessions (P < or = 0.0001). A short prophylactic antibiotic regime does not reduce the risk of early bacteremia or the frequency of infection after sclerotherapy. The higher risk of infection after emergency sclerotherapy may be therefore related more to the gastrointestinal hemorrhage and its associated effects than to sclerotherapy.

Epithelial colonies cultured from human explanted liver in subacute hepatic failure exhibit hepatocyte, biliary epithelial, and stem cell phenotypic markers

The liver in subacute hepatic failure may become enriched for hepatic progenitor cells. Liver tissue from such a patient was collagenase digested and, from the nonparenchymal cell fraction, epithelioid colonies were developed. Albumin and alpha‐1‐antitrypsin (AAT) were secreted for greater than 120 days from these colonies. Reverse transcription‐polymerase chain reaction showed expression of markers of both hepatocyte and biliary epithelial phenotypes (cytokeratins 7, 18, and 19, albumin and AAT, hepatocyte growth factor receptor, transforming growth factor beta receptor type II, gamma‐glutamyl transpeptidase, biliary glycoprotein). The cell cycle regulator p21 was also expressed. The POU domain transcription factor octamer‐binding protein 4 was present in these cells, but not in RNA or cDNA prepared from adult human liver. These markers were maintained even after 165 days culture. Proliferating epithelial‐like cells with combined hepatocyte‐ and biliary‐epithelial‐specific functional markers and a stem cell marker can be isolated from the nonparenchymal fraction of liver cells in subacute hepatic failure.

Neutrophil superoxide and hydrogen peroxide production in patients with acute liver failure.

Defects in superoxide and hydrogen peroxide production may be implicated in the high incidence of bacterial infections in patients with acute liver failure (ALF). In the present study, oxygen radical production in patients with ALF due to paracetamol overdose was compared with that of healthy volunteers. Neutrophils from 14 ALF patients were stimulated via the complement receptors using zymosan opsonized with ALF or control serum. Superoxide and hydrogen peroxide production by ALF neutrophils stimulated with zymosan opsonized with ALF serum was significantly reduced compared with the control subjects (P < 0.01). This defect persisted when zymosan opsonized by control serum was used (P < 0.05). Superoxide and hydrogen peroxide production in neutrophils stimulated with formyl‐methionyl‐leucyl‐phenylalanine (fMLP) from a further 18 ALF patients was unaffected compared with control neutrophils. Serum C3 complement levels were significantly reduced in ALF patients compared with control subjects (P < 0.0005). These results demonstrate a neutrophil defect in ALF due to paracetamol overdose, that is complement dependent but independent of serum complement, possibly connected to the complement receptor.

Granulocyte colony-stimulating factor improves function of neutrophils from patients with acute liver failure.

Objective To evaluate the in vitro effects of granulocyte colony‐stimulating factor (G‐CSF) on function of neutrophils in acute liver failure (ALF). Methods Neutrophil functions (superoxide and hydrogen peroxide production; phagocytosis and killing; complement receptor expression) were determined simultaneously in 23 patients with ALF due to paracetamol overdose and compared with 23 healthy control subjects. Results Phagocytosis was reduced in neutrophils from ALF patients compared to controls ( P <0.005) and was significantly increased by incubation with 1000 or 5000 IU/ ml G‐CSF ( P <0.05). This correlated with increased expression of CD11b ( r =0.93) and CD18 ( r =0.98) after incubation with 5000 IU/ml G‐CSF ( P <0.05). Killing was reduced in ALF neutrophils compared to controls ( P <0.005) and was similarly restored by G‐CSF ( P <0.005). An increase in killing correlated with increases in production of superoxide ( r =0.96) and hydrogen peroxide ( r =0.97) by ALF neutrophils after incubation with 1000 and 5000 IU/ml of G‐CSF when formylmethionyl‐leucylphenylalanine (fMLP) was the stimulant. G‐CSF at 5000 IU/ml increased the production of hydrogen peroxide ( P <0.01) when zymosan was the stimulant. Conclusions G‐CSF improves the neutrophil dysfunction of ALF.

Administering granulocyte colony-stimulating factor to acute liver failure patients corrects neutrophil defects

Objectives Neutrophil function is defective in acute liver failure (ALF) and the in vitro ability of granulocyte colonystimulating factor (G‐CSF) to reverse these defects has been reported. The effects of administering G‐CSF to ALF patients are presented in this study. Design This was a prospective, phase I/II, open label, study. Setting The liver intensive therapy unit at Kings College Hospital, London. Participants Sequential patients admitted with acute liver failure due to acetaminophen overdose. Interventions G‐CSF was given to four groups (each n = 6) of ALF patients as a daily infusion at 25, 50, 100 or 150 μg/m2. A control group of eight patients did not receive G‐CSF. Main outcome measures Neutrophil phagocytosis and killing of Staphylococcus aureus and superoxide release before G‐CSF administration and at 24 and 96 h thereafter. Results Neutrophils from patients receiving 50, 100 or 150 μg/m2 G‐CSF, but not from control patients or those receiving 25 μg/m2, showed significantly increased phagocytosis and killing at 96 h. Doses of 50 or 150 μg/m2 G‐CSF resulted in increased superoxide production at 96 h. No patients discontinued treatment as a consequence of side effects related to G‐CSF administration. Conclusions G‐CSF administration is a safe and effective means of reversing the neutrophil defects of ALF, and may have a role in the prevention and treatment of infection in these patients. A dose of 50 μg/m2/day is as effective as higher doses and was associated with fewer side effects.