Less Anti-infliximab Antibody Formation in Paediatric Crohn Patients on Concomitant Immunomodulators.

OBJECTIVES: To evaluate the effect of immunomodulators on formation of antibodies to infliximab (ATI) in paediatric patients with Crohn disease (CD) and the association of ATI and loss of response. METHODS: Retrospective multicentre observational study (January 2009-December 2014) among Dutch children with CD treated with infliximab (IFX). ATI formation was analysed with Chi-square test and time-to-ATI formation with Kaplan-Meier and log-rank test. RESULTS: A total of 229 children were identified. ATIs were measured in 162 patients (70.7%) and 25 (15%) developed ATIs: 6 of 62 (10%) on continuous combined immunosuppression (CCI), 11 of 81 (14%) on early combined immunosuppression (ECI), and 8 of 19 (42%) on IFX monotherapy. ATI formation was higher in patients on IFX monotherapy compared to CCI (P = 0.003) and ECI (P = 0.008), whereas no significant difference was found between CCI and ECI. Sixteen out of 25 patients (64%) with ATIs had loss of response, compared with 32 of 137 patients (19%) without ATIs (P < 0.00002, log rank 0.02). Among patients treated with ECI, 10 of 55 (18%) developed ATIs within the first 12 months, compared to 1 of 26 (4%) after more than 12 months. CONCLUSIONS: In children with CD combination therapy is associated with significant reduction of antibody formation and prolonged effectivity compared to IFX monotherapy. ECI for at least 12 months, followed by IFX monotherapy, may be an equally effective alternative to CCI.

Complications and Disease Recurrence After Primary Ileocecal Resection in Pediatric Crohn's Disease: A Multicenter Cohort Analysis.

BACKGROUND: Studies on the outcome of ileocecal resection in pediatric Crohn's disease (CD) have a limited follow-up and fail to assign predictors of adverse outcomes. Therefore, we aimed to investigate (I) the complication and disease recurrence rates and (II) identify risk factors for these adverse outcomes after ileocecal resection for pediatric CD. METHODS: This is a retrospective cohort analysis of all children (<18 years) that underwent ileocecal resection as first intestinal resection for CD derived from 7 tertiary hospitals in the Netherlands (1990-2015). Risk factors were identified using multivariable analysis. RESULTS: In total, 122 children were included (52% male; median age 15.5 years [interquartile range 14.0-16.0]). Severe postoperative complications rate was 10%. Colonic disease (odds ratio: 5.6 [95% confidence interval {CI}: 1.3-26.3], P = 0.024), microscopically positive resection margins (odds ratio: 10.4 [95% CI: 1.1-100.8] P = 0.043), and emergency surgery (odds ratio: 6.8 [95% CI: 1.1-42.2], P = 0.038) were risk factors for severe complications. Clinical and surgical recurrence rates after 1, 5 and 10 years were 19%, 49%, 71% and 2%, 12%, 22%, respectively. Female sex (hazard ratio [HR]: 2.1 [95% CI: 1.1-3.8], P = 0.023) was a risk factor for clinical recurrence, whereas ileocecal disease (HR: 3.9 [95% CI: 1.2-12.5], P = 0.024) and microscopically positive resection margins (HR: 9.6 [95% CI: 1.2-74.5], P = 0.031) were risk factors for surgical recurrence. Immediate postoperative therapy reduced the risk of both clinical (HR: 0.3 [95% CI: 0.1-0.6], P = 0.001) and surgical (HR: 0.5 [95% CI: 0.1-0.9], P = 0.035) recurrence. CONCLUSIONS: Ileocecal resection is an effective and durable treatment of pediatric CD, although postoperative complications occur frequently. Postoperative therapy may be started immediately to prevent disease recurrence.

Pediatric IBD-unclassified Is Less Common than Previously Reported; Results of an 8-Year Audit of the EUROKIDS Registry.

BACKGROUND: Inflammatory bowel disease-unclassified (IBD-U) is diagnosed in ∼10% of pediatric and adolescent onset IBD patients. The EUROKIDS registry (2004) initiated by the Porto IBD working group of ESPGHAN prospectively monitors diagnostic workup of newly diagnosed pediatric and adolescent onset IBD patients. We aimed to describe diagnostic workup, phenotype, and change of diagnosis over time in pediatric IBD-U patients. METHODS: Data were collected on children from 52 centers across 20 European countries and Israel, diagnosed with IBD from May 2005 through November 2013. Full endoscopy plus small bowel radiology was considered complete diagnostic workup. Participating centers reporting IBD-U patients were queried in 2014 for follow-up data. RESULTS: IBD-U was the provisional first diagnosis in 265 of 3461 children (7.7%) (91/158 [58%] with pancolitis; 140 [53%] male), diagnosed more frequently under the age of 10 (median age 12.3 years, 89 [34%] under 10 years). Half (48%) had undergone complete diagnostic workup. Lack of small bowel radiology was the prevailing reason for incomplete workup. As a result of reinvestigations (endoscopy in 54%, radiology in 38%) during a median follow-up of 5.7 years (interquartile range, 2.5-7.8), a change in diagnosis from IBD-U to Crohn's disease (12%) or ulcerative colitis (20%) was reported. CONCLUSIONS: Only half of patients reported as IBD-U in EUROKIDS had undergone complete diagnostic workup. Follow-up with reinvestigations resulted in a reduction of IBD-U rate to 5.6%. A diagnosis of IBD-U becomes less likely in case of complete diagnostic workup. Implementation of clear diagnostic criteria will further reduce the rate of IBD-U in the future.

[Treatment of children with intestinal failure: intestinal rehabilitation, home parenteral nutrition or small intestine transplantation?]. / Behandeling van kinderen met darmfalen: darmrevalidatie, parenterale voeding thuis of dunnedarmtransplantatie?

Intestinal failure is characterised by inadequate absorption of food or fluids, which is caused by insufficient bowel surface area or functioning. Children with chronic intestinal failure are dependent on parenteral nutrition (PN), which can be provided at home (HPN). In the Netherlands, HPN for children is coordinated by special HPN and intestinal failure teams from the Emma Children's Hospital, the Erasmus MC-Sophia Children's Hospital and the Radboud University Medical Center. HPN is the treatment of choice for children with chronic intestinal failure. Small intestine transplantation is only justified if HPN fails because complications arise; this procedure is carried out at the University Medical Center in Groningen. In addition to medical complications, HPN has psychosocial implications both for the children and their parents. Systematic attention to these can be provided by the 'Quality of Life in Clinical Practice' method, which also enables collection of data relevant for research purposes.

[A child with an oesophageal foreign body for 1.5 years]. / Kind met 1,5 jaar een corpus alienum in de oesofagus.

A 2-year-old boy presented with a 1.5-year history of recurrent cough, wheeze and feeding problems. An x-ray of the thorax and an oesophagogram showed constriction of the trachea and proximal portion of the oesophagus. On endoscopy a foreign body was found, embedded in extensive granulation tissue. This could only be removed surgically via oesophagotomy, and turned out to be a plastic toy coin.

Overlap, common features, and essential differences in pediatric granulomatous inflammatory bowel disease.

Overlap in the clinical presentation of pediatric granulomatous inflammatory bowel disease may be substantial, depending on the mode of presentation. Chronic granulomatous disease (CGD) may present with granulomatous colitis, perianal abscesses, hepatic abscesses or granulomas, failure to thrive, and obstruction of the gastrointestinal tract (including esophageal strictures and dysmotility, delayed gastric emptying, and small bowel obstruction). Anemia, thrombocytosis, elevated C-reactive protein and erythrocyte sedimentation rate, and hypoalbuminemia are nonspecific and may occur in any of the granulomatous inflammatory bowel diseases. In histology, macrophages with cytoplasmic inclusions will be rather specific for CGD. Sarcoidosis may present with abdominal pain or discomfort, diarrhea, weight loss, growth failure, delayed puberty, erythema nodosum, arthritis, uveitis, and hepatic granulomata. Only in 55% of the patients will angiotensin-converting enzyme be elevated. The noncaseating epithelioid granulomata will be unspecific. Bronchoalveolar lymphocytosis and abnormalities in pulmonary function are reported in sarcoidosis and in Crohn disease (CD) and CGD. Importantly, patients with CD may present with granulomatous lung disease, fibrosing alveolitis, and drug-induced pneumonitis. Sarcoidosis and concomitant gastrointestinal CD have been reported in patients, as well as coexistence of CD and sarcoidosis in siblings. Common susceptibility loci have been identified in CD and sarcoidosis. CD and CGD share defects in the defense mechanisms against different microbes. In the present review, common features and essential differences are discussed in clinical presentation and diagnostics--including histology--in CGD, sarcoidosis, and CD, together with 2 other granulomatous inflammatory bowel diseases, namely abdominal tuberculosis and Hermansky-Pudlak syndrome. Instructions for specific diagnosis and respective treatments are provided.

Screening rules for growth to detect celiac disease: a case-control simulation study.

BACKGROUND: It is generally assumed that most patients with celiac disease (CD) have a slowed growth in terms of length (or height) and weight. However, the effectiveness of slowed growth as a tool for identifying children with CD is unknown. Our aim is to study the diagnostic efficiency of several growth criteria used to detect CD children. METHODS: A case-control simulation study was carried out. Longitudinal length and weight measurements from birth to 2.5 years of age were used from three groups of CD patients (n = 134) (one group diagnosed by screening, two groups with clinical manifestations), and a reference group obtained from the Social Medical Survey of Children Attending Child Health Clinics (SMOCC) cohort (n = 2,151) in The Netherlands. The main outcome measures were sensitivity, specificity and positive predictive value (PPV) for each criterion. RESULTS: Body mass index (BMI) performed best for the groups with clinical manifestations. Thirty percent of the CD children with clinical manifestations and two percent of the reference children had a BMI Standard Deviation Score (SDS) less than -1.5 and a decrease in BMI SDS of at least -2.5 (PPV = 0.85%). The growth criteria did not discriminate between the screened CD group and the reference group. CONCLUSION: For the CD children with clinical manifestations, the most sensitive growth parameter is a decrease in BMI SDS. BMI is a better predictor than weight, and much better than length or height. Toddlers with CD detected by screening grow normally at this stage of the disease.

Infliximab dependency in pediatric Crohn's disease: long-term follow-up of an unselected cohort.

BACKGROUND: Infliximab is effective for induction and maintenance of remission in Crohn's disease. It is unknown how long patients should be kept on infliximab therapy. The primary aim of this study was to assess duration of effective maintenance therapy and infliximab dependency in pediatric CD patients initially responding to infliximab therapy. METHODS: All pediatric patients treated with infliximab by pediatric gastroenterologists in the Netherlands because of severe luminal or fistulizing CD with initial response to infliximab therapy were reviewed. Duration of therapy, clinical response and adverse events were recorded. RESULTS: Sixty-six CD patients (37 boys) in 10 hospitals were initially responding to infliximab therapy. Mean age at the start of infliximab therapy was 14.5 years (range, 8.1-18.5 years). Mean follow-up since infliximab was started was 41.3 months (range 12-165). In total, 991 infusions were administered. Analysis demonstrates that 15.2% of patients had prolonged response, while 56.1% were infliximab dependent and 28.8% lost response. In total, 10 patients (15.2%) developed an infection during infliximab therapy and 8 (12.1%) had an immediate allergic reaction. CONCLUSIONS: Good clinical response to maintenance infliximab therapy was seen in 70% of patients. Infliximab maintenance therapy seems very effective and safe in pediatric CD. However, more than half of the patients in this cohort is dependent on repeated infliximab infusions. The number of infliximab infusions received when patients lost response to infliximab was diverse. There was no statistical difference regarding response to infliximab therapy when started early as compared to later in the course of Crohn's disease.

Chemokine production by buccal epithelium as a distinctive feature of pediatric Crohn disease.

OBJECTIVES: Inflammatory bowel diseases (IBD) represent an aberrant immune response by the mucosal immune system to luminal bacteria. Because the oral mucosa harbors the first epithelial cells that interact with microorganisms, we assessed the immunologic activity of buccal epithelium in children with IBD and adults with Crohn disease. METHODS: Buccal epithelial cells were obtained from 17 children and 14 adults with Crohn disease, 18 children with ulcerative colitis, and 40 controls. Cells were cultured with and without microbial stimulation. Chemokine levels were determined in culture supernatants by cytometric bead array and enzyme-linked immunoabsorbent assay. CXCL-8 production was studied by immunohistochemical analysis of these cells. CXCL-8 production by lipopolysaccharide stimulated monocyte-derived dendritic cells from these patients was determined. RESULTS: Compared with controls, pediatric ulcerative colitis patients, and adult Crohn disease patients, only in children with Crohn disease did buccal epithelial cells exhibit enhanced production of CXCL-8, CXCL-9, and CXCL-10. In vitro stimulation with lipopolysaccharide or zymosan resulted in a further increase of chemokine levels only in cells from pediatric Crohn disease patients. CXCL-8 production by stimulated monocyte-derived dendritic cells from children with Crohn disease was equal to that of children with ulcerative colitis. CONCLUSIONS: Buccal epithelium of children with Crohn disease is immunologically active, even in the absence of oral lesions. The enhanced chemokine production is associated with pediatric Crohn disease and appears restricted to cells derived from the epithelial barrier. Assessment of chemokine production by buccal epithelial cells may become a new, rapid, noninvasive test for screening and classification of IBD in children.