Javier Bueno

Clinical intestinal transplantation: new perspectives and immunologic considerations.

Background: Although tacrolimus-based immunosuppression has made intestinal transplantation feasible, the risk of the requisite chronic high-dose treatment has inhibited the widespread use of these procedures. We have examined our 1990–1997 experience to determine whether immunomodulatory strategies to improve outlook could be added to drug treatment. Study Design: Ninety-eight consecutive patients (59 children, 39 adults) with a panoply of indications received 104 allografts under tacrolimus-based immunosuppression: intestine only (n = 37); liver and intestine (n = 50); or multivisceral (n = 17). Of the last 42 patients, 20 received unmodified adjunct donor bone marrow cells; the other 22 were contemporaneous control patients. Results: With a mean followup of 32 ± 26 months (range, 1–86 months), 12 recipients (3 intestine only, 9 composite grafts) are alive with good nutrition beyond the 5-year milestone. Forty-seven (48%) of the total group survive bearing grafts that provide full (91%) or partial (9%) nutrition. Actuarial patient survival at 1 and 5 years (72% and 48%, respectively) was similar with isolated intestinal and composite graft recipients, but the loss rate of grafts from rejection was highest with intestine alone. The best results were in patients between 2 and 18 years of age (68% at 5 years). Adjunct bone marrow did not significantly affect the incidence of graft rejection, B-cell lymphoma, or the rate or severity of graft-versus-host disease. Conclusions: These results demonstrate that longterm rehabilitation similar to that with the other kinds of organ allografts is achievable with all three kinds of intestinal transplant procedures, that the morbidity and mortality is still too high for their widespread application, and that the liver is significantly but marginally protective of concomitantly engrafted intestine. Although none of the endpoints were markedly altered by donor leukocyte augmentation (and chimerism) with bone marrow, establishment of the safety of this adjunct procedure opens the way to further immune modulation strategies that can be added to the augmentation protocol.The advent of tacrolimus allowed clinical intestinal transplantation to become a feasible procedure for patients with irreversible intestinal failure. Over last 5 years, 71 patients underwent intestinal transplantation. Forty-one recipients were children, and 30 recipients were adults. Twenty-five patients received an isolated intestinal graft, 34 patients received a combined liver-intestinal graft, and 12 received a multivisceral graft. The colon was included the intestinal graft in 29 patients. One-year, 2-year, and 4-year actuarial patient survival is 72%, 57%, and 45%, respectively. Our experience has shown that infectious, and immunological problems have caused significant morbidity and mortality. In this paper, we present our clinical experience and overview with intestinal transplantation.

Current status of intestinal transplantation in children

PURPOSE A clinical trial of intestinal transplantation (Itx) under tacrolimus and prednisone immunosuppression was initiated in June 1990 in children with irreversible intestinal failure and who were dependent on total parenteral nutrition (TPN). METHODS Fifty-five patients (28 girls, 27 boys) with a median age of 3.2 years (range, 0.5 to 18 years) received 58 intestinal transplants that included isolated small bowel (SB) (n = 17), liver SB (LSB) (n=33), and multivisceral (MV) (n=8) allografts. Nine patients also received bone marrow infusion, and there were 20 colonic allografts. Azathioprine, cyclophosphamide, or mycophenolate mofetil were used in different phases of the series. Indications for Itx included: gastroschisis (n=14), volvulus (n=13), necrotizing enterocolitis (n=6), intestinal atresia (n=8), chronic intestinal pseudoobstruction (n=5), Hirschsprungs disease (n=4), microvillus inclusion disease (n=3), multiple polyposis (n=1), and trauma [n=1). RESULTS Currently, 30 patients are alive (patient survival, 55%; graft survival, 52%). Twenty-nine children with functioning grafts are living at home and off TPN, with a mean follow-up of 962 (range, 75 to 2,424) days. Immunologic complications have included liver allograft rejection (n=18), intestinal allograft rejection (n=52), posttransplant lymphoproliferative disease (n=16), cytomegalovirus (n=16) and graft-versus-host disease (n=4). A combination of associated complications included intestinal perforation (n=4), biliary leak (n=3), bile duct stenosis (n=1), intestinal leak (n=6), dehiscence with evisceration (n=4), hepatic artery thrombosis (n=3), bleeding (n=9), portal vein stenosis (n=1), intraabdominal abscess (n=11), and chylous ascites (n=4). Graft loss occurred as a result of rejection (n=8), infection (n=12), technical complications (n=8), and complications of TPN after graft removal (n=3). There were four retransplants (SB, n=1; LSB n=3). CONCLUSIONS Intestinal transplantation is a valid therapeutic option for patients with intestinal failure suffering complications of TPN. The complex clinical and immunologic course of these patients is reflected in a higher complication rate as well as patient and graft loss than seen after heart, liver, and kidney transplantation, although better than after lung transplantation.

Logistics and Technique for Procurement of Intestinal, Pancreatic, and Hepatic Grafts From the Same Donor

ObjectiveTo assess a technique for simultaneous recovery of the intestine, pancreas, and liver from the same donor. Summary Background DataWith the more frequent use of pancreatic and intestinal transplantation, a procurement procedure is needed that permits retrieval of both organs as well as the liver from the same cadaveric donor for transplantation to different recipients. It is believed by many procurement officers and surgeons, however, that this objective is not technically feasible. MethodsA technique for simultaneous recovery of the intestine, pancreas, and liver was used in 13 multiorgan cadaver donors during a 26-month period, with transplantation of the organs to 33 recipients. The intestine was removed from 11 donors separately and in continuity with the pancreas in the other 2. Six additional pancreases were excised and transplanted separately. Thirteen livers were retrieved, one of which was discarded because of steahorrhea. Ten of the remaining 12 livers were transplanted intact; the other 2 were split in situ and used as reduced-size hepatic allografts in four recipients. ResultsNone of the 11 intestinal, 6 pancreatic, 2 intestinal–pancreatic, or 14 whole or partial liver allografts sustained serious ischemic injury or were lost as a result of technical complications. One liver recipient died 25 months after surgery of recurrent C virus hepatitis. The other 32 recipients had adequate allograft function with a mean follow-up of 8 months. ConclusionIt was possible using the described technique to retrieve intestine, pancreas, and liver allografts safely from the same donor and to transplant these organs to different recipients.

Hepatic hemangioendothelioma: Clinical experience and management strategy

PURPOSE This study sought to define management strategies based on clinical experience in treating infantile hepatic hemangioendothelioma. METHODS A retrospective analysis of patients with hemangioendothelioma presenting to a tertiary liver transplantation center between 1989 and 1997 was performed. RESULTS Thirteen patients (median age, 14 days) with hemangioendothelioma were identified. Congestive heart failure (P<.03) and abdominal mass (P<.081) were predictive of 5-month mortality rates. Ultrasonography and computerized axial tomography were the diagnostic modalities most commonly used. Treatment strategies consisted of medical management (steroids and alpha-interferon) and interventional modalities (hepatic artery ligation or embolization, resectional surgery, or orthotopic liver transplantation). Patients who underwent resectional surgery, with or without orthotopic liver transplantation, had a lower 5-month mortality rate (P<.02) and a greater 2-year survival rate (P<.003) than did those who underwent hepatic artery ligation or embolization. Early morbidity and mortality tended to be a consequence of the primary lesion, whereas late morbidity and mortality were reflective of the treatment modality used. CONCLUSIONS In cases of failed medical management, resectional therapy should be used when possible. If partial hepatectomy is not technically achievable, hepatic artery embolization should be used either as definitive therapy or as a temporizing measure until orthotopic liver transplantation is possible.

Epstein-Barr virus infections in children after transplantation of the small intestine

Epstein-Barr virus (EBV) infection in association with immunosuppressive drugs used for solid organ transplantation can produce a spectrum of illnesses. Forty-one children who ranged in age from 6 months to 18.5 years received small intestinal transplants alone or in combination with other organs while undergoing primary tacrolimus (FK506) immunosuppression between July 1990 and June 1995. We reviewed hematoxylin and eosin-stained sections from all biopsy, surgical, and autopsy material from these children to determine the incidence and morphology of EBV-associated disease. Nuclear staining with in situ hybridization for EBV early RNA transcript (EBER) using the EBER-1 probe confirmed the presence of EBV. The EBV lymphoproliferations were graded as 1 to 4 according to histopathology and EBV quantitation determined in the area of greatest positivity. Twenty-one patients (51%) had EBV documented histologically on one or more occasions; only 8 (38%) are alive; 5 of these had the highest grade of 2. Posttransplant lymphoproliferative disease (PTLD) developed in 13 patients. Three of 10 patients (30%) with grade 3 lesions (polymorphous PTLD) are alive with intermittent evidence of EBV infection; 6 died with PTLD. Monomorphic PTLD (grade 4) was the cause of death in the three additional patients. Thirteen of 20 patients (65%) with no histologic evidence of EBV are alive. The incidence of EBV infection in pediatric small intestinal transplant recipients is higher than reported for any other solid organ cohort. With the aid of frequent EBER staining we were able to diagnose EBV infections in 51% of 41 patients; PTLD (grade 3 or 4) developed in 32% of these children. Low-grade EBV infections often preceded the development of PTLD and were identified in gastrointestinal biopsy samples from patients with concurrent PTLD; however, results of gastrointestinal biopsy samples may be negative for EBV in some patients with PTLD and, thus, underestimate systemic EBV-associated lymphoproliferations. Rejection and EBV infection can occur simultaneously, therefore, attention to low-grade infection may be useful to patient management.

Predictive negative value of persistent low Epstein-Barr virus viral load after intestinal transplantation in children.

Background. The correlation between an elevated Epstein-Barr virus(EBV) viral load in the peripheral blood and the subsequent development of EBV-associated posttransplant lymphoproliferative disease (PTLD) is the basis for strategies using serial measurements of the EBV viral load to guide preemptive therapy (PT). Neither the frequency, duration of monitoring, nor the predictive negative value of viral load monitoring for asymptomatic patients with persistent low or nondetectable viral loads against the development of PTLD has been established. Methods. Since April 1994, children undergoing intestinal transplantation (ITx) underwent serial monitoring of the EBV viral load in their peripheral blood using a quantitative competitive EBV polymerase chain reaction assay (PCR). Samples were obtained every 2 weeks for the first 3 months and then every 1–3 months depending on the patients clinical condition. EBV viral loads ≥40 (for patients who were EBV seronegative pre-ITx) and≥200 (for those who were seropositive) genome copies/105 peripheral blood lymphocytes were felt to identify patients at increased risk for PTLD and generally prompted PT. Results. A total of 30 ITx recipients were compliant with our monitoring protocol; 23/30 are alive 6–59 months post-ITx. A total of 12/30 never had a viral load >40 and did not receive PT. In contrast, 18/30 had ≥1 high viral load (≥200); the first high viral load was measured a median of 59 days post-ITx (range 1–440). A late rise (>6 months post-ITx) was seen in only 2/18 children. A total of 0/12 patients with persistently low viral loads received PT and none developed PTLD. In contrast, 5/18 with ≥1 one high viral load (including 2/14 who received and 3/4 who did not receive PT) developed PTLD. All five children with PTLD were EBV seropositive pre-ITx and experienced their first high EBV PCR within the first 3 months after ITx. Conclusions. The predictive negative value of persistently low or nondetectable EBV viral loads was 100% in this study. Patients with nondetectable or low viral loads for the first 6 months after ITx did not develop PTLD regardless of their pretransplant EBV serological status. The frequency of viral load monitoring can be safely decreased for patients whose viral loads remain low for the first 6 months ITx.

Intestinal transplantation in children with chronic intestinal pseudo-obstruction

BACKGROUND Children with chronic intestinal pseudo-obstruction (CIPO) often require total parenteral nutrition (TPN) which puts them at risk of liver failure and recurrent line infections. Intestinal transplantation has become a therapeutic option for TPN dependent children with intestinal failure who are failing management with TPN. AIMS To investigate the outcome of children with CIPO referred for intestinal transplantation. METHODS A retrospective review was carried out of records and diagnostic studies from 27 patients with CIPO referred for intestinal transplantation. RESULTS Five children were not listed for transplantation: two because of parental decision, two because of suspicion of Munchausen syndrome by proxy, and one because he tolerated enteral nutrition. Six are still TPN dependent and awaiting transplantation. Eight children died awaiting transplantation. Eight children underwent transplantation. Three died (two months, seven months, and four years after transplant). Five children are alive with a median follow up of 2.6 years (range two months to six years). All transplanted children were able to tolerate full enteral feedings. The postoperative course was complicated by dumping syndrome, Munchausen syndrome by proxy, narcotic withdrawal, and uncovering of achalasia.Conclusion—Intestinal transplantation may be a life saving procedure in children with CIPO. Early referral and thorough pretransplant evaluation are keys to successful transplantation.

Current Management Strategies for the Prevention and Treatment of Cytomegalovirus Infection in Pediatric Transplant Recipients

Cytomegalovirus (CMV) is a significant cause of morbidity and mortality following transplantation, especially in the pediatric population, who remain at high risk of primary infection. The availability of effective antiviral therapy has led to dramatic improvements in the outcome of CMV infection in patients undergoing transplantation. In recent years, three major strategies have been developed for the prevention of CMV disease in this population: (i) reduction of risk of viral acquisition or reactivation by management of risk factors; (ii) prophylaxis of all ‘at-risk’ patients using prophylactic strategies for a defined period of time, initiated at or near the time of transplant; and (iii) pre-emptive treatment with ganciclovir of selected ‘at-risk’ patients, guided by either laboratory markers indicative of subclinical infection or the presence of specific risk factors.In general, well designed comparative studies of one or more antiviral agents for the prevention of CMV have not been carried out. While ganciclovir appears to be more effective than aciclovir, its tolerability profile is less optimal. The use of foscarnet avoids myelosuppresions, but is associated with significant nephrotoxicity. Its use should be reserved for patients unable to tolerate ganciclovir or with ganciclovir-resistant CMV disease. Similar to foscarnet, the high frequency of nephrotoxicity associated with the use of cidofovir limits its use to clinical scenarios suggestive of ganciclovir resistance. Newer options, such as valaciclovir and valganciclovir, are currently under investigation and preliminary experience has been promising. Finally, passive immunoprophylaxis has been shown to prevent CMV disease after solid organ transplantation, but its use in bone marrow transplantation is controversial.Essentially, pre-emptive strategies have relied on the quantitation in the peripheral blood of CMV phosphoprotein pp65 antigen and/or the polymerase chain reaction assay. Strict guidelines for the use of those assays as a guide to pre-emptive therapy have not been standardized. Prospective trials comparing pre-emptive therapy using either intravenous or oral ganciclovir, and now oral valganciclovir or valaciclovir, are necessary to determine the relative cost effectiveness and efficacy of these alternative strategies. Finally, it remains controversial as to whether prophylaxis or pre-emptive therapy is the optimal strategy for preventing CMV disease. While a growing body of literature describes these approaches in adult transplant recipients, published experience in children has been much more limited.

Cytomegalovirus infection after intestinal transplantation in children.

Sixteen episodes of cytomegalovirus (CMV) disease occurred in 10 of 41 children undergoing intestinal transplantation from 1990 to 1995. Stratification of CMV disease by donor (D)/recipient (R) serological status was as follows: 3 of 8, D+/R-; 3 of 9, D+/R+; 4 of 9, D-/R+; and 0 of 15, D-/R-. Treatment resulted in resolution of CMV disease in 93.3% of episodes. No deaths attributable to CMV disease occurred in this series. CMV in D+/R- children resulted in more extensive and persistent disease. However, patient and graft survival rates were similar in the different D/R subgroups and between children with and without CMV disease. Cumulative dose of steroid boluses (relative risk [RR], 1.59; 95% confidence interval [CI], 1.14-2.21) and history of steroid recycles (RR, 2.72; 95% CI, 1.21-6.13) were associated with CMV disease. These results suggest that although CMV-associated morbidity in pediatric intestinal transplant recipients was substantial, it was not associated with an increased rate of mortality or graft loss, even among high-risk D+/R- patients.

Reduced-size orthotopic composite liver-intestinal allograft

A composite graft consisting of a reduced left lateral hepatic segment in continuity with the small intestine was procured from an adult cadaveric donor using a modified in situ split technique. The primary recipient was a 3-year-old boy with hepatointestinal failure. The right side of the liver was transplanted into a 63-year-old man with a central hepatoma and hepatitis C cirrhosis. This was accomplished with center-to-center sharing of the liver portion of the allograft. The in situ split technique was feasible, with good initial allograft function. However, both grafts failed subsequently because of peri-operative recipient-related complications. The adult patient died of an infected pseudoaneurysm of the arterial graft, and the pediatric patient required repeat transplantation as a result of the late diagnosis of a native pancreatic fistula with cholestatic damage to the reduced liver allograft. The child is currently alive 8 months after repeat transplantation.