ESPGHAN position paper on management of percutaneous endoscopic gastrostomy in children and adolescents.

OBJECTIVES: This European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) position statement provides a comprehensive guide for health care providers to manage percutaneous endoscopic gastrostomy tubes in a safe, effective, and appropriate way. METHODS: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of evidence, recommendations reflect the expert opinion of the authors. Final consensus was obtained by multiple e-mail exchange and during 3 face-to-face meetings of the gastroenterology committee of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. RESULTS: Endoscopically placed gastrostomy devices are essential in the management of children with feeding and nutritional problems. The article focuses on practical issues such as indications and contraindications. CONCLUSIONS: The decision to place an endoscopic gastrostomy has to be made by an appropriate multidisciplinary team, which then provides active follow-up and care for the child and the device.

High-dose azathioprine in children with inflammatory bowel disease.

BACKGROUND: Azathioprine is widely used as maintenance therapy in children with moderate to severe inflammatory bowel disease (IBD). There is no data on safety at higher doses and its impact on growth and surgical morbidity in children. METHODS: This retrospective cohort study included all children treated with azathioprine and diagnosed with IBD between 1996-2001. Outcome measures included indications for azathioprine use, adverse-effects and reasons for treatment discontinuation. Height and weight at diagnosis, treatment onset and current follow-up was recorded, and Z scores for height standardised for time. RESULTS: 107 children received azathioprine at 3 mg/kg. 61% had Crohn's disease and 83% started azathioprine within 2 years of diagnosis. Only 2/107 children had to stop azathioprine because of persistent adverse effects and 16/107 required surgery. There was a trend toward better growth in a group of children with Crohn's disease following treatment with high dose azathioprine therapy (P = 0.08). CONCLUSIONS: Azathioprine is a safe and well-tolerated maintenance therapy at 3 mg/kg for children with IBD. The prevalence of surgery and growth failure in a cohort of children with moderate to severe IBD appears less than previously reported. In children with Crohn's disease, growth velocity may be maximised by an emphasis on nutritional therapy and the use of high dose azathioprine.

Colitis-associated sclerosing cholangitis in children: a single centre experience.

OBJECTIVE: Sclerosing cholangitis (SC) is an important immune-mediated extra-intestinal manifestation of inflammatory bowel disease (IBD), primarily affecting patients with ulcerative colitis (UC). The reported prevalence of SC in adults and children with UC is low at between 2 and 7%. We present findings from a hepatological work-up in children with inflammatory colitis and elevated liver function tests (LFT) from a tertiary paediatric gastroenterology unit. DESIGN: This study is designed as a retrospective review of the medical records of 17 children and adolescents with inflammatory colitis and abnormal LFTs who presented to our IBD service between April 2004 and April 2012. RESULTS: Over the eight year period a total of 52 patients were diagnosed with inflammatory colitis (ulcerative colitis and unclassified colitis). Seventeen of the 52 patients had abnormal liver function tests and underwent liver biopsy and cholangiography. All 17 patients (32.6%) were diagnosed with hepato-biliary disease. CONCLUSION: This is one of the largest reported series of children with inflammatory colitis and associated hepato-biliary disease. The data from this patient group indicate that the prevalence of IBD-associated hepato-biliary disease in children with abnormal LFTs is much higher than previously reported. As the diagnosis of IBD-associated hepato-biliary disease affects patient management, we recommend liver biopsy and cholangiography in all children with inflammatory colitis and abnormal liver function tests.

Tissue transglutaminase antibody levels predict IgA deficiency.

OBJECTIVE: Measuring serum tissue transglutaminase immunoglobulin A (tTG IgA) levels is the most widely used screening test for coeliac disease. However, given an increased prevalence of IgA deficiency among coeliac patients there is a risk of false negative results. Hence, in addition to specific serum tTG IgA, screening tests frequently include total IgA levels. The objective of this study was to determine whether tTG IgA antibody levels might be used to predict IgA deficiency and hence avoid unnecessary testing of total IgA levels in all individuals. DESIGN: Retrospective analysis of 9429 serum tTG IgA and corresponding total IgA levels obtained from children and young adults in the East of England between 2007 and 2011. RESULTS: The overall prevalence of IgA deficiency was found to be very low with only 0.9% of individuals affected. Using receiver operating characteristic curve analysis we identified a cut-off value for tTG IgA of ≥0.10 µ/mL to be predictive for the absence of total IgA deficiency (IgA<0.06 g/L). Specifically, using this cut-off value, total IgA deficiency could be excluded with a sensitivity of 0.92 and specificity of 0.84. In our cohort, only 16.4% of our patient sample would have needed total IgA measurement to rule out a false negative result due to IgA deficiency. CONCLUSIONS: Our data provide a simple means of avoiding unnecessary total IgA measurements in the assessment of coeliac disease. By using tTG IgA value quantitatively, only values <0.10 µ/mL require total IgA measurements to rule out IgA deficiency and hence a potentially false negative screening result.

Aberrant response to commensal Bacteroides thetaiotaomicron in Crohn's disease: an ex vivo human organ culture study.

BACKGROUND: Human ex vivo evidence indicating that an inappropriate immune response(s) to nonpathogenic bacteria contributes to disease pathogenesis in pediatric Crohn's disease (CD) is limited. The aim of the present study was to compare and contrast the early innate immune response of pediatric "healthy" versus CD mucosa to pathogenic, probiotic, and commensal bacteria. METHODS: "Healthy control" and CD pediatric mucosal biopsies (terminal ileum and transverse colon) were cocultured for 8 hours with E. coli O42, Lactobacillus GG (LGG), Bacteroidesthetaiotaomicron (B. theta), or stimulated with interleukin (IL)-1ß (positive control). Matched nonstimulated biopsies served as experimental controls. IL-8 was the immune marker of choice. IL-8 mRNA and protein levels were quantified by quantitative polymerase chain reaction and sandwich enzyme-linked immunosorbent assay, respectively. RESULTS: IL-8 secretion was observed when control, ileal biopsies were exposed to pathogenic O42 and probiotic LGG, with no response noted to commensal B. theta. In comparison, Crohn's ileal biopsies showed impaired ability to induce IL-8 in response to O42 and LGG. Control colonic tissue showed a limited response to O42 or B. theta and LGG significantly reduced IL-8 secretion. Unlike control tissue, however, Crohn's ileal and colonic tissue did respond to B. theta, with more enhanced expression in the colon. CONCLUSIONS: We provide the first ex vivo data to support the notion that aberrant mucosal recognition of commensal bacteria may contribute to pediatric CD. While IL-8 responses to O42 and LGG varied with disease status and anatomical location, B. theta consistently induced significant IL-8 both in ileal and colonic CD tissue, which was not seen in control, healthy tissue.

A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease.

BACKGROUND: Adalimumab is efficacious therapy for adults with Crohn's disease (CD). AIM: To summarise the United Kingdom and Republic of Ireland paediatric adalimumab experience. METHODS: British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) members with Inflammatory Bowel Disease (IBD) patients <18 years old commencing adalimumab with at least 4 weeks follow-up. Patient demographics and details of treatment were then collected. Response and remission was assessed using the Paediatric Crohn's Disease Activity Index (PCDAI)/Physicians Global Assessment (PGA). RESULTS: Seventy-two patients [70 CD, 1 ulcerative colitis (UC), 1 IBD unclassified (IBDU)] from 19 paediatric-centres received adalimumab at a median age of 14.8 (IQR 3.1, range 6.1-17.8) years; 66/70 CD (94%) had previously received infliximab. A dose of 80 mg then 40 mg was used for induction in 41(59%) and 40 mg fortnightly for maintenance in 61 (90%). Remission rates were 24%, 58% and 41% at 1, 6 and 12 months, respectively. Overall 43 (61%) went into remission at some point, with 24 (35%) requiring escalation of therapy. Remission rates were higher in those on concomitant immunosuppression cf. those not on immunosuppression [34/46 (74%) vs. 9/24 (37%), respectively, (χ(2) 8.8, P=0.003)]. There were 15 adverse events (21%) including four (6%) serious adverse events with two sepsis related deaths in patients who were also on immunosuppression and home parenteral nutrition (3% mortality rate). CONCLUSIONS: Adalimumab is useful in treatment of refractory paediatric patients with a remission rate of 61%. This treatment benefit should be balanced against side effects, including in this study a 3% mortality rate.

Limited ileo-caecal resection for localised Crohn's disease in childhood: Clinical outcome and predictors of further surgery.

OBJECTIVES: To investigate the outcome of limited ileo-caecal resection in children with localised Crohn's disease (CD) and determine predictors of further surgery. METHODS: Review of children diagnosed with CD and operated on for ileo-caecal disease from 1995 to 2005. Age at diagnosis, endoscopic disease distribution, indication for surgery, site of recurrence and date of last follow-up were recorded. Surgery required removal of only the ileo-caecal junction and caecal pole with removal of the minimum terminal ileal length. RESULTS: Thirty seven children underwent intestinal resection. Time between primary operation and most recent follow-up was 3.8 years (range 1 month-8.8 years). Indications for surgery were obstruction/stricture (20), treatment-resistant disease (13) and abscess/perforation peritonitis (4). Follow-up was available in 32. Nine (28%) required re-laparotomy. Median time to second laparotomy was 12 months (range 4-58 months). Eighteen children required no endoscopies after surgery (median follow-up 3.4 years). CONCLUSION: Most conservative surgery occurs about 2 years after diagnosis. About 1 in 4 children have a further laparotomy within 12 months. Over half of these require division of adhesions. Limited ileo-caecal resection for localized Crohn's disease is not associated with early peri-anastomotic recurrence. Developments in laparoscopic surgery are likely to further reduce complications from adhesions.

Inflammatory bowel disease.

Twenty five per cent of inflammatory bowel disease presents in childhood. Growth and nutrition are key issues in the management with the aim of treatment being to induce and then maintain disease remission with minimal side effects. Only 25% of Crohn's disease presents with the classic triad of abdominal pain, weight loss, and diarrhoea. Most children with ulcerative colitis have blood in the stool at presentation. Inflammatory markers are usually although not invariably raised at presentation (particularly in Crohn's disease). Full investigation includes upper gastrointestinal endoscopy and ileocolonoscopy. Treatment requires multidisciplinary input as part of a clinical network led by a paediatrician with special expertise in the management of the condition.

New immunologic treatments for inflammatory bowel disease.

After many years with little progress in new treatments for patients with inflammatory bowel disease, there is now rapid expansion of a new class of immunologic agents. These agents are designed to disrupt proinflammatory pathways at specific sites. Monoclonal antibodies to tumor necrosis factor-alpha (TNF-alpha) are already transforming the lives of some patients with previously intractable Crohn disease, and further TNF-alpha directed therapies are being developed. Clinical trials are now underway on agents that inhibit adhesion molecules and antiinflammatory cytokines, while attempts are being made to actively immunize against TNF-alpha. Promising data continue to be reported, although long-term safety data are still mostly unavailable. Although these agents are proving to be very effective in the treatment of patients with Crohn disease, their use should continue to be restricted while indications and dose regimens are defined.

Enteral nutrition and corticosteroids in the treatment of acute Crohn's disease in children.

BACKGROUND: The optimal treatment of acute Crohn's disease in children remains controversial. In adults, steroid therapy has been shown to be superior to exclusive enteral nutrition. However, enteral nutrition is effective at inducing a remission in many children with acute Crohn's disease. Steroid usage in children has been associated with adverse side effects, particularly with delayed growth and pubertal development. METHODS: Randomized clinical trials comparing exclusive enteral nutrition with corticosteroids were identified. Two independent reviewers extracted data from selected studies. Studies were assessed for heterogeneity and relative risks for remission induction with enteral nutrition were obtained. Sensitivity analyses were performed in partially randomized studies. Estimates were made of the number of studies needed to overturn the current result. Other outcome measures were qualitatively assessed. RESULTS: In five randomized clinical trials comprising 147 patients, enteral nutrition was as effective as corticosteroids at inducing a remission (RR = 0.95 [95% confidence interval 0.67, 1.34]). Addition of two further nonrandomized trials did not significantly alter the result. A minimum of 10 further studies, equal in size and outcome to the largest reported pediatric trial to date (n = 68, RR = 0.84), would be required to demonstrate a significant benefit of steroid therapy over enteral nutrition. CONCLUSIONS: There is no difference in efficacy between enteral nutrition and corticosteroid therapy in the treatment of acute Crohn's disease in children. Improved growth and development, without the side effects of steroid therapy, make enteral nutrition a better choice for first-line therapy in children with active Crohn's disease.

Imbalance of stromelysin-1 and TIMP-1 in the mucosal lesions of children with inflammatory bowel disease.

BACKGROUND: Degradation of the extracellular matrix and ulceration of the mucosa are major features of inflammatory bowel disease (IBD). One of the most important enzymes in degrading the matrix and produced in excess by cytokine activated stromal cells, is stromelysin-1. The activity of stromelysin-1 is controlled by tissue inhibitor of metalloproteinase (TIMP-1), its natural inhibitor. In model systems excess stromelysin-1 produces mucosal degradation. METHODS: Quantitative competitive RT-PCR was used to analyse stromelysin-1 and TIMP-1 transcripts; western blotting was used to measure the amount of stromelysin-1 and TIMP-1 protein in biopsy samples from children with IBD. RESULTS: In biopsies from patients with active Crohn's disease (n=24), ulcerative colitis (n=23), and controls (n=16), TIMP-1 transcripts and protein were abundant and unchanged. Stromelysin-1 transcripts and protein were markedly elevated in mucosal biopsies obtained from inflamed sites of patients with active IBD but were not elevated in adjacent endoscopically normal mucosa (n=10). Elevated levels of stromelysin-1 transcripts in active Crohn's disease (n=5) returned to normal levels following treatment with enteral nutrition. CONCLUSIONS: Stromelysin-1 is markedly overexpressed at inflamed sites in patients with IBD whereas TIMP-1 remains unaltered. Excess stromelysin-1 is likely to be responsible for loss of mucosal integrity in IBD.