Jean-Pierre Cezard

Efficacy and tolerance of infliximab in children and adolescents with Crohn's disease.

Infliximab, a monoclonal antibody against tumor necrosis factor-alpha, has been shown to be effective for the treatment of refractory Crohn’s disease in adult patients, but experience in pediatrics is limited. This retrospective study included 88 children and adolescents, 39 girls and 49 boys, with a median age of 14 years (range 3.3–17.9). Infliximab was indicated for active disease (66%) and/or fistulas (42%) that were refractory to corticosteroids (70%), and/or other immunosuppressive (82%) agents, and/or parenteral nutrition (20%). Patients received 1 to 17 infusions (median 4) of 5 mg/kg (range 3.8–7.3) of infliximab during a median time period of 4 months (1–17 months). Infusion reaction was noted in 13 patients (15%), with a total of 16 reactions in 450 infusions (4%). At Day 90 after the first infusion of infliximab, symptoms improved in 49% of patients, whereas 29% of patients were in remission and 13% of patients relapsed. From Day 0 to Day 90, Harvey–Bradshaw score decreased from 7.5 to 2.8 (P < 0.001), C-reactive protein from 36 to 16 mg/L (P < 0.01), and 1-hour erythrocyte sedimentation rate from 35 to 17 mm (P < 0.01). Dosage of corticosteroids decreased from to 0.59 to 0.17 mg/kg/d (P < 0.001); 53% of patients could be weaned of corticosteroids and 92% of parenteral nutrition. Treatment with infliximab is well tolerated and effective in most children and adolescents with Crohn’s disease that is refractory to conventional immunosuppressive therapy. Nevertheless, long-term efficacy remains to be shown, and further studies are urgently needed to precisely determine the best modality of continuing treatment.

Further delineation of the congenital form of X-linked dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome)

Hoyeraal-Hreidarsson syndrome represents a severe variant of dyskeratosis congenita (Zinsser-Cole-Engman syndrome). This X-linked recessive, progressive, multisystemic disorder reported so far in 12 pedigrees is characterised by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, mental retardation, progressive combined immune deficiency and aplastic anaemia. Mutations in the DKC1gene on Xq28 have been identified in the X-linked form of dyskeratosis congenita and in some Hoyeraal-Hreidarsson syndrome patients. We report on two sibs and two other unrelated patients with the striking clinical features of Hoyeraal-Hreidarsson syndrome. Noticeably, all four had early digestive problems, with chronic, bloody diarrhoea and feeding problems causing one of the most difficult problems in the supportive treatment of this uniformly lethal condition. Pathological changes in the proliferative compartment of the digestive mucosa included alterations of the glandular architecture and focal rarefaction of the glands. This aspect seems consistent with altered telomerase function associated with a dyskerin mutation which may decrease the proliferative capacity of digestive epithelial cells. A missense mutation 146 C→T (Thr49Met) in the DKC1gene was found in two unrelated patients, whereas mutation screening was negative for one single case. The absence of mutations of the DKC1gene in patients with Hoyeraal-Hreidarsson syndrome emphasises the probable implication of one or more other loci.

Up-to-date evolution of small bowel transplantation in children with intestinal failure

PURPOSEnThe aim of the authors was to report an up-to-date review of their experience with 26 intestinal transplantations in children since 1987.nnnMETHODSnA retrospective study was conducted of 26 patients with a mean age of 5 years (range, 0.3 to 14 years). Three groups were isolated. In group A (1987 to 1990), seven patients received nine isolated intestinal transplants for short bowel syndrome. Immunosuppression therapy consisted of cyclosporine, aziathioprine, and corticosteroids. In group B (1994-current), nine patients received nine isolated intestinal transplants for short bowel syndrom (n = 2), intestinal pseudoobstruction (n = 2), neonatal intractable diarrhea (n = 3), and Hirschsprung disease (n = 1); hepatic biopsy results showed weak cholestasis or fibrosis. In group C (1994-current), 10 patients received 10 combined liver-small bowel transplants for short bowel syndrome (n = 3), neonatal intractable diarrhea (n = 4), and Hirschsprung disease (n = 3); hepatic cirrhosis related to total parenteral nutrition (TPN) was shown in all cases. Groups B and C received immunosupressive treatment consisting of tacrolimus, aziathioprine, and corticosteroids. Posttransplant follow-up included intestinal biopsies of the small bowel twice a week and more frequently or combined with liver biopsy if rejection was suspected.nnnRESULTSnOverall patient survival (PS) and graft survival (GS) are 61% (16 of 26) and 50% (13 of 26), respectively. In group A, severe intestinal allograft rejection occurred in six patients leading to graft removal (GS, 11%). Five patients died of TPN complications after graft removal (PS, 28%). One survivor is off TPN, and one currently is waiting for a second graft. In group B, six patients survived (PS, 66%). Causes of death include hepatic failure (n = 1), renal and liver failure (n = 1), and systemic infection (n = 1). Severe intestinal allograft rejection occurred in five patients, which neccessitated aggressive immunosuppression (antilymphocyte serum) leading to an incomplete functional recovery of the graft. Only two patients currently are off TPN. In group C, eight patients survived (PS, 80%) all of which are currently off TPN. One patient died during the procedure, and one died of severe systemic infection. Intestinal graft rejection occurred in six patients; rejection of the liver allograft occurred in five patients, yet all rejections were weak and successfully treated by corticosteroids (GS, 80%).nnnCONCLUSIONSnIntestinal transplantation is a valid therapeutic option for children with definitive intestinal failure and not only for short bowel syndrome. Tacrolimus improves graft and patient survival (group A v group B). The lower severity of graft rejection in combined liver-small bowel transplantation improves functional results of intestinal transplantation in children without additional mortality or morbidity (group B vgroup C).

Small Bowel Transplantation Alone or With the Liver in Children: Changes by Using FK506

AFTER the successful results of experimental studies using cyclosporine A (CsA) in animals, we started small bowel transplantation (SBTx) in pediatric patients 10 years ago. During the period from 1987 to 1990, nine isolated SBTx have been performed in seven children aged 5 months to 9 years with short bowel syndrome. CsA was used as the main immunosuppressive agent associated with methylprednisolone and antilymphoglobulines. Two graft underwent early failure (1 death); five grafts were removed within 2 months after transplantation for uncontrolled acute graft rejection. One patient died after 6 months from sepsis and multiorgan failure. Two additional grafts were removed 6 and 17 months after transplantation for chronic rejection. Finally, only the youngest recipient having received a small bowel graft from ananencephalic neonate remains with a functioning graft 9 years later. She is enjoying normal life at home, free of TPN, growing normally. She is the longest isolated small bowel survival worldwide. Her current immunosuppression includes low doses of steroids and Neoral. Of the four patients who have survived after graft removal, three died within 2 years with end-stage liver cirrhosis. The last one is currently on long-term home parenteral nutrition (PN) waiting for isolated small bowel retransplantation.

Centrilobular necrosis in children after combined liver and small bowel transplantation.

BACKGROUNDnCentrilobular necrosis is not an uncommon finding after isolated liver transplantation. In this study, we sought to describe hepatic centrilobular necrosis in children after combined liver and small bowel transplantation (LSBT), and to assess the predictive factors, possible causes, and prognosis.nnnMETHODSnSix children aged 4 to 11 years, in whom liver biopsy showed centrilobular necrosis at least once, 3 weeks to 2 years after LSBT, were compared with nine children without this pathology. All six children experienced an acute complication in the few weeks preceding the finding of centrilobular necrosis. In addition, one child had an early arterial thrombosis and one, severe colitis 3 years after LSBT.nnnRESULTSnCentrilobular necrosis was associated with centrilobular swelling, dropout, endotheliitis, and inflammation. Fibrosis developed early and worsened on follow-up biopsy in three children. Portal symptoms of acute rejection were not constant, and there was no ductopenia. Biologic abnormalities were responsive to increased immunosuppression, including mycophenolate in four cases. However, follow-up biopsies showed persistent lesions in five patients, mildly inflammatory in four. Baseline immunosuppression had to be maintained at high levels. No viral infections, vascular compromise (except in one), and autoimmunity were found. We compared the two groups of children for initial diagnosis, age at transplantation, time receiving parenteral nutrition, ischemic time, presence of an associated transplanted colon, number of reoperations and infections, intestinal rejection, and immunosuppression, and found no differences.nnnCONCLUSIONSnThis severe manifestation of chronic liver rejection occurred despite the heavy immunosuppression needed for LSBT. The previous acute clinical event could have triggered rejection by modifying the effective immunosuppression at the tissue level. Despite high baseline immunosuppression, histologic lesions persisted and significant fibrosis developed in half the children. We speculate that the lack of induction of tolerance in this particular setting of LSBT could be responsible for constant immune stimulation, thus chronic rejection. The optimal protocol of immunosuppression has yet to be defined to avoid this complication.

Intestinal Transplantation in Children: Experience of a Single Center in Paris

Intestinal transplantation (ITx) has become an alternative for patients with permanent intestinal failure who are dependent on parenteral nutrition (PN) [1], Our center has been involved in the management of pediatric patients with intestinal failure for a long time. After developing a home PN program [2, 3], we started ITx in 1987 using cyclosporine [4]. One of our earliest patients still survives with a fully functioning graft 12 years later [5]. With the development of FK506 (tacrolimus) in the early 1990s [6], we restarted our ITx program. We now report the results of the largest current European series of consecutive intestinal transplantations in pediatric patients at the Necker-Enfants Malades University Hospital in Paris.