Stuart S. Kaufman

Influence of bacterial overgrowth and intestinal inflammation on duration of parenteral nutrition in children with short bowel syndrome

OBJECTIVES Massive intestinal resection results in short bowel syndrome and necessitates prolonged parenteral feeding. The purpose of this work was to assess the impact of late complications of short bowel syndrome, including intestinal bacterial overgrowth and enterocolitis, on the duration of parenteral nutrition (PN) in comparison with factors evident in the neonatal period. METHODS Retrospective chart review. RESULTS Of 49 children, 42 were weaned from parenteral nutrition after a treatment course of 17 +/- 14 months. In these 42, postresection small intestinal length equaled 81 +/- 65 cm; 45% had an ileocecal valve. Small intestinal length in the seven children who were PN dependent was 31 +/- 30 cm (p < 0.05); none had an ileocecal valve (p < 0.05). Bacterial overgrowth occurred in all seven PN-dependent children and in 23 of 42 children eventually weaned from PN (p < 0.05). When bacterial overgrowth was identified before weaning (n = 12), the duration pf PN was 28 +/- 17 months, but when bacterial overgrowth was first identified only after weaning (n = 11), the duration of PN was 16 +/- 13 months (p < 0.05). Small intestinal inflammation correlated with bacterial overgrowth (r = 0.69). Those children with severe enteritis identified before weaning remained on the PN regimen for 36 +/- 15 months, in comparison with 21 +/- 14 months in those with mild enteritis and 13 +/- 11 months in those without inflammation (p < 0.02). CONCLUSIONS Although the length of small intestine remaining after resection is the best immediate predictor of final success in terminating PN in children with short bowel syndrome, PN is prolonged by bacterial overgrowth and associated enteritis in those who will ultimately be weaned.

Treatment strategies for small bowel bacterial overgrowth in short bowel syndrome

BACKGROUND Small bowel bacterial overgrowth is a common complication of short bowel syndrome, and although it is often controlled with antimicrobial therapy, alternative strategies may occasionally be needed. METHODS Six patients with bacterial overgrowth are described, who did not respond to antimicrobial therapy and required additional medical or surgical measures to control the overgrowth. RESULTS Recalcitrant bacterial overgrowth was successfully treated with periodic small bowel irrigation with a balanced hypertonic electrolyte solution, colonic flushes, encouraging frequent stooling, intestinal lengthening procedure, or probiotic therapy with Lactobacillus plantarum 299V and Lactobacillus GG. CONCLUSIONS Small bowel bacterial overgrowth should be aggressively evaluated in patients with short bowel syndrome who are not progressing in a normal manner. Inadequate or incomplete response to antibiotic therapy is common, and several additional treatment possibilities are available.

Isolated intestinal transplantation for intestinal failure

OBJECTIVE:Parenteral nutrition sustains life in patients with intestinal failure. However, some experience life-threatening complications from parenteral nutrition, and in these individuals intestinal transplantation may be lifesaving.METHODS:This is a retrospective review of 28 consecutive isolated small bowel transplants performed in eight adults and 20 children between December 1993 and June 1998 at the University of Nebraska Medical Center.RESULTS:The 1-yr patient and graft survivals were 93% and 71%, respectively. The causes of graft loss were hyperacute rejection (n = 1), acute rejection (n = 5), vascular thrombosis (n = 1), and patient death (n = 1). The median length of time required until full enteral nutrition was 27 days. All 28 patients have experienced acute rejection of their small bowel grafts and rejection led to graft failure in five. Jaundice and/or hepatic fibrosis was present preoperatively in 17 of the 28 recipients and hyperbilirubinemia was completely reversed in all patients with functional grafts within 4 months of transplantation. Three patients developed posttransplant lymphoproliferative disease (11%). Three recipients developed cytomegalovirus enteritis and all were successfully treated.CONCLUSIONS:Patient survival after intestinal transplantation is comparable to parenteral nutrition for patients with intestinal failure. Better immunosuppressive regimens are needed to decrease the risk of graft loss from acute rejection. The incidence of posttransplant lymphoproliferative disorder is higher after intestinal transplantation than after other solid organ transplants and the risk of cytomegalovirus enteritis is low with the use of cytomegalovirus seronegative donors. Liver dysfunction in the absence of established cirrhosis can be reversed.

Intolerance to protein hydrolysate infant formulas:: An underrecognized cause of gastrointestinal symptoms in infants

The purpose of this study was to determine the effectiveness of an amino acid-based infant formula in infants with continued symptoms suggestive of formula protein intolerance while they were receiving casein hydrolysate formula (CHF). Twenty-eight infants, 22 to 173 days of age, were enrolled; each had received CHF for an average of 40 days (10 to 173 days) and continued to have bloody stools, vomiting, diarrhea, irritability, or failure to gain weight, or a combination of these symptoms. Sigmoidoscopy with rectal biopsy was performed in all infants. The infants then received an amino acid-based infant formula, Neocate, for 2 weeks. After 2 weeks of treatment, 25 of the infants demonstrated resolution of their symptoms and underwent challenge with CHF. Of the 25 who were challenged, eight tolerated the CHF and the remainder had recurrence of their symptoms. The histologic features in these infants varied from eosinophilic infiltration to normal. We conclude that not all infants with apparent formula protein-induced colitis respond to CHF and that these infants may have resolution of their symptoms when fed an amino acid-based infant formula.

Low-Dose Chemotherapy for Epstein-Barr Virus–Positive Post-Transplantation Lymphoproliferative Disease in Children After Solid Organ Transplantation

PURPOSE To evaluate the efficacy of a low-dose chemotherapy regimen in children with Epstein-Barr virus (EBV) -positive, post-transplantation lymphoproliferative disease (PTLD) after organ transplantation who have experienced failure with front-line therapy for PTLD. PATIENTS AND METHODS Eligible patients received cyclophosphamide (600 mg/m2 intravenous for 1 day) and prednisone (2 mg/kg orally for 5 days) every 3 weeks for six cycles. RESULTS Thirty-six patients treated on study were assessable for analyses. Front-line therapies for PTLD before study entry included immune suppression reduction or withdrawal (n = 36), antiviral therapy (n = 33), surgical resection (n = 8), rituximab (n = 2), and interferon alfa (n = 1). Reasons for failure of front-line therapy included progressive disease (PD; n = 33) and persistent disease with concurrent allograft rejection (n = 3). Thirty patients (83%) had stage III to IV disease, 92% had extranodal disease, and 75% had > or = three sites of disease. The overall response rate was 83% (75% complete response + 8% partial response). The relapse rate was 19%, with only one of five relapsed patients alive and disease-free. Four patients presented with fulminant, disseminated PTLD; only one of these four patients achieved a response, and all four died of PD. Two patients died of treatment-related toxicity. Three patients (8%) experienced allograft loss, but two of the three patients are alive and disease-free after a second transplantation. The 2-year overall, relapse-free, and failure-free (without PTLD and with functioning original allograft) survival rates were 73%, 69%, and 67%, respectively. CONCLUSION This low-dose chemotherapy regimen is effective for children with EBV-positive, nonfulminant PTLD who have experienced treatment failure with front-line therapy, and this study represents the largest series of PTLD patients treated prospectively with a uniform chemotherapy regimen.

NOD2-expressing bone marrow-derived cells appear to regulate epithelial innate immunity of the transplanted human small intestine

Background: Intestinal allograft rejection resembles Crohn’s disease clinically and pathologically. An understanding of its mechanism could impact this life-saving procedure, as well as provide insight into the pathophysiology of inflammatory bowel disease. The NOD2 protein has been implicated as a key player in intestinal immune health, as a consequence of the discovery of three polymorphisms linked with Crohn’s disease. An investigation was carried out to determine whether epithelial immune function and graft survival were influenced by NOD2 mutations in an intestinal transplant population. Methods: The NOD2 genotypes of 34 transplants performed consecutively over the past 3 years were determined. The NOD2 genotypes were related to clinical outcomes and the expression of certain intestinal antimicrobial peptides (AMPs) believed to protect the epithelium. Results: An unexpectedly high percentage of recipients, 35%, possessed NOD2 polymorphisms, while 8.6% of donors had comparable mutations. The likelihood of allograft failure was about 100-fold higher in recipients with mutant NOD2 alleles compared with recipients with wild-type NOD2 loci. Rejection in NOD2 mutant recipients was characterised by decreased expression of certain Paneth cell and enterocyte AMPs, prior to the onset of epithelial injury and inflammation. Conclusions: Crohn’s disease-associated polymorphisms in the NOD2 gene in the recipient represent a critical immunological risk factor for intestinal allograft rejection. Compromised epithelial defences precede visible epithelial injury and inflammatory infiltration. The association of impaired epithelial immunity with the recipient’s genotype suggests that certain NOD2-expressing cells of haematopoietic origin play a role in the process, perhaps by regulating expression of certain epithelial AMPs within the allograft.

Isolated intestinal transplantation: proof of clinical efficacy.

Background and Aims. Isolated intestinal transplantation has been limited by poor patient and graft survival. If high survival could be achieved and if parenteral nutrition-associated liver disease were reversible, this procedure could be more widely applied, with early liver dysfunction indicating the need for transplant evaluation. Methods. Twenty-six patients who had failed parenteral nutrition received 28 isolated intestinal transplants. We analyzed patient and graft survival, the effect of sirolimus on the severity and frequency of rejection, and the reversibility of liver dysfunction after transplant. Results. Three-year actuarial patient and primary graft survival were 88% and 71%, respectively. Two patients underwent successful retransplants. Twenty-two patients are alive at a mean of 21±15 (median 18; range 3–51) months. Actuarial survival with freedom from parenteral support is 81% at 3 years (21 of 26 patients). Actuarial freedom from parenteral support among survivors is 95.5% at 3 years (21 of 22 patients). Early rejection was less frequent with sirolimus (34% vs. 70% without sirolimus) (P =0.007). Moderate and severe rejection was less frequent with sirolimus (1/11 episodes vs. 9/17 episodes without sirolimus) (P =0.05). No grafts were lost after introduction of sirolimus. In all four patients with advanced liver dysfunction, fibrosis and cholestasis regressed within 1 year. Conclusions. High patient survival and parenteral nutrition-free survival can be achieved after isolated intestinal transplantation. Sirolimus treatment has eliminated graft loss. Parenteral nutrition-associated liver disease is reversible with intestinal transplantation. Refractory liver dysfunction in patients receiving parenteral nutrition should prompt consideration for isolated intestinal transplantation.

Intestinal transplantation before and after the introduction of sirolimus

Introduction. Small bowel transplantation has been limited by high rates of rejection and graft loss. In June 2000, we began using sirolimus, an immunosuppression agent with proven efficacy in kidney transplantation. We reviewed results among intestinal transplant recipients before and after the introduction of sirolimus. Methods. Thirty-one intestinal transplants were performed in 29 patients at our center between July 1998 and April 2001. All patients were followed for at least 30 days posttransplant. In the first 19 transplants (group 1), patients received tacrolimus, steroids, and antibody induction therapy (either daclizumab or OKT3). In the next 12 consecutive transplants (group 2), patients received tacrolimus, steroids, basiliximab, and sirolimus. Results. Eighteen children (7 males and 11 females, mean age 2.1±2.2 years) and 11 adults (9 males and 2 females, mean age 38.1±12.4 years) underwent transplantation. All patients survived transplantation. The overall reoperation rate was 1.7 procedures per patient in group 1 and 1.1 procedures per patient in group 2. The most common indications were abscess (n=7), planned second look (n=7), leaks/fistulas (n=6), dehiscence (n=6), obstruction (n=4), ischemic bowel (n=3), perforations (n=3), stomal complications (n=3), and graft removal (n=3). The incidence of biopsy-proven rejection in the first 30 days was 73.7% in group 1 and 16.7% in group 2 (P <0.002). Sirolimus was temporarily held or discontinued in 66.7% of patients. Actuarial 1-year graft survival was 91.7% with sirolimus and 57.9% without sirolimus (P <0.04). Actuarial 1-year patient survival was 91.7% with sirolimus and 79% without sirolimus (P =0.12). Conclusions. An immunosuppressive regimen that includes sirolimus has improved graft survival. Furthermore, this regimen has significantly decreased the incidence of early rejection and has eliminated early graft loss caused by fulminant rejection.

Nutritional support for the infant with extrahepatic biliary atresia

Some infants with biliary atresia obtain dramatic improvement for prolonged periods after the performance of hepatic portoenterostomy. Such infants may have life styles not substantially different from those of normal children. In others, the benefit from this operation, if any, is short lived. These infants are very vulnerable to the debilitating effects of severe, prolonged malabsorption and ultimately require orthotopic liver transplantation to sustain life. The physician caring for infants awaiting liver transplantation can do much, not only to prolong survival but to maintain satisfactory growth and development. The key consideration is to provide adequate nitrogen and nonnitrogen calories, liberally utilizing modern methods of enteral alimentation when necessary. In addition, attention must be directed toward several vitamin and mineral deficiencies, particularly those of the fat-soluble vitamins, that inevitably accompany severe malabsorption in children. Management of extrahepatic biliary atresia in infants is difficult and requires meticulous attention to details. Nevertheless, the long-term cure of this disorder provided by liver transplantation makes their care a rewarding experience.

Calicivirus Enteritis in an Intestinal Transplant Recipient

Protracted diarrhea of uncertain etiology is a significant problem following intestinal transplantation. We report an infant who developed severe secretory diarrhea 178 days after intestinal transplantation that persisted for more than 120 days. Repeated allograft biopsies demonstrated only nonspecific inflammation. Enzyme immunoassay (for rotavirus), culture, and reverse transcription polymerase chain reaction [calicivirus (Norwalk‐like virus)] were used to identify the allograft viral infection. A heavy density of calicivirus RNA nucleotide sequences (genogroup II, strain Miami Beach) was isolated from the jejunal and ileal allograft. Following a reduction in immunosuppressive therapy, diarrhea and enteritis remitted in association with the disappearance of all calicivirus RNA sequences. Calicivirus may cause severe allograft dysfunction in intestinal transplant recipients.