Recurrent pericarditis as an extra-intestinal manifestation of ulcerative colitis in a 14-year-old girl.

Pericarditis is a known complication of mesalazine in the treatment of ulcerative colitis. This case study illustrates that after diagnostic work-up, pericarditis should not always be attributed to the use of mesalazine. It may be the presentation of an extra-intestinal manifestation of ulcerative colitis. Restarting of mesalazine should be considered.

Definitions and Outcome Measures in Pediatric Functional Upper Gastrointestinal Tract Disorders: A Systematic Review.

OBJECTIVES: Functional disorders of the upper gastrointestinal tract are frequently diagnosed in children. Four different clinical entities are addressed by the Rome III committee: functional dyspepsia (FD), cyclic vomiting syndrome (CVS), adolescent rumination syndrome (ARS), and aerophagia. Management of these disorders is often difficult leading to a wide variety in therapeutic interventions. We hypothesize that definitions and outcome measures in these studies are heterogeneous as well. Our aim is to systematically assess how these disorders and outcomes are defined in therapeutic randomized controlled trials (RCTs). STUDY DESIGN: CENTRAL, Embase, and MEDLINE/PubMed were searched from inception to February 25, 2015. Search terms were FD, CVS, ARS, and aerophagia. Therapeutic RCTs, or systematic reviews of RCTs, in English language including subjects ages 4 to 18 years (0-18 years for CVS) were evaluated. Quality was assessed using the Delphi list. RESULTS: A total of 1398 articles were found of which 8 articles were included. Seven concerned FD and 1 concerned CVS. In all of the studies, Rome criteria or similar definitions were used; all the studies however used different outcome measures. Seventy-five percent of the trials were of good methodological quality. Only 57% used validated pain scales. CONCLUSIONS: Different outcome measures are used in therapeutic trials on functional disorders of the upper gastrointestinal tract. There is a clear paucity of trials evaluating different treatment regimens regarding CVS, ARS, and aerophagia. Uniform definitions, outcome measures, and validated instruments are needed to make a comparison between intervention studies possible.

Cystic fibrosis and the role of gastrointestinal outcome measures in the new era of therapeutic CFTR modulation.

With the development of new drugs that directly affect CFTR protein function, clinical trials are being designed or initiated for a growing number of patients with cystic fibrosis. The currently available and accepted clinical endpoints, FEV1 and BMI, have limitations. The aim of this report is to draw attention to the need and the ample possibilities for the development and validation of relevant gastrointestinal clinical endpoints for scientific evaluation of CFTR modulation treatment, particularly in young children and infants. The gastrointestinal tract offers very good opportunities to measure CFTR protein function and systematically evaluate CF related clinical outcomes based on the principal clinical gastrointestinal manifestations of CF: intestinal pH, intestinal transit time, intestinal bile salt malabsorption, intestinal inflammation, exocrine pancreatic function and intestinal fat malabsorption. We present a descriptive analysis of a variety of gastrointestinal outcome measures for clinical relevance, reliability, validity, responsiveness to interventions, feasibility in particular in young children and the availability of reference values.

Surveillance of hepatic late adverse effects in a large cohort of long-term survivors of childhood cancer: prevalence and risk factors.

BACKGROUND: Childhood cancer survivors (CCS) are a growing group of young individuals with a high risk of morbidity and mortality. We evaluated the prevalence and risk factors of hepatic late adverse effects, defined as elevated liver enzymes, in a large cohort of CCS. METHODS: The cohort consisted of all five-year CCS treated in the EKZ/AMC between 1966 and 2003, without hepatitis virus infection and history of veno-occlusive disease (VOD). Liver enzyme tests included serum levels of alanine aminotransferase (ALT) for hepatocellular injury and gamma-glutamyltransferase (γGT) for biliary tract injury. We performed multivariable linear and logistic regression analyses. RESULTS: The study population consisted of 1404 of 1795 eligible CCS, of whom 1362 performed liver enzyme tests at a median follow-up of 12 years after diagnosis. In total, 118 (8.7%) of 1362 CCS had hepatic late adverse effects defined as ALT or γGT above the upper limit of normal. Abnormal ALT and γGT levels were found in 5.8% and 5.3%, respectively. In multivariable regression analyses treatment with radiotherapy involving the liver, higher body mass index, higher alcohol intake and longer follow-up time were significantly associated with elevated ALT and γGT levels; older age at diagnosis was only significantly associated with elevated γGT levels (all p<0.05). CONCLUSION: One in twelve CCS showed signs of hepatic late adverse effects after a median follow-up of 12 years. Several risk factors have been identified. Future studies should focus on the course of long-term liver related outcomes and on the influence of radiotherapy and chemotherapy dose.

Evaluation of 28 years of surgical treatment of children and young adults with familial adenomatous polyposis.

BACKGROUND: In this retrospective study, 28 years of surgical treatment of children and young adults with familial adenomatous polyposis (FAP) was analyzed. METHODS: Forty-three patients were operated on before the age of 26 years. Endoscopic aspects, operative data, and complications were analyzed, and the resection specimens were reevaluated. Functional outcome was assessed by telephone questionnaire. RESULTS: Primary ileorectal anastomosis (IRA) was performed in 34 patients with a mean age of 16 years (range, 7-25 years). Primary ileal-pouch anal anastomosis (IPAA) was performed in 9 patients at a mean age of 19 years (range, 15-24 years). Secondary excision of the rectum was performed in 7 patients. Overall, rectal carcinoma was present in 4 patients, at the age of 35, 36, 37, and 38 years. Two patients, aged 39 and 40 years, died because of invasive carcinoma with distant metastasis. The functional outcome and postoperative complications after both procedures were similar to those described in literature for children with FAP. Most patients did not experience alterations in lifestyle, and there was no urinary incontinence. CONCLUSIONS: In this retrospective study, both IRA and IPAA showed to be feasible techniques in young patients with FAP. A prospective study with a sufficient follow-up is needed to compare both techniques in this specific group of patients.

Veno-occlusive disease as a complication of preoperative chemotherapy for Wilms tumor: A clinico-pathological analysis.

BACKGROUND: Vincristine (VCR) and actinomycin D (ACD) form the backbone of chemotherapeutic regimens of Wilms tumor treatment. Veno-occlusive disease (VOD) is a potentially life-threatening complication of ACD. OBJECTIVES: To investigate the incidence of VOD after preoperative chemotherapy and assess the effect of dose and frequency of administrating ACD on the occurrence of VOD. METHODS: A single-center retrospective study of patients where liver biopsies were performed after 4 or 8 weeks of preoperative chemotherapy. Patients had localized or metastatic Wilms tumor and were treated according to SIOP 9, 93-1, or 2001 protocol. A correlation was analyzed between histologically confirmed VOD, laboratory parameters, and mode and frequency of ACD administration. Long-term hepatic toxicity was assessed 5 years after the end of therapy. RESULTS: Ninety-one patients were included in this analysis. Forty-one patients (45.1%) had histological evidence of VOD. The incidence of histologically proven VOD was significantly correlated with single administration of 45 microg/kg ACD (SIOP 2001 protocol) as compared to repeated dosing of l5 microg/kg (P = 0.003). Fifty-two percent of all patients had mild-to-severe abnormal liver enzymes 5 years after accomplishing therapy. CONCLUSION: Despite short-course preoperative chemotherapy regimen, patients are at risk of developing histological VOD. This risk is higher when ACD is administered in a 1-day 45 microg/kg regimen as compared to 3 days l5 microg/kg.

Infliximab use in children and adolescents with inflammatory bowel disease.

Infliximab is a chimeric monoclonal antibody (75% human, 25% murine) against tumor necrosis factor-alpha, a cytokine with a central role in the pathogenesis of inflammatory bowel disease. Large randomized controlled trials have shown the efficacy and safety of infliximab for the induction and maintenance of remission in adult patients with active Crohn disease (CD). In children and adolescents, mostly small, nonrandomized, non-placebo-controlled studies have supported the notion that infliximab is a potent drug in a population that does not respond to standard therapies. The safety of infliximab is of major concern, and the most frequent severe adverse events are related to severe infections and reactivation of tuberculosis. Non-life-threatening infusion reactions occur rather frequently and seem to be related to the formation of antibodies. The indications for infliximab treatment are therapy-resistant luminal CD (no efficacy or insufficient efficacy of conventional treatment) and therapy-resistant fistulas. An efficient remission induction strategy consists of 3 initial infliximab infusions at 0, 2, and 6 weeks in a dosage of 5 mg/kg to sustain remission. Patients needing maintenance therapy are subsequently treated with an infliximab infusion every 8 weeks. There are indications that the early stages of CD may be more susceptible to immunomodulation, and the natural history of CD may be altered by the introduction of infliximab early in the disease process instead of waiting until conventional therapy has failed. Major points of discussion are whether infliximab maintenance treatment should be episodic (on demand) or scheduled and when infliximab therapy can be discontinued.

Genetic susceptibility has a more important role in pediatric-onset Crohn's disease than in adult-onset Crohn's disease.

BACKGROUND: Genetic susceptibility may play a more important role in the etiology of early-onset inflammatory bowel disease (IBD) than in late-onset IBD, and therefore pediatric-onset IBD patients can be expected to have a higher frequency of gene mutations. We aimed to determine genotypes and phenotypes of patients with pediatric-onset IBD, to compare them with those of patients with adult-onset IBD and with controls, and to identify genotype-phenotype associations. METHODS: Polymorphisms R702W, G908R, and 3020insC of CARD15 (caspase activating recruitment domain 15); Asp299Gly and Thr399Ile of TLR4; -207G-->C, 1672C-->T (L503F), rs3792876, rs274551, rs272893, and rs273900 of SLC22A4/5; and 113G-->A as well as rs2289311, rs1270912, and rs2165047 of DLG5 (Drosophila discs large homologue 5) were assessed in 103 pediatric-onset and 696 adult-onset IBD patients. Phenotypic classification was based on disease localization and behavior. RESULTS: Homozygosity for 3020insC in CARD15 was significantly higher in patients with pediatric-onset Crohn's disease (CD) than in patients with adult-onset CD (4.2% versus 0.6%, 95% confidence interval [CI] 1.2-42.0). Homozygosity for single-nucleotide polymorphism (SNP) rs3792876 in SLC22A4/5 was significantly higher in patients with pediatric-onset CD than in patients with adult-onset CD (6.1% versus 1.1%, P=0.02). Polymorphism 3020insC in CARD15 was associated with ileal involvement (1.9% versus 13.3%, CI 1.0-53.8) and a positive family history (6.1% versus 20%, CI 1.2-9.0). DLG5 SNP rs2165047 was significantly associated with perianal disease (50% versus 21.2%, CI 1.4-4). CONCLUSIONS: Polymorphisms 3020insC in CARD15 and SNP rs3792876 in SLC22A4/5 occurred statistically significantly more often in patients with pediatric-onset CD than in patients with adult-onset CD. Polymorphisms 3020insC in CARD15 and SNP rs2165047 in DLG5 were associated with specific phenotypes in this pediatric-onset CD cohort.

The clinical effect of a new infant formula in term infants with constipation: a double-blind, randomized cross-over trial.

BACKGROUND: Nutrilon Omneo (new formula; NF) contains high concentration of sn-2 palmitic acid, a mixture of prebiotic oligosaccharides and partially hydrolyzed whey protein. It is hypothesized that NF positively affects stool characteristics in constipated infants. METHODS: Thirty-eight constipated infants, aged 3-20 weeks, were included and randomized to NF (n = 20) or a standard formula (SF; n = 18) in period 1 and crossed-over after 3 weeks to treatment period 2. Constipation was defined by at least one of the following symptoms: 1) defecation frequency < 3/week; 2) painful defecation; 3) abdominal or rectal palpable mass. RESULTS: Period 1 was completed by 35 infants. A significant increase in defecation frequency (NF: 3.5 pre versus 5.6/week post treatment; SF 3.6 pre versus 4.9/week post treatment) was found in both groups, but was not significantly different between the two formulas (p = 0.36). Improvement of hard stool consistency to soft stool consistency was found more often with NF than SF, but did not reach statistical significance (90% versus 50%; RR, 1.8; 95% CI, 0.9-3.5; p = 0.14). No difference was found in painful defecation or the presence of an abdominal or rectal mass between the two groups. Twenty-four infants completed period 2. Only stool consistency was significantly different between the two formulas (17% had soft stools on NF and hard stools on SF; no infants had soft stools on SF and hard stools on NF, McNemar test p = 0.046). CONCLUSION: The addition of a high concentration sn-2 palmitic acid, prebiotic oligosaccharides and partially hydrolyzed whey protein resulted in a strong tendency of softer stools in constipated infants, but not in a difference in defecation frequency. Formula transition to NF may be considered as treatment in constipated infants with hard stools.

Rectal bleeding in children: endoscopic evaluation revisited.

OBJECTIVES: Rectal bleeding is an alarming event both for the child and parents. It is hypothesized that colonoscopy instead of sigmoidoscopy and adding esophago-gastro-duodenoscopy in case of accompanying complaints, improves the diagnostic accuracy in children with prolonged rectal bleeding. STUDY DESIGN: All pediatric patients undergoing colonoscopy because of prolonged rectal bleeding over an 8-year period at the Emma Children's Hospital/Academic Medical Centre were reviewed. Patient demographics, clinical features, number and extent of endoscopic examinations and the endoscopic and histopathological findings were assessed. RESULTS: A total of 147 colonoscopies were performed in 137 pediatric patients (63 boys) because of prolonged rectal bleeding. Inflammatory bowel disease and polyp(s) were the most prevalent diagnoses. In 72% of patients diagnosed as Crohn's disease, focal, chronically active gastritis was seen on histology, giving support to the diagnosis Crohn's disease. In 22% of the cases polyps would have been missed in the case where only sigmoidoscopy was performed. No complications after endoscopic intervention were seen. CONCLUSIONS: Colonoscopy is the investigation of choice in children with prolonged rectal bleeding. In patients presenting with accompanying complaints such as abdominal pain or diarrhea, it is advisable to perform ileocolonoscopy combined with esophago-gastro-duodenoscopy. This combines a high diagnostic yield with a safe procedure.

Azathioprine maintains first remission in newly diagnosed pediatric Crohn's disease.

6-Mercaptopurine (6-MP) maintains remission in pediatric Crohn's disease (CD). Azathioprine, a prodrug of 6-MP, is used for maintenance of remission of CD in Europe. We evaluated to what extent azathioprine is used in newly diagnosed pediatric CD patients and whether maintenance of remission differed between patients using azathioprine or not. Charts of children (diagnosed 1998-2003, follow-up > or = 18 mo) were reviewed. Active disease was defined as Pediatric Crohn's Disease Activity Index (PCDAI) greater than 10 or systemic corticosteroid use. Remission was defined as PCDAI 10 or less without use of corticosteroids. Eighty-eight children (55M/33F, age 12 +/- 3 yr) were included. Seventy-two (82%) patients received azathioprine during the follow-up period (38 +/- 17 mo). Patients diagnosed after 2000 received azathioprine significantly earlier during the course of disease compared with those diagnosed earlier (median, at 233 vs. 686 days; P < 0.05). At initial presentation, moderate-severe disease activity and prescription of corticosteroids were more prevalent in patients using azathioprine compared with nonazathioprine patients (75% vs. 52%; P < 0.05; and 89% vs. 58%; P < 0.005, respectively). Duration of corticosteroid use was longer in patients receiving azathioprine (232 vs. 168 days; P < 0.005). Median maintenance of first remission in patients who initially used corticosteroids, however, was longer in patients receiving azathioprine compared with nonazathioprine patients (PCDAI, 544 vs. 254 days, P = 0.08; corticosteroid free, 575 vs. 259 days, P < 0.05, respectively). We conclude that, since 2000, azathioprine is being introduced earlier in the treatment of newly diagnosed pediatric CD patients. The use of azathioprine is associated with prolonged maintenance of the first remission.

New insight into rectal function in pediatric defecation disorders: disturbed rectal compliance is an essential mechanism in pediatric constipation.

OBJECTIVE: To evaluate rectal sensitivity in patients with pediatric constipation (PC) and nonretentive fecal soiling (FNRFS) using pressure-controlled distention (barostat). STUDY DESIGN: Thresholds for rectal sensitivity (first sensation, urge to defecate, and pain), and rectal compliance were determined using a barostat. RESULTS: A total of 69 patients with PC (50 males; mean age, 10.9 +/- 2.2 years) and 19 patients with FNRFS (15 males; mean age, 10.0 +/- 1.9 years) were compared with 22 healthy volunteers (HVs) (11 males; mean age, 12.7 +/- 2.6 years). Sensitivity thresholds were not significantly different among the 3 groups. Rectal compliance was increased in 58% of the patients with PC (P < .0001 vs HVs). Rectal compliance did not differ between patients with FNRFS and HVs. Children with PC with abnormal rectal function required significantly larger rectal volumes at urge to defecate. CONCLUSIONS: Increased compliance is the most prominent feature in patients with PC. Because of higher compliance in these children, larger stool volumes are required to reach the intrarectal pressure of the urge to defecate. Children with FNRFS have normal rectal function.

Longitudinal follow-up of children with functional nonretentive fecal incontinence.

BACKGROUND & AIMS: Functional nonretentive fecal incontinence (FNRFI), incontinence in the absence of signs of fecal retention, is a frustrating phenomenon in children. No data on long-term outcome are available. The aim was to investigate the long-term outcome of FNRFI patients after intensive medical treatment. METHODS: Between 1990 and 1999, 119 patients (96 boys) with FNRFI were enrolled in 2 prospective, randomized trials investigating the effect of biofeedback training and/or laxative treatment. Follow-up (FU) was performed at 6 months, 1 year, and thereafter annually until September 2004. A standardized questionnaire was used to evaluate symptoms. Success was defined as a fecal incontinence frequency <1 per 2 weeks. RESULTS: Median age (25th-75th percentiles) was 9.2 years (range, 7.9-11.6 years). A 90% FU was achieved at all stages of the study. After 2 years of intensive therapy, 33 of 112 (29.5%) patients were successfully treated. The cumulative success percentage after 7 years of FU was 80%. At the biologic ages of 12 and 18 years, 49.4% (40/81) and 15.5% (9/58), respectively, of the patients still had fecal incontinence. Duration of fecal incontinence, with 4 years of age as the starting age for fecal incontinence (when a child should be toilet trained), was not related to successful outcome or relapse. Relapse occurred in 37% of patients. CONCLUSIONS: Only 29% of the patients with FNRFI were successfully treated after 2 years of intensive treatment. Despite recovery in the majority of patients beyond puberty, at age 18 years, 15% continued to have fecal incontinence.

The Leech method for diagnosing constipation: intra- and interobserver variability and accuracy.

BACKGROUND: The data concerning the value of a plain abdominal radiograph in childhood constipation are inconsistent. Recently, positive results have been reported of a new radiographic scoring system, "the Leech method", for assessing faecal loading. OBJECTIVE: To assess intra- and interobserver variability and determine diagnostic accuracy of the Leech method in identifying children with functional constipation (FC). MATERIALS AND METHODS: A total of 89 children (median age 9.8 years) with functional gastrointestinal disorders were included in the study. Based on clinical parameters, 52 fulfilled the criteria for FC, six fulfilled the criteria for functional abdominal pain (FAP), and 31 for functional non-retentive faecal incontinence (FNRFI); the latter two groups provided the controls. To assess intra- and interobserver variability of the Leech method three scorers scored the same abdominal radiograph twice. A Leech score of 9 or more was considered as suggestive of constipation. ROC analysis was used to determine the diagnostic accuracy of the Leech method in separating patients with FC from control patients. RESULTS: Significant intraobserver variability was found between two scorers (P=0.005 and P<0.0001), whereas there was no systematic difference between the two scores of the other scorer (P=0.89). The scores between scorers differed systematically and displayed large variability. The area under the ROC curve was 0.68 (95% CI 0.58-0.80), indicating poor diagnostic accuracy. CONCLUSIONS: The Leech scoring method for assessing faecal loading on a plain abdominal radiograph is of limited value in the diagnosis of FC in children.

Esophagitis and Barrett esophagus after correction of esophageal atresia.

BACKGROUND: Gastroesophageal reflux is a frequent problem after esophageal atresia (EA) repair. Our aim was to determine the prevalence of esophagitis and Barrett esophagus more than 10 years after repair of EA. METHODS: Ninety-two patients treated between 1973 and 1985 were included in this prospective study. A questionnaire was completed by 86 patients; esophagogastroscopy was performed in 49 patients. RESULTS: Only 36 patients had no complaints at all. Thirty-one patients complained of difficulties swallowing solid food; 23 complained of heartburn. Esophagogastroscopy revealed grade 3 esophagitis in 2 patients and a macroscopic image of Barrett esophagus in 2. Histology showed esophagitis in 30 patients, gastric metaplasia in 3, and no intestinal metaplasia (Barrett esophagus). CONCLUSIONS: For epidemiologic reasons, that is, the short interval of follow-up (10 years) and the low compliance of the study group, larger numbers are needed to decide if routine long-term endoscopic screening after repair of EA is necessary. For now, it cannot yet be recommended. The prevalence of symptoms of gastroesophageal reflux disease in this study group is higher than that in the general population, but we found no severe complications of gastroesophageal reflux in the pediatric age group.

Diagnosis of Hirschsprung's disease: a prospective, comparative accuracy study of common tests.

OBJECTIVE: To compare the diagnostic accuracy of contrast enema (CE), anorectal manometry (ARM), and rectal suction biopsy (RSB) for the detection of Hirschsprung's disease (HD). STUDY DESIGN: Following a prospective protocol, infants suspected of HD underwent all 3 index tests. Children with positive results on 2 or more index tests or who continued to have severe bowel problems underwent a full thickness biopsy as reference standard. Clinical follow-up was the reference standard in all other children. RESULTS: Between 2000 and 2003, 111 consecutive patients (67 boys; median age, 5.3 months) in whom HD was suspected were enrolled. HD was found in 28 patients. RSB had the highest sensitivity (93%) and specificity (100%) rates, but values were not significantly different from CE (sensitivity, 76%; specificity, 97%) or from ARM (sensitivity, 83%; specificity, 93%). Inconclusive test results occurred in 8 infants with CE, in 15 infants with ARM because of agitation, and in 2 infants with RSB. CONCLUSION: RSB is the most accurate test for diagnosing HD, and it has the lowest rate of inconclusive test results.