Clinical intestinal transplantation: a decade of experience at a single center.

OBJECTIVE: To assess the long-term efficacy of intestinal transplantation under tacrolimus-based immunosuppression and the therapeutic benefit of newly developed adjunct immunosuppressants and management strategies. SUMMARY BACKGROUND DATA: With the advent of tacrolimus in 1990, transplantation of the intestine began to emerge as therapy for intestinal failure. However, a high risk of rejection, with the consequent need for acute and chronic high-dose immunosuppression, has inhibited its widespread application. METHODS: During an 11-year period, divided into two segments by a 1-year moratorium in 1994, 155 patients received 165 intestinal allografts under immunosuppression based on tacrolimus and prednisone: 65 intestine alone, 75 liver and intestine, and 25 multivisceral. For the transplantations since the moratorium (n = 99), an adjunct immunosuppressant (cyclophosphamide or daclizumab) was used for 74 transplantations, adjunct donor bone marrow was given in 39, and the intestine of 11 allografts was irradiated with a single dose of 750 cGy. RESULTS: The actuarial survival rate for the total population was 75% at 1 year, 54% at 5 years, and 42% at 10 years. Recipients of liver plus intestine had the best long-term prognosis and the lowest risk of graft loss from rejection (P =.001). Since 1994, survival rates have improved. Techniques for early detection of Epstein-Barr and cytomegaloviral infections, bone marrow augmentation, the adjunct use of the interleukin-2 antagonist daclizumab, and most recently allograft irradiation may have contributed to the better results. CONCLUSION: The survival rates after intestinal transplantation have cumulatively improved during the past decade. With the management strategies currently under evaluation, intestinal transplant procedures have the potential to become the standard of care for patients with end-stage intestinal failure.

Clofazimine enteropathy in a pediatric bone marrow transplant recipient.

Clofazimine, previously used in the treatment of leprosy, is now used for treatment of Mycobacterium avium complex infection in patients with acquired immune deficiency syndrome, dermatologic disorders, and graft-versus-host disease. An 11-year-old boy developed a severe enteropathy 2 years after initiation of clofazimine treatment for graft-versus-host disease. Clofazimine enteropathy caused by crystal deposition can be life-threatening.

Linear ablation using an irrigated electrode electrophysiologic and histologic lesion evolution comparison with ablation utilizing a non-irrigated electrode.

OBJECTIVES: To characterize the electrophysiologic and histologic sequelae of linear atrial ablation utilizing an irrigated electrode. To compare "irrigated" lesions with lesions deployed using the same electrode in a non-irrigated mode. BACKGROUND: Previous reports of radiofrequency catheter ablation using an irrigated electrode have emphasized its favorable effect on lesion depth. We hypothesized that electrode irrigation would also benefit linear ablation of smooth atrial myocardium, a relatively superficial target. METHODS: In healthy pigs, lesions were deployed in the right and left atria. Acutely, lesions resulting from ablation using an irrigated electrode, with radiofrequency energy titration guided by electrogram amplitude reduction, were compared to lesions using the same electrode without irrigation, with energy titration guided by electrode thermometry. Irrigated lesions were also assessed serially. RESULTS: Acutely, irrigated lesions formed complete conduction barriers and were uncomplicated. In contrast, non-irrigated lesions formed complete conduction barriers but were frequently complicated, exhibiting endocardial charring, barotrauma, and pericardial damage. The rate and pattern of histologic evolution of irrigated lesions were uniform throughout each lesion; right and left atrial lesions healed similarly. During healing, 90 % of lesions remained complete conduction barriers and 10 % manifested single discrete conduction gaps where viable appearing myocytes bridged the lesion. CONCLUSIONS: Complete, uncomplicated linear lesions could be reliably deployed in either atrium with an irrigated electrode. Not all lesions remained complete barriers to conduction during their histologic evolution. Lesions deployed with the same electrode in a non-irrigated mode were complete but frequently complicated.

Enteric adenovirus infection in pediatric small bowel transplant recipients.

Three of 70 small bowel transplant recipients were diagnosed with adenovirus enteritis. The biopsies were performed for surveillance in one patient at 2.7 years after transplantation and in two symptomatic children 1.5 years and 4.5 months after transplantation. In all three patients the characteristic epithelial changes were not noted by the primary observers. Two biopsies had been called "suggestive of acute rejection" and both patients had been so treated. One biopsy had been diagnosed as "regenerative". Once the epithelial changes were recognized as being viral, confirmation was possible by stool culture in one patient, immunohistochemistry in two patients, or by lift technique of the H&E sections for electron microscopy. The immune suppression was reduced and none of the patients developed disseminated infection. As in other transplanted organs, such as lung and liver, adenovirus infection may be limited largely to the allograft but can be destructive. Early recognition of the characteristic changes that are illustrated can lead to confirmation of the virus and appropriate reduction of immune suppression. A mistaken diagnosis of rejection and augmentation of immune suppression can lead to viral dissemination and potential fatality.

Long term management of liver transplant rejection in children.

The current management of hepatic allograft rejection after liver transplantation in children requires effective baseline immunosuppression to prevent rejection and rapid diagnosis and treatment to manage acute rejection episodes. The subsequent impact on chronic rejection is dependent on the combination of adequate prevention and the treatment of acute rejection. Tacrolimus is a macrolide lactone that inhibits the signal transduction of interleukin-2 (IL-2) via calcineurin inhibition. Introduced in 1989, tacrolimus was first used in the salvage of refractory acute or chronic rejection under cyclosporin or to rescue patients with significant cyclosporin-related complications. The majority of paediatric transplant centres use a combination of steroids with tacrolimus as a basic immunosuppressant regimen following paediatric liver transplantation. This combination has allowed the acute cellular rejection-free rate to increase to between 30 and 60%, while lowering the rate of refractory rejection to less than 5%. Corticosteroid-resistant rejection is commonly treated with monoclonal (muromonab CD3) or polyclonal preparations. Although most episodes of acute cellular rejection occur during the first 6 weeks after liver transplant, the appearance of late acute liver allograft rejection must raise the question of noncompliance, especially in the adolescent population. Chronic rejection is becoming increasingly rare under tacrolimus-based immunosuppression. Tacrolimus is effective in reversing refractory acute cellular rejection or early chronic rejection in patients initially treated with cyclosporin-based regimens. Patients with a history of noncompliance as well as children with autoimmune liver disease are at risk of chronic rejection. Retransplantation therapy for chronic rejection has, fortunately, become more rare in the tacrolimus era with only 3% of retransplants being performed for this indication. Newer immunosuppressive agents are further modifying the long term management of liver allograft rejection. These include mycophenolate mofetil, rapamycin and IL-2 antibodies such as daclizumab. The development of these agents is allowing patient-specific immunosuppressive management to minimise rejection as well as the complications related to immunosuppression.

Hemophagocytic syndrome presenting as acute hepatic failure in two infants: clinical overlap with neonatal hemochromatosis.

Two patients with hemophagocytic lymphohistiocytosis who presented with acute liver failure are reported. Both presented with fever, hepatosplenomegaly, markedly elevated liver function tests, abnormal coagulation profiles, and an increase in serum ferritin. Both infants were diagnosed with neonatal hemochromatosis based on a clinical picture of hepatic insufficiency with hyperferritinemia and were referred for liver transplantation. The first patient died of liver failure and septicemia before transplantation. Review of autopsy material revealed a hepatitis-like pattern and extensive infiltration of liver and other organs including bone marrow by histiocytes, some of which were hemophagocytic. The second patient underwent liver transplantation but died 44 days thereafter from progressive hemophagocytic lymphohistiocytosis. Examination of the resected liver demonstrated a hepatitis-like pattern, proliferation of histiocytes, and hemophagocytosis, and the bone marrow revealed hemophagocytic histiocytosis. Hemophagocytosis recurred in the allograft. Hepatic manifestations are common in hemophagocytic lymphohistiocytosis and overt hepatic failure may occur, but initial presentation as fulminant hepatic failure is not well recognized. Elevated serum ferritin can make the distinction from neonatal hemochromatosis and other forms of neonatal liver failure difficult. Hemophagocytic lymphohistiocytosis should be considered in the differential diagnosis of neonatal liver disease, especially when it is accompanied by cytopenias.

Immunoglobulin A supplementation abrogates bacterial translocation and preserves the architecture of the intestinal epithelium.

BACKGROUND: Breast milk has been shown to prevent gut-origin infections in neonates through undefined mechanisms. Putative protective factors in breast milk include immunoglobulin (Ig)A, IgG, and lactoferrin. We examined their role in bacterial translocation in neonatal rabbits. METHODS: IgA, IgG, and lactoferrin were isolated from rabbit breast milk through gel filtration and ion-exchange chromatography. Neonates were randomized to receive breast milk, formula alone, or formula supplemented with IgA, IgG, or lactoferrin. Quantitative cultures were performed on day 7 for bacterial translocation. Hematoxylin-eosin-stained sections of distal ileum were examined by light microscopy. Transmucosal bacterial passage was determined in vitro, and the ileal mucosal membranes were examined by confocal microscopy. RESULTS: IgA supplementation abrogated bacterial translocation. IgG and lactoferrin had no significant effect. Neonates that received IgA or breast milk gained more weight than those in the other groups. IgA reduced transmucosal bacterial passage in vitro. In contrast to the normal-appearing distal ileum of neonates fed breast milk, intestinal epithelium from neonates that received formula or formula with IgG or IgA demonstrated prominent vacuoles by light microscopy. Those fed formula alone or formula with lactoferrin had slightly shortened villi. CONCLUSIONS: IgA supplementation prevents bacterial translocation by enhancing gut mucosal barrier function.