Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease.

Children and adolescents with Crohn's disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohn's and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

Genetic susceptibility and genotype-phenotype association in 588 Danish children with inflammatory bowel disease.

AIM: To investigate the association between known inflammatory bowel disease (IBD)-associated genetic variants and development of paediatric IBD, and specific clinical sub-phenotypes. MATERIAL AND METHODS: In this case-control study we included IBD patients <18 years of age at diagnosis from the Danish National Patient Registry and healthy children <18 years of age were randomly selected from the Danish Central Office of Civil Registration. The latter had filled out a questionnaire regarding health status, and DNA was obtained from blood samples and the buccal mucosa. Patient files were retrieved and clinical information was extracted. DNA was obtained from Guthrie cards from the Danish National Neonatal Screening Biobank (PKU-biobanken) at Statens Serum Institut and from blood samples. RESULTS: A total of 588 IBD patients (244 Crohn's disease (CD), 318 ulcerative colitis (UC) and 26 IBD-unclassified (IBDU)) and 543 healthy controls were included. We found an association between CD and rs22411880 (ATG16L1, odds ratio (OR)=1.7 [1.1-1.7], p=0.003), rs5743289 (NOD2, OR=1.4 [1.1-1.9], p=0.009) and the paediatric specific rs1250550 (ZMIZ1, OR=0.7 [0.5-0.9], p=0.01). None of the investigated 41 SNPs were associated with disease localisation, medical treatment or surgery after correcting for multiple analyses. CONCLUSION: We found an association between CD and three previously published genetic variants and replicated the association with the paediatric specific ZMIZ1 gene. No Bonferroni corrected significant genotype-phenotype associations were found. For future studies aimed at finding predictors for disease course in (paediatric) IBD, it will be worthwhile to include a combination of genetic, clinical and serological markers.

Rapid test for fecal calprotectin levels in children with Crohn disease.

Assessment of fecal calprotectin, a surrogate marker of mucosal inflammation, is a promising means to monitor therapeutic response in pediatric inflammatory bowel disease, especially if the result is readily available. We tested the performance of a novel calprotectin rapid test, Quantum Blue, versus the conventional enzyme-linked immunosorbent assay in 134 stool samples from 56 pediatric patients with Crohn disease. The intraclass correlation coefficient analysis reflected good agreement (intraclass correlation coefficient 0.97 [95% confidence interval 0.95-0.98]) but agreement was better in lower values, where dilutions were not required. Using a cutoff of 100 µg/g for normal values, the percentage agreement between the 2 tests was 87%. The optimal cutoff values to guide clinical decisions in the therapy of inflammatory bowel disease have yet to be determined.

Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease--a population-based study.

BACKGROUND: Few studies have compared phenotype and disease course in children and adults with inflammatory bowel disease (IBD). AIM: To compare phenotype, treatment and disease course in children (<15 years) and adults (≥18 years) with IBD. METHODS: Two population-based cohorts comprising paediatric (2001-2006) and adult (2003-2004) patients from Copenhagen County and City were studied. RESULTS: Twenty children and 106 adults with ulcerative colitis (UC), and 29 children and 67 adults with Crohn's disease (CD) were included. Median follow-up time was 4.8 years (children) and 5.2 years (adults). Children with UC had more extensive disease compared to adult patients [14 (70%) vs. 20 (19%), P<0.001]. The risks of starting systemic steroid treatment and AZA/MP were higher for paediatric UC patients compared to adult UC patients; hazard ratio (HR): 3.1 (95% CI: 1.8-5.3) and HR: 2.5 (1.3-5-9), respectively. Steroid dependency was more frequent in paediatric than in adult UC patients [9 (45%) vs. 9 (8%), P<0.001]. Mild disease course was less frequent in children with UC compared to adult patients [7 (35%) vs. 76 (72%), P=0.002]. Paediatric and adult CD patients did not differ regarding treatment or disease course. Cumulative 5-year surgery rates for paediatric and adult patients were 5% and 9% for UC (N.S.) and 18% and 21% for CD (N.S.), respectively. CONCLUSIONS: Paediatric UC patients had more extensive disease, were more often treated with systemic steroids and AZA, had a higher frequency of steroid dependency and a more severe disease course compared to adult UC patients. No differences were found when comparing paediatric and adult CD patients.

Changes in the epidemiology of acute appendicitis and appendectomy in Danish children 1996-2004.

PURPOSE: Aim of the study was to describe changes in the epidemiology of acute appendicitis in Danish children between 0-19 years of age for the period 1996-2004. METHODS: The study was based on discharge diagnoses taken from the Danish National Patient Registry of all 28 274 patients with a diagnosis of acute uncomplicated or complicated appendicitis, and/or a registered procedure code of appendectomy. These data were computed together with data on the background population, and incidences were calculated. RESULTS: A significant decrease in the incidence of acute uncomplicated appendicitis was found for all age groups (range, 13-36%). The decrease was present for both sexes, but most prominent in girls. The incidence of complicated acute appendicitis decreased by 10%. CONCLUSION: The incidence of acute appendicitis is declining. The incidence of uncomplicated appendicitis appears to be declining more rapidly than that of complicated appendicitis. This finding does not necessarily imply poorer management of the disease, but-as suggested by others-could be due to different behaviours of uncomplicated and complicated appendicitis.

Nutrition, anthropometry, gastrointestinal dysfunction, and circulating levels of tumour necrosis factor alpha receptor I and interleukin-1 receptor antagonist in children during stem cell transplantation.

To evaluate anthropometry, nutrition and gastrointestinal dysfunction, and to characterize the relation between these parameters and the inflammatory activity evaluated by plasma levels of soluble tumour necrosis factor alpha receptor I (sTNFRI) and interleukin-1 receptor antagonist (IL-1Ra) levels during stem cell transplantation (SCT) in children. Clinical assessments and blood sampling were performed on days -3, 0, +7, +15 and +31 in eight children undergoing SCT. Energy intake, anthropometry, gastrointestinal dysfunction (WHO toxicity score) and sTNFRI and IL-1Ra were evaluated. The energy intake was below recommended levels. There was a loss of lean body mass (arm muscle area)(median, 2031 mm(2) (day -3) vs 1477 mm(2) (day 31); p = 0.04), and of fat mass (arm fat area) (791 mm(2) (day -3) vs 648 mm(2) (day +31); p = 0.04). sTNFRI was elevated throughout the course of transplantation, and peaked after the day of graft infusion (day 0). sTNFRI levels at day 0 predicted changes in weight SDS (r = 0.65; p = 0.05), triceps skinfold SDS (r = 0.85; p = 0.007) and gastrointestinal dysfunction (r = 0.88; p = 0.004). Likewise, IL-1Ra levels at day 0 correlated with the gastrointestinal dysfunction (r = 0.83; p = 0.01) and with the change in weight SDS (r = 0.77; p = 0.03). This study suggests that pretransplant levels of inflammatory markers are associated with posttransplant symptoms of gastrointestinal dysfunction and loss of both fat and lean body mass. Future studies should address if the use of conditioning regimens with limited proinflammatory cytokine inducing activity, anti-inflammatory agents, or more optimised nutritional support can reduce the burden of such posttransplant complications.

Severe blue rubber bleb nevus syndrome in a neonate.

We report on a child with blue rubber bleb nevus syndrome (BRBNS) presenting during the first days of life with severe bleeding from the upper gastrointestinal tract. Medical treatment with methylprednisolone, cyklokapron, interferon 1 alpha and numerous blood transfusions were given to control bleeding during the first 3 years of life. Afterwards repeated endoscopic electrocoagulation were performed over a period of one year resulting in a termination of bleeding episodes. At ten years of age the patient developed spastic diplegia with slight walking disabilities, coordination and fine motor problems. The case is unique because 1) it is the first neonatal case with BRBNS and severe gastrointestinal bleeding; 2) the patient was successfully treated by endoscopic electrocoagulation; and 3) the long-term follow-up. The use of electrocoagulation appears to have been effective and ablation of the stomach could be avoided until now.

Denmark: botulism in an infant or infant botulism?

A 4.5 months old, previously healthy Danish girl was admitted to a paediatric department after six days of passive behaviour and weak suck. Over the next days she became increasingly weak, developed bilateral ptosis, the muscle stretch reflexes were lost, and mydriasis with slow pupillary responses was noted. Botulism was suspected and confirmed by testing of patient serum in a bioassay. The condition of the patient improved following administration of botulism antiserum. The clinical picture was suggestive of intestinal (infant) botulism. However, botulism acquired from consumption of food with preformed neurotoxin could not be excluded.

Response pattern recognition in paediatric Crohn's disease patients treated with enteral nutrition.

AIM: To describe the response pattern to enteral nutrition (EN) in paediatric patients with moderately to severely active Crohn's disease (CD). MATERIAL AND METHODS: A previously described method for assessment of response pattern to various treatments for CD was used. Patients who received EN during the 10-year period 1995-2005 were prospectively registered. Patient data, clinical outcome, time to relapse and subsequent need for treatment were extracted from the files. Four weeks treatment with polymeric ready-to-use liquid formula was given. The clinical outcome was assessed by pattern recognition of the disease course 30 days (immediate response) and 90 days (long-term response) after start of EN. RESULTS: Thirty-one patients (17/14 M/F), median age 14 years (range 7.5 -19.8 years), received 46 courses of EN. Thirty-seven courses (80%) were completed. Immediate response: twenty-five courses (67%) led to complete response (CR), 8 (22%) to partial response (PR) and in 4 courses (11%) no response (NR) was achieved. Long-term response: 21 courses (64%) led to prolonged response (PRO), defined as either maintenance of complete response (CR) or partial response (PR), while 12 courses (36%) were followed by loss of response (LR). The median time to relapse was 8.3 months (range 0.5-39 months). CONCLUSION: We found our model of response pattern to be a useful instrument for the description of results obtained during EN in children with CD.

Glucagon-like peptide-2 (GLP-2) response to enteral intake in children during anti-cancer treatment.

BACKGROUND: Intestinal dysfunction is frequent in cancer and during anti-cancer treatment. Glucagon-like peptide-2 (GLP-2) is secreted in a nutrition-dependent manner from the intestinal enteroendocrine L-cells. It accelerates crypt cell proliferation and nutrient absorption, inhibits enterocyte apoptosis and decreases mucosal permeability. Lack of GLP-2 may increase the risk of malabsorption and intestinal bacterial translocation. The aim of this study is to evaluate meal stimulated secretion of GLP-2 in children with cancer undergoing anti-cancer treatment. METHODS: Plasma-GLP-2 analysis after an overnight fast and 1 hour after intake of a mixed test meal. Data on gastrointestinal toxicity, blood neutrophile counts and food records were included in the analysis. RESULTS: Forty-four meal stimulation tests were performed in 25 children (median age, 6.0 years; range, 2.5-19) during anti-cancer treatment. Median GI toxicity score was 5 (range, 0-15), and mean energy intake was 62.4% of recommended values. P-GLP-2 values increased from mean (SD) 38 (18) to 63 (51) pmol/l (P < 0.0001). Twelve of the meal stimulation tests (28%) resulted in a p-GLP-2 increase >2 fold, which is assumed to be the lower limit of normal values. The increase was strongly dependent on the energy intake (r = 0.62, P < 0.0001), while toxicity score and neutrophile count had no significant influence (multiple regression). CONCLUSION: In children treated with anti-cancer therapy, GLP-2 secretion seems to be normal if the enteral energy intake is sufficient. Insufficient GLP-2 secretion could influence the gastrointestinal problems seen in the children with a low enteral energy intake.

Case study of the distribution of mucosa-associated Bifidobacterium species, Lactobacillus species, and other lactic acid bacteria in the human colon.

The distribution of mucosa-associated bacteria, bifidobacteria and lactobacilli and closely related lactic acid bacteria, in biopsy samples from the ascending, transverse, and descending parts of the colon from four individuals was investigated by denaturing gradient gel electrophoresis (DGGE). Bifidobacterial genus-specific, Lactobacillus group-specific, and universal bacterial primers were used in a nested PCR approach to amplify a fragment of the 16S rRNA gene. DGGE profiles of the bifidobacterial community were relatively simple, with one or two amplicons detected at most sampling sites in the colon. DGGE profiles obtained with Lactobacillus group-specific primers were complex and varied with host and sampling site in the colon. The overall bacterial community varied with host but not sampling site.

Treatment of Helicobacter pylori in children with recurrent abdominal pain.

BACKGROUND: The role of Helicobacter pylori remains unclear in children with recurrent abdominal pain (RAP). In this study children with RAP were included in a double blind treatment study to elucidate whether symptoms disappear in children with a H. pylori infection and RAP, if the bacteria are eradicated. METHODS: Thirty-seven H. pylori-infected children aged 4.9-14.5 years (median 9.8 years) with RAP were included. H. pylori was identified by histology and culture. The children were treated with amoxicillin and metronidazole for 14 days. A re-endoscopy including biopsies for histology and culture was done at least one month after the end of treatment. Simple questions for symptoms were asked and blood for serology was repeated 3 and 6 months after the end of treatment. During the observation period the results of the re-endoscopy and the serology 3 and 6 months after the re-endoscopy were blinded for 23 patients and opened to 14 of the patients according to the choice of the families. RESULTS: The eradication rates were 81% (30/37) in the total group and 74% (17/23) in the blinded group. The IgG antibodies to H. pylori decreased significantly 3 (p =.03) as well as 6 months after end of treatment (p <.001) in children with successful eradication. The number of children with RAP decreased after examination and treatment and the well-being improved after 6 months in almost 95% of the children. However, no correlation was seen between eradication of H. pylori and disappearance of RAP, neither after 3 nor after 6 months' observation in the total group of patients (p =.94 and p =.90) or in the blinded group (p =.42 and p =.65). CONCLUSIONS: These results do not provide evidence for a causal relationship between RAP and H. pylori.

Regression of HIV-associated progressive encephalopathy of childhood during HAART.

HIV-associated progressive encephalopathy of childhood is characterized by impaired brain growth, decline in cognitive and neurobehavioral performances, and progressive motoric dysfunction The diagnosis is based on neurological examination, neuropsychological assessment and cerebral CT or MR imaging. While the importance of early use of antiretroviral combination therapy has been emphasized, limited data exist as to the effect of protease inhibitors in children with HIV-associated encephalopathy. We describe the effect of 3-drug antiretroviral combination therapy, including the protease inhibitor nelfinavir, in a 7-y-old girl with vertically acquired HIV infection and late onset progressive encephalopathy.

[Treatment of severe acute disseminated encephalomyelitis with intravenous immunoglobulin]. / Behandling af svaer akut dissemineret encephalomyelitis med intravenøs immunglobulin.

A three year-old boy with severe acute disseminated encephalomyelitis (ADEM) responding dramatically to treatment with intravenous immunoglobulin (IVIG) 1 g/kg/day is described. Initial treatment with intravenous methylprednisolone 2 mg/kg/day had failed. This and two earlier case reports indicate that IVIG might be efficient in the treatment of ADEM, and we believe that its use should be considered, at least in cases of severe ADEM with insufficient treatment effect of steroids. A synergistic effect of treatment with steroids and IVIG in ADEM is possible.

[Meckel's diverticulum. From embryology to therapy]. / Meckels divertikel. Fra embryologi til behandling.

Meckel's diverticulum (MD), an remnant of the omphalomesenteric duct, is the most common congenital abnormality of the small bowel. The aim of this paper is to give a review of MD, from embryology to diagnosis, complications and treatment.

Screening of probiotic activities of forty-seven strains of Lactobacillus spp. by in vitro techniques and evaluation of the colonization ability of five selected strains in humans.

The probiotic potential of 47 selected strains of Lactobacillus spp. was investigated. The strains were examined for resistance to pH 2.5 and 0.3% oxgall, adhesion to Caco-2 cells, and antimicrobial activities against enteric pathogenic bacteria in model systems. From the results obtained in vitro, five strains, Lactobacillus rhamnosus 19070-2, L. reuteri DSM 12246, L. rhamnosus LGG, L. delbrueckii subsp. lactis CHCC 2329, and L. casei subsp. alactus CHCC 3137, were selected for in vivo studies. The daily consumption by 12 healthy volunteers of two doses of 10(10) freeze-dried bacteria of the selected strains for 18 days was followed by a washout period of 17 days. Fecal samples were taken at days 0 and 18 and during the washout period at days 5 and 11. Lactobacillus isolates were initially identified by API 50CHL and internal transcribed spacer PCR, and their identities were confirmed by restriction enzyme analysis in combination with pulsed-field gel electrophoresis. Among the tested strains, L. rhamnosus 19070-2, L. reuteri DSM 12246, and L. rhamnosus LGG were identified most frequently in fecal samples; they were found in 10, 8, and 7 of the 12 samples tested during the intervention period, respectively, whereas reisolations were less frequent in the washout period. The bacteria were reisolated in concentrations from 10(5) to 10(8) cells/g of feces. Survival and reisolation of the bacteria in vivo appeared to be linked to pH tolerance, adhesion, and antimicrobial properties in vitro.