Todd Pillen

Cytomegalovirus infection and disease after liver transplantation. An overview.

Cytomegalovirus is the single most important pathogen in clinical transplantation. Although much progress has been made in our understanding of the molecular biology and epidemiology of CMV infection and in our ability to diagnosis and treat CMV disease, it remains a major cause of morbidity but is no longer a major cause of mortality after liver transplantation. Risk factors for CMV disease after liver transplantation include donor and recipient serologic status, the use of antilymphocyte therapy, and retransplantation. CMV disease occurs early after transplantation, and the most frequent site of disease is the hepatic allograft. We have treated 79 patients with intravenous ganciclovir, with ultimate control of disease achieved in 69 patients (87.3%). Preliminary results using intravenous immunoglobulin and oral acyclovir for CMV prophylaxis in high-risk patients have been encouraging. In addition to producing clinical syndromes, CMV may have direct immunologic effects and is a marker of the net state of immunosuppression.

Optimal therapy for patients with biliary atresia: portoenterostomy ("Kasai" procedures) versus primary transplantation.

As the results with liver transplantation have improved, a controversy has arisen regarding the precise role of a portoenterostomy in the treatment of infants with biliary atresia. The controversy centers around three issues: (1) the short- and long-term survival rates achieved with both procedures, (2) the influence of a portoenterostomy on a subsequent transplant, and (3) the shortage of suitable liver donors for very small infants. To address these questions, we retrospectively reviewed the charts of 48 children with biliary atresia who underwent liver transplantation and compared these results with 35 children transplanted for other liver diseases. As a group, the biliary atresia patients had significantly lower mean body weights and ages and spent a significantly longer time on the waiting list. In addition, significantly more of the biliary atresia patients had undergone prior abdominal surgery when compared with the non-biliary atresia group. There was no difference in the intraoperative variables of mean anesthesia time, mean operative time, mean anesthesia preparation time, nor the mean amount of blood transfused intraoperatively between the two groups. However, when the biliary atresia patients who had undergone a portoenterostomy with a stoma were compared with either the biliary atresia patients who did not have a stoma created as part of their portoenterostomy or the non-biliary atresia patients, significant differences were noted in mean total anesthesia time, mean operative time, and the mean amount of blood transfused intraoperatively. The survival rate of the biliary atresia patients was significantly greater than the non-biliary atresia patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The impact of extended preservation on clinical liver transplantation.

The introduction of UW solution into clinical transplantation has permitted extended cold storage preservation of the liver. Over a 46-month period, we have performed 308 orthotopic liver transplants (268 primary, 42 retransplants) in 266 recipients. Our experience is divided into cold-storage preservation in Eurocollins (163 transplants in 140 recipients) and UW (145 transplants in 131 recipients) solutions. Donor and recipient factors were comparable between the two groups. The use of UW solution has permitted an increase in the mean preservation time from 5.2±1.0 [EC] to 12.8±4.3 [UW] hr (P<0.001). The mean total operating time was reduced but intraoperative blood loss was unchanged with UW preservation. The number of transplants performed during the daytime hours has increased dramatically (21.5% [EC] vs. 71% [UW], P<0.001). The incidence of primary nonfunction, hepatic artery thrombosis, 1-month graft survival, and early retransplantation were similar in the 2 groups. Initial allograft function as determined by bile production, histology, and clinical assessment were likewise similar. Mean serum bilirubin, transaminase, and prothrombin levels were virtually identical by 5 days post-transplant. The enhanced margin of safety afforded by extended preservation has increased the capability for distant organ procurement and sharing, minimized organ wastage, and improved the efficiency of organ retrieval. With the relaxation of logistical constraints, our rate of liver import has nearly doubled (20.9% [EC] vs. 39.3% [UW]. P<0.001). Extended preservation has permitted the development of reduced-size liver grafting (n=12), resulting in a significant reduction in the number of deaths occurring while awaiting transplantation. Therefore, we advocate the use of UW solution with selective extension of preservation based not only on donor and recipient factors but also on manpower, resource, and logistical considerations.

Pediatric liver transplantation with daclizumab induction therapy

Background. A new class of monoclonal antibodies (non-T–cell depleting) has gained favor for induction therapy after transplantation. This study evaluated the non-T–cell depleting antibody to the CD25 cell, daclizumab, as a single-dose induction agent immediately after pediatric liver transplantation to spare the use of the calcineurin inhibitor, tacrolimus, for 7 days in respect to both efficacy and renal function. Methods. From January 1998 to November 2001, 81 pediatric orthotopic liver transplant recipients receiving 89 liver grafts were evaluated. The treatment arm (n=61) received daclizumab 1 mg/kg immediately after liver transplantation along with mycophenolate, steroids, and, on postoperative day 7, tacrolimus. The control group did not receive induction therapy, whereas tacrolimus, mycophenolate, and steroids were started immediately after surgery. Results. The induction group had fewer patients with rejection within the first 30 days after liver transplantation (9 [14.8%] vs. 10 [50%]; P =0.003). The mean time to first rejection was similar between groups (12.1 [±7.8] days vs. 18.5 [±8.1] days; P =not significant). There was a 3.39 increase in relative risk to develop rejection within the first 30 days after orthotopic liver transplantation if the patient did not receive induction therapy (relative risk=3.39; 95% confidence interval [1.61, 7.14]). Two-year actuarial survival for the induction group was 93.2% compared with 85% in the control; graft survival was also similar between groups (87.8% vs. 72.7%) at 2 years. Conclusion. Daclizumab 1 mg/kg given immediately after pediatric liver transplantation and withholding tacrolimus, is safe, efficacious, and reduces rejections within the first 30 days after surgery.

Successful ABO-incompatible pediatric liver transplantation utilizing standard immunosuppression with selective postoperative plasmapheresis

Transplanting blood group A, B, or O (ABO)‐incompatible (ABO‐I) liver grafts has resulted in lower patient and graft survival with an increased incidence of vascular and biliary complications and rejection. We report that, without modification of our standard immunosuppression protocol, crossing blood groups is an acceptable option for children requiring liver transplantation. In our study, ABO‐I liver grafts—regardless of recipient age—have comparable long‐term survival (mean follow‐up of 3.25 yr) with ABO‐compatible grafts without any difference in rejection, vascular or biliary complications. From January 1, 1999 to October 1, 2005, we studied 138 liver transplants in 121 children: 16 (13.2%) received an ABO incompatible liver allograft. One‐year actuarial patient survival for ABO‐matched grafts vs. ABO‐I grafts was 93.0% and 100%, respectively, whereas graft survival was 83.4% and 92.3%. Additionally, 6 of 16 (37.5%) ABO‐I transplanted children had 8 rejection episodes, whereas 47 patients (44.8%) had 121 rejection episodes in the ABO‐compatible group. There were no vascular complications and 2 biliary strictures in the ABO‐I group. Plasmapheresis was not used for pretransplantation desensitization and was only required in 1 posttransplantation recipient. No child was splenectomized. Six of the 16 children were older than 13 yr of age, suggesting the possibility of successfully expanding this technique to an older population. In conclusion, our outcomes may support the concept of using ABO‐I grafts in a more elective setting associated with split and living donor liver transplants. Liver Transpl 12:972–978, 2006.

Hepatic artery thrombosis in pediatric liver transplantation

PURPOSE Children have been reported to be at greater risk for hepatic artery thrombosis when compared to adults due to small arterial size, nonuse of intraoperative microscope, and postoperative hypercoagulable state. METHODS We evaluated arterial anastomosis type, intraoperative field magnification, and hepatic artery complications and how they were managed. All patients underwent ultrasound, anticoagulation consisted of 41 mg aspirin once a day, and 35 patients received alprostadil (PGE) for the first 7 days after transplantation. No patients were administered intravenous heparin following liver transplantation. RESULTS Of the 74 livers transplanted, 36 grafts (48.6%) were whole organ transplants and 38 grafts (51.4%) were partial livers. We observed HAT in 1 of 74 (1.35%) transplants in our pediatric liver transplant population. The only patient with HAT was a young girl with a history of biliary atresia. The occurrence of a hepatic artery thrombosis on day 7 was caused by the migration of an intimal plaque dissection within the artery graft. She was emergently taken back into the operating room for graft revision. This individual currently has a survival time of 426 days following her last transplant. CONCLUSIONS Hepatic artery thrombosis may be minimized in pediatric liver transplantation without the use of microsurgery. Anticoagulation utilizing ASA and alprostadil is sufficient to avoid HAT. Accurate use of ultrasound is crucial to avoid this complication. Graft and patient salvage is possible with expedient surgical treatment; microsurgery, anticoagulant therapy, site of arterial inflow, and recipient size and weight.

Peripheral eosinophilia and eosinophilic gastroenteritis after pediatric liver transplantation.

Abstract:  Reports indicate peripheral eosinophilia (PE) and gastrointestinal eosinophilic inflammation can occur after pediatric liver transplantation. The incidence of these conditions, potential risk factors, and the impact of PE and gastrointestinal eosinophilic inflammation on liver transplant outcome were determined in this pediatric liver transplant program. Medical records of liver transplant recipients from 1 to 97 and from 12 to 99 were reviewed. Fifty‐seven transplants on 54 patients were performed during the study period. Fifty‐three patients were evaluated; all had normal pre‐transplantation peripheral eosinophil counts. PE of >10% developed in 28% of patients. Using this definition, all such identified patients had absolute eosinophil counts of >350/mm3. History of immediate hypersensitivity did not differ between patients with or without eosinophilia. Gastrointestinal endoscopy and biopsy was performed in 23 patients with gastrointestinal complaints. Of those, six had eosinophilic gastroenteritis and all six had PE. Compared with patients without eosinophilia, those with PE were younger at the time of transplantation (p < 0.05), had more frequent rejection (p < 0.01), were more commonly managed with tacrolimus‐based immunosuppression (p < 0.001), and experienced more frequent episodes of detectable EBV viral load (p < 0.04). Patients with eosinophilic gastroenteritis were more frequently retransplanted (p < 0.006). PE associated with symptomatic eosinophilic gastroenteritis is common after pediatric liver transplantation. Age at transplant, frequency of rejection episodes, tacrolimus‐based immunosuppression, and EBV viral load may be associated with the development of this condition. There may be higher rates of graft loss in such patients. Whether innate immune responsiveness or an acquired immune dysregulation accounts for these findings merits further evaluation.

Incidence, impact, and treatment of portal and hepatic venous complications following pediatric liver transplantation: A single-center 12 year experience

Heffron TG, Pillen T, Smallwood G, Henry S, Sekar S, Casper K, Solis D, Tang W, Fasola C, Romero R. Incidence, impact, and treatment of portal and hepatic venous complications following pediatric liver transplantation: A single‐center 12 year experience.
Pediatr Transplantation 2010: 14:722–729.

Low incidence of hepatic artery thrombosis after pediatric liver transplantation without the use of intraoperative microscope or parenteral anticoagulation

Abstract:  The risk of hepatic artery thrombosis (HAT) after pediatric liver transplantation (PLT) has been reported to range from 0 to 25%. We report our experience focusing on the interrelationships between risk factors, surgical technique and the incidence of HAT after liver transplantation in the pediatric age group. From February 18, 1997 to December 31, 2003, 150 consecutive liver transplants were performed in 132 pediatric patients. There were similar numbers of whole grafts when compared with partial grafts, 80 (53.3%) vs. 70 (46.7%), p = 0.30. Four grafts (2.7%) developed HAT. Of the grafts with HAT, three were successfully revascularized within the first 24 h. Only one graft (0.66%) was lost to HAT. A single surgeon utilizing 3.5–6.0 magnification loupes performed all but one hepatic arterial anastomoses. All patients were followed postoperatively by a daily ultrasound protocol and with anticoagulation of aspirin and alprostadil only. Living and deceased donor left lateral segment grafts had an increased rate of HAT when compared with whole liver grafts. HAT with subsequent graft loss may be minimized in PLT with the use of surgical loupes only, anticoagulation utilizing aspirin, alprostadil, and daily ultrasounds.

Experience with protocol biopsies after solitary pancreas transplantation

The early detection of allograft rejection remains elusive after solitary pancreas transplantation (PTX). We have previously described a modified technique of cystoscopic transduodenal PTX biopsy using the Biopty gun under ultrasound guidance. During the last 2 years, we performed 24 solitary PTXs with prospective protocol biopsy monitoring as well as biopsies performed whenever clinically indicated. The study group included 17 pancreas transplants alone, 6 sequential pancreas after kidney transplants, and 1 sequential pancreas after liver transplant. Five patients received pancreas retransplants. A total of 92 cystoscopically directed core PTX biopsies were performed, including 50 protocol biopsies (mean 2.1 per patient). Protocol biopsies were performed at 1 month (19), 2 months (3), 3 months (20), 6 months (7), and 12 months (1) after PTX. Adequate PTX tissue for histopathologic examination was obtained in 49 cases (98%). Biopsy findings included no rejection (34), mild rejection (13), pancreatitis (1), and cytomegalovirus infection (1). Overall, 15 of the 49 evaluable biopsies (31%) had significant histopathologic findings. All but 1 of the cases of mild rejection were treated with bolus steroids. Eight of these patients subsequently developed recurrent biopsy-proven rejection within 2 months; 5 grafts were subsequently lost to rejection between 3 and 13 months after PTX. Three biopsy complications occurred: 1 hematoma, 1 pancreatitis, and 1 ileus. Patient survival is 96% and PTX graft survival (complete insulin independence) is 75% after a mean follow-up of 15 months. In the remaining 42 clinically indicated biopsies, 3 were insufficient, 8 showed no rejection, and 31 (79%) had rejection. In half of these cases, the rejection was graded as moderate to severe. In conclusion, prospective monitoring with protocol PTX biopsies may result in the earlier detection of allograft rejection and have a direct effect on improving results after solitary PTX.