Thomas V. Cacciarelli

Long-term survival after liver transplantation in 4,000 consecutive patients at a single center

ObjectiveTo evaluate the long-term survival outcomes of a large cohort of liver transplant recipients and to identify static and changing factors that influenced these outcomes over time. Summary Background DataLiver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, with continual improvements in patient survival as a result of advances in immunosuppression and medical management, technical achievements, and improvements in procurement and preservation. Although many reports, including registry data, have delineated short-term factors that influence survival, few reports have examined factors that affect long-term survival after liver transplantation. MethodsFour thousand consecutive patients who underwent liver transplantation between February 1981 and April 1998 were included in this analysis and were followed up to March 2000. The effect of donor and recipient age at the time of transplantation, recipient gender, diagnosis, and year of transplantation were compared. Rates of retransplantation, causes of retransplantation, and cause of death were also examined. ResultsThe overall patient survival for the entire cohort was 59%; the actuarial 18-year survival was 48%. Patient survival was significantly better in children, in female recipients, and in patients who received transplants after 1990. The rates of retransplantation for acute or chronic rejection were significantly lower with tacrolimus-based immunosuppression. The risk of graft failure and death was relatively stable after the first year, with recurrence of disease, malignancies, and age-related complications being the major factors for loss. ConclusionSignificantly improved patient and graft survival has been observed over time, and graft loss from acute or chronic rejection has emerged as a rarity. Age-related and disease-related causes of graft loss represent the greatest threat to long-term survival.

Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience.

ObjectiveTo evaluate the incidence of posttransplant lymphoproliferative disease (PTLD) and the risk factors and the impact of this complication on survival outcomes in a large cohort of liver transplant recipients at a single institution. Summary Background DataLiver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, in large part due to the availability and reliance on the use of nonspecifically directed immunosuppression. However, as predicted and subsequently verified in 1968, an increased incidence of certain de novo malignancies has been observed, particularly with regards to lymphoid neoplasms. While many reports have confirmed and clarified the nature of PTLD, the literature is fraught with conflicting experience and outcomes with PTLD. MethodsFour thousand consecutive patients who underwent liver transplants between February 1981 and April 1998 were included in this analysis and were followed to November 2001. The effect of recipient age at the time of transplant, recipient gender, diagnosis, baseline immunosuppression, grading of PTLD, and association with Epstein-Barr virus were compared. The causes of death were also examined. Treatment for PTLD varied over the 20-year period, but all included massive reduction or elimination of baseline immunosuppression. ResultsThe 1-year patient survival for liver transplant patients with PTLD was 85%, while the overall patient survival for the entire cohort was 53%. The actuarial 20-year survival was estimated at 45%. The overall median time to PTLD presentation was 10 months, and children had an incidence of PTLD that was threefold higher than adults. Patient survival was better in children, in patients transplanted in the era of tacrolimus immunosuppression, in patients with polymorphic PTLD, and in those with limited disease. Interestingly, neither the presence or absence of Epstein-Barr virus nor the timing of PTLD presentation appeared to influence overall patient survival. Patients transplanted for alcohol-related liver disease had a similar incidence of PTLD but had a higher risk of mortality. ConclusionsWhile PTLD continues to pose problems in patients receiving liver transplants, improvements in patient survival have been observed over time. While it is too early to assess the impact of new advances in prophylaxis, diagnosis, and treatment, such approaches are based on an increased knowledge of the pathophysiology of PTLD.

Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors

BACKGROUND The shortage of donor organs occasionally mandates the use of hepatic allografts from anti-HBc+ donors in recipients who are susceptible to de novo hepatitis B virus (HBV) infection. The efficacy of hepatitis B immune globulin and lamivudine to prevent de novo HBV infection in anti-HBs negative recipients of allografts from anti-HBc+ donors has not been investigated. METHODS After liver transplantation with an allograft from a donor positive for anti-HBc, recipients who were anti-HBs-, HbsAg- received hepatitis B immune globulin (HBIG) 10,000 IU i.v. daily for 7 days and monthly for 6 months. After 6 months, 1000 IU of HBIG was given IM. every 2 weeks for 18 months. Patients transplanted after 4/1/97 were given lamivudine 150 mg daily starting postoperative day 1. RESULTS Between 8/14/96 and 6/10/98, 264 orthotopic liver transplants were performed and 16 anti-HBs-, HbsAg- patients received an hepatic allograft from a donor positive for anti-HBc. HBIG mono-therapy was administered to one patient. HBIG and lamivudine combination therapy was administered to 15 patients. Of the 16 patients, 8 were positive only for anti-HBc before transplant, and 8 were naive (anti-HBs-, anti-HBc-). The single patient who received HBIG monotherapy became HbsAg+ at 6 months. All patients receiving combination therapy with HBIG and lamivudine have remained HbsAg-. The average follow-up is 459 days (range 170-754). Two patients died from unrelated causes. CONCLUSIONS Combination therapy with HBIG and lamivudine may prevent de novo HBV infection in anti-HBs-, HbsAg- recipients of hepatic allografts from anti-HBc+ donors.

Pregnancy after liver transplantation with tacrolimus immunosuppression: a single center's experience update at 13 years.

Background. Chronic liver disease often leads to amenorrhea in women of childbearing age. There are several reports of successful pregnancy after liver transplantation (LTx) with cyclosporine A immunosuppression. Tacrolimus has been increasingly used in solid-organ transplantation, and the effect of the drug on pregnancy is still of interest to clinicians. This study updates our single-center experience. Methods. All pregnancies after LTx with tacrolimus immunosuppression were followed prospectively. Patients’ clinical courses during pregnancy and labor along with gestational period and birth weight were catalogued. Changes in liver function, renal function, and immunosuppression also were recorded. The birth weight percentile was calculated on the basis of the gestational period using a standard chart. Results. Thirty-seven mothers delivered 49 babies. Three mothers delivered three times, and six mothers delivered two times. Thirty-six mothers (97%) survived the pregnancy, and 36 allografts (97%) survived. The one death and graft loss was in a patient who demonstrated infra-aortic arterial graft, which clotted by the gravid uterus during labor. The patient developed a gangrenous liver and died before she could undergo retransplantation. The mean gestational period was 36.4±3.2 weeks, excluding two premature deliveries at 23 and 24 weeks gestation. Twenty-two babies (46.9%) were delivered by cesarean section, and the other babies were delivered vaginally. In addition to the two premature babies, one baby, who was born to a mother with Alagille syndrome, died from congenital birth defects. The rest of the newborns survived. The mean birth weight was 2,797±775 g, with 38 babies (78%) weighing more than 2,000 g. The mean birth weight percentile to gestational period was 54±23. Four babies (8.5%) had a birth weight percentile of less than 25, and 28 babies (59.6%) had a birth weight percentile greater than 50. Twelve patients demonstrated an increase in hepatic enzymes without jaundice during the pregnancy. All of them responded to augmentation of immunosuppression. Conclusion. The present report reconfirms the safety of tacrolimus during pregnancy after LTx. Preterm delivery and low birth weight seem to be a persistent problem in all solid-organ transplantation under any form of immunosuppression. However, toxemia of pregnancy and new onset of hypertension seem to be have a low occurrence with the use of tacrolimus.

Bacteremias in liver transplant recipients: Shift toward gram‐negative bacteria as predominant pathogens

During the 1990s, gram‐positive bacteria emerged as major pathogens after liver transplantation. We sought to determine whether the pathogens associated with bacteremias in liver transplant recipients have changed. Patients included 233 liver transplant recipients transplanted between 1989 and 2003. The proportion of all infections due to bacteremias increased significantly over time (P < .0001). Of other major infections, a trend toward a decrease in fungal infections (P = .089) and a significant decrease in cytomegalovirus (CMV) disease (P = .0004) were documented. Whereas the proportion of bacteremias due to gram‐negatives increased from 25% in the period of 1989–1993 to 51.8% in 1998–03, that of gram‐positive bacteria decreased from 75% in the period of 1989–93 to 48.2% in the period of 1998–2003. Methicillin‐resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most frequent pathogens in bacteremic patients. The incidence of bacteremias due to MRSA and Pseudomonas aeruginosa has remained unchanged (P < .20); however, that due to enteric gram‐negative bacteria, particularly Klebsiella pneumoniae has increased (P = .02). Klebsiella pneumoniae isolates in the current quartile were not clonally related. In conclusion, bacteremias as a proportion of all infections in liver transplant recipients have increased significantly over time, due in part to a decline in infections due to other major pathogens, e.g., fungi, primarily Candida species, and CMV. Gram‐negative bacteria have emerged as predominant pathogens in bacteremic liver transplant recipients. (Liver Transpl 2004;10:844–849.)

MANAGEMENT OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE IN PEDIATRIC LIVER TRANSPLANT RECIPIENTS RECEIVING PRIMARY TACROLIMUS (FK506) THERAPY

BACKGROUND Posttransplant lymphoproliferative disease (PTLD) after pediatric liver transplantation has been associated with high mortality rates. METHODS The present study examined 282 consecutive pediatric liver transplant recipients from October 1989 to June 1996 who received primary tacrolimus immunosuppression. The aim was to determine the incidence of PTLD, management strategies, and patient outcome. RESULTS The incidence of PTLD was 13% (361282) with a mean age of 5.5+/-0.7 years (range 0.6 to 15) at diagnosis. The average time from transplantation to PTLD was 10.1+/-2.1 months. Initial treatment of PTLD consisted of reduction (3 patients) or discontinuation (33 patients) of tacrolimus and initiation of antiviral therapy (intravenous ganciclovir, 14 patients; intravenous acyclovir, 22 patients; or both, 5 patients). Alpha-interferon was used in four patients (two successfully). One patient also received gamma-interferon, chemotherapy, and radiation for a central nervous system lesion. Chemotherapy was also used in one patient with Burkitts, whereas one patient with a pulmonary lesion received additional radiation therapy. Three patients received supportive surgery for gastrointestinal involvement, and one patient had a splenectomy for hemolysis. Overall mortality was 22% (8/36) with 5 (14%) PTLD-related deaths (disseminated disease, 4 patients; bowel perforation, 1 patient). Of 31 survivors, 23 had acute rejection at a median time of 24 days after PTLD, with 2 patients developing chronic rejection. One patient required retransplantation. Present immunosuppression consists of tacrolimus monotherapy in 14 patients, tacrolimus/prednisone in 8 patients, and none in 6 patients. CONCLUSION In summary, PTLD can be successfully treated with reduction of immunosuppression and administration of antiviral agents in most patients. The management of rejection after PTLD requires reassessment of disease status and judicious reintroduction of immunosuppression therapy.

Factors affecting survival after orthotopic liver transplantation in infants.

The technical and medical management of small infants requiring orthotopic liver transplantation remains a challenge. The present study examined 117 orthotopic liver transplantations performed in 101 infants from <1 to 23 months of age between March 1988 and February 1995 to determine factors that influence patient and graft outcome. Factors analyzed included etiology of liver disease, recipient and donor age and weight, United Network for Organ Sharing (UNOS) status, retransplantation, ABO-compatibility, full-size (FS) versus reduced-size grafts, vascular thrombosis (VT), including hepatic artery and portal vein (PVT), and the presence of lymphoproliferative disease (LPD). UNOS status 1, fulminant hepatic failure, and the development of Epstein-Barr virus-associated LPD were each associated with 10-20% lower patient and graft survival rates. Of 101 infants, 11 (11%) developed LPD with an associated 36% mortality. VT occurred in 10 (9 hepatic artery and 1 portal vein) of 117 orthotopic liver transplantations (9%), all less than 1 year of age, and was associated with significantly poorer 1-year (50% vs. 85% no VT, P<0.01) and 5-year patient survival rates (50% vs. 83% no VT, P<0.01). One-year graft survival rates for FS grafts in recipients <12 months versus 12-23 months were 67% vs. 94% (P<0.01); the patient survival rate was also significantly lower in FS graft recipients <12 months (76% vs. 100%, P<0.05). Recipients <5 months of age had the worst survival rates: 1-year and 5-year patient survival rates were 65% and 46% for recipients 0-4 months (n=17) versus 82% and 82% for recipients 5-11 months (n=56), and 93% and 93% for recipients age 12-23 months (n=28; P<0.05). In summary, factors associated with reduced survival rates include recipient age <5 months, recipient age <12 months who received FS grafts, development of VT and donor weight <6 kg. There was a trend for UNOS status 1, fulminant hepatic failure, and presence of LPD to be associated with reduced survival rates.

Recurrent Hepatitis C in Liver Allografts: Prospective Assessment of Diagnostic Accuracy, Identification of Pitfalls, and Observations About Pathogenesis

Rationale and Design:The accuracy of a prospective histopathologic diagnosis of rejection and recurrent hepatitis C (HCV) was determined in 48 HCV RNA-positive liver allograft recipients enrolled in an “immunosuppression minimization protocol” between July 29, 2001 and January 24, 2003. Prospective entry of all pertinent treatment, laboratory, and histopathology results into an electronic database enabled a retrospective analysis of the accuracy of histopathologic diagnoses and the pathophysiologic relationship between recurrent HCV and rejection. Results:Time to first onset of acute rejection (AR) (mean, 107 days; median, 83 days; range, 7–329 days) overlapped with the time to first onset of recurrent HCV (mean, 115 days; median, 123 days; range, 22–315 days), making distinction between the two difficult. AR and chronic rejection (CR) with and without co-existent HCV showed overlapping but significantly different liver injury test profiles. One major and two minor errors occurred (positive predictive values for AR = 91%; recurrent HCV = 100%); all involved an overdiagnosis of AR in the context of recurrent HCV. Retrospective analysis of the mistakes showed that major errors can be avoided altogether and the impact of unavoidable minor errors can be minimized by strict adherence to specific histopathologic criteria, close clinicopathologic correlation including examination of HCV RNA levels, and a conservative approach to the use of additional immunosuppression. In addition, histopathologic diagnoses of moderate and severe AR and CR were associated with relatively low HCV RNA levels, whereas relatively high HCV RNA levels were associated with a histopathologic diagnosis of hepatitis alone, particularly the cholestatic variant of HCV. Conclusions:Liver allograft biopsy interpretation can rapidly and accurately distinguish between recurrent HCV and AR/CR. In addition, the histopathologic observations suggest that the immune mechanism responsible for HCV clearance overlap with those leading to significant rejection.

Antifungal Management Practices in Liver Transplant Recipients

We sought to determine the approach to antifungal prophylaxis, and diagnostic and therapeutic practices for the management of invasive aspergillosis in liver transplant recipients. Data were collected by an electronic survey questionnaire sent to all active liver transplant programs in North America; 63% (67/106) of the sites completed the survey. Overall, 91% of the sites employed antifungal prophylaxis; 28% used universal prophylaxis and 72% targeted it toward high‐risk patients. Fluconazole was the most commonly used agent for universal and targeted prophylaxis. The leading choice for mold‐active agents for antifungal prophylaxis was the echinocandins. Combination therapy was used as primary therapy for invasive aspergillosis in 47%, and as salvage in 80%. Thus, a vast majority of the surveyed programs employ antifungal prophylaxis and most use targeted prophylaxis. Consideration of these practices could guide clinical trial design to optimize antifungal prophylaxis in these patients. Our findings also merit investigations to better define the role of diagnostic assays and combination therapeutic strategies for invasive aspergillosis in liver transplant recipients.

Primary tacrolimus (FK506) therapy and the long-term risk of post-transplant lymphoproliferative disease in pediatric liver transplant recipients.

Abstract: While the overall incidence of post‐transplant lymphoproliferative disease (PTLD) in pediatric liver transplant recipients has been reported to be 4–11%, the long‐term risk of PTLD associated with primary tacrolimus therapy is unknown. Therefore, in order to determine the incidence and long‐term risk of PTLD, the present study examined 131 pediatric recipients who underwent liver transplantation (LTx) between October 1989 and December 1991 and received primary tacrolimus therapy. This cohort of children was evaluated over an extended time‐period (until December 31 1996) with a mean follow‐up of 6.3 yr. Actuarial Kaplan–Meier analysis was utilized to determine the risk of PTLD over time. The overall incidence of PTLD was 13% (17/131) with an average age of 4.3 ± 0.75 yr at diagnosis. Pretransplant Epstein–Barr virus (EBV) serologies were negative in 82%, positive in 12%, and not available in 6% of the patients. The median time to diagnosis of PTLD post‐Tx was 11.9 months (mean 16.4 ± 3.9, range 1.7–63.0 months). Mean tacrolimus dose and plasma trough level (as evaluated by enzyme‐linked immunosorbent assay [ELISA]) at the time of diagnosis was 0.32 ± 0.06 mg/kg/day and 1.3 ± 0.3 ng/mL, respectively. The cumulative long‐term risk of PTLD was found to increase over time: 3% at 6 months, 8% at 1 yr, 12% at 2 yr, 14% at 3 yr, and 15% at 4 and 5 yr. Mortality from PTLD was 12% (two of 17 patients). Primary tacrolimus use in pediatric LTx has a long‐term risk of PTLD approaching 15%, with the majority of episodes (78%) occurring in the first 2 yr, suggesting that intense EBV surveillance should occur early post‐transplantation.