Pediatric CD Patients Research Articles

A228 EVOLUTION OF MRE FINDINGS IN PAEDIATRIC PATIENTS WITH SMALL BOWEL CROHN’S DISEASE ON MAINTENANCE METHOTREXATE

Abstract Background Observational data in children and RCT data in adults indicate that methotrexate (MTX) is associated with induction and maintenance of clinical remission in luminal Crohn’s disease, but efficacy in achieving intestinal healing has not been examined. Aims To examine the evolution of MRE signs of inflammation in children treated with MTX. Methods In this retrospective cohort study, we reviewed paediatric CD patients on maintenance MTX monotherapy for >4 months who underwent serial MREs between July 2010 and October 2015. MREs were reviewed by a radiologist blind to clinical data. Overall inflammatory activity on each MRE was scored as minimal, mild, moderate or severe, informed by the presence of bowel wall thickness, wall enhancement, T2 hyperintensity, comb sign, mesenteric edema, penetrating disease, stricturing, diffusion restriction and motility. The radiologist’s global assessment of change from MRE 1 to MRE 2 was scored as improved, unchanged or worsened. Clinical findings, disease activity (assessed by weighted paediatric CD activity index [wPCDAI]) and surgical history were also extracted from medical records by a clinician blind to MRE results. Results Thirty-five patients were included (median age at diagnosis 12 [IQR 11–14] years; 77% male; 60% inflammatory (B1), 17% stricturing (B2), 23% penetrating (B3) disease). Between baseline and follow-up MRE, wPCDAI (median 15 [IQR 7–43] decreased to 8 [IQR 0–18]; p=0.006) and CRP (median 9 [IQR 2–36] decreased to 5 [IQR 5–9]; p=0.013) and 74% (N=26) were in clinical remission (wPCDAI < 12.5) at MRE 2. MRE features that significantly improved from MRE 1 to 2 were comb sign from 63% (N=37) to 38% (N=14) (p=0.02) and penetrating disease from 14% (N=8) to 0 (p=0.03). After a median of 17 months (IQR 13–23), 51% (N=18) of patients improved, 29% (N=10) worsened and 20% (N=7) had no change based on the radiologist’s global assessment. Of the 21 patients with moderate/severe disease at MRE 1, 33% (N=7) had minimal/mild disease by MRE 2. 66% (N=14/21) continued to have moderate/severe disease at MRE 2. Additionally, a further 14% (N=2/14) of those with minimal/mild disease at baseline MRE progressed to moderate/severe disease at MRE 2. Complete details of change between MRE 1 and MRE 2 are displayed in Figure 1. Conclusions Despite signs of clinical improvement, many paediatric CD patients on maintenance MTX therapy for >4 months have unchanged or worsened MRE findings. This underscores the need for follow-up imaging in these cases. Funding Agencies None

P041 DEVELOPMENT OF PROMIS PEDIATRIC PATIENT-REPORTED OUTCOME SHORT FORMS FOR FATIGUE AND PAIN INTERFERENCE IN CHILDREN WITH CROHN’S DISEASE

Abstract Introduction There is a need for reliable, valid patient-reported outcome (PRO) measures to assess the health and quality of life in pediatric Crohn’s disease (PCD). The development of PROs for this population may be facilitated by using Patient-Reported Outcomes Measurement Information System (PROMIS) item banks, which were developed using rigorous psychometric methods. We aimed to develop disease-specific PROMIS short forms by conducting qualitative research to identify the items that are most relevant to children with PCD. Methods Participants in an initial card sorting study included 42 children with CD (ages 8–17), 70 parents of children with CD, and 26 clinicians with expertise in CD. Using an online program, participants rated the importance of PROMIS items for pediatric CD patients. This exercise indicated that children, parents, and clinicians endorse Fatigue and Pain Interference items as important for PCD. In a separate study, trained research coordinators conducted one-on-one semi-structured interviews with 37 children with CD to further explore their experiences with fatigue and pain. Research coordinators also conducted one-on-one cognitive interviews with 14 children with CD. Each participant completed a questionnaire and then was interviewed about the reasoning for their answers. All interviews were transcribed and coded for meaning units, defined as conceptually distinct statements in the words of the participant. Results In semi-structured interviews, highly reported facets of fatigue and its impact included feelings of tiredness, friendships, and sports/exercise. Highly reported facets of pain and its impact included feelings of hurt, friendships, family, attention, and sports/exercise. Participants’ responses revealed the same breadth and types of lived experiences of fatigue and pain as children from the development samples drawn from the general population. Ratings of children’s reasoning and logic in cognitive interviews showed strong understanding of PROMIS items. Final item selection for the PCD-specific PROMIS short forms involved consideration of the concepts that participants identified as important, item understandability, psychometric evaluation of precision and coverage, and balance across different facets of each domain. Conclusions Results support the content validity and comprehensibility of PROMIS Pediatric Fatigue and Pain Interference measures in PCD. This work contributed to the development of 8-item short forms that are tailored to assess the lived experiences of fatigue and pain interference in PCD.

P365 Identification of predictive factors of AZA/6-MP treatment outcome in paediatric luminal Crohn’s disease: a multicentre study of the paediatric IBD Porto group of ESPGHAN

Abstract Background According to current guidelines, most paediatric patients in Europe diagnosed with Crohn′s disease (CD) are prescribed long-term immunosuppressive therapy with azathioprine (AZA). This study aimed to develop a predictive model allowing to stratify patients who will not benefit from AZA maintenance treatment and who require a more intensive therapeutic approach early after diagnosis. Methods The study was designed to develop a clinical prediction rule using retrospective data analysis from patients included to prospective inception cohort, the EUROKIDS-IBD until 2017. In total, 1190 CD patients using AZA were selected from the registry in 13 European centres. Of these, 441 patients who responded to induction treatment, started AZA treatment within 6 weeks from the time of diagnosis and maintained remission at week 12 were entered into this multicentre study. The primary outcome was time to clinical relapse defined as a necessity of re-induction of remission. A sequence of Cox models was fitted to predict the risk of relapse. Variables appearing to be significant in univariate risk analyses were added to the model one by one and non-significant terms were dropped. Results More than 50 % of patients did not experience a clinical relapse within 2 years of AZA treatment (Figure 1). The median time to relapse was 2.11 (CI 1.59–2.46) years. Out of all tested parameters available at the time of diagnosis,8 were predictive in the context of early relapse. Only 4 of these variables, namely centre (p = 0.0009), age (HR = 1.389 95% CI (1.004–1.921), p = 0.047), CRP (HR = 1.504 95% CI (1.116–2.027), p = 0.008) and BMI Z-score (HR = 0.830 95% CI (0.742–0.928), p = 0.001), remained significant in multivariate analyses. Conclusion In paediatric CD patients achieving clinical remission after induction treatment at week 12, AZA was effective as maintenance treatment in over 50% of patients for 2 years. Due to low values of HR, the possibility to predict relapse on AZA treatment appears to be limited. Acknowledgement: This work was supported by the Grant Agency of Charles University in Prague [grant number 364617] and by Ministry of Health, Czech Republic-conceptual development of research organisation, Motol University Hospital, Prague, Czech Republic [00064203].

Circulating microRNAs as potential non-invasive biomarkers in pediatric patients with celiac disease.

Celiac disease is an enteropathy induced by ingestion of gluten triggering an immune response in genetically predisposed individuals. MiRNAs are small non-coding RNAs that have a role as regulators of gene expression at the post transcriptional level. The aim of this study is to evaluate the possibility of using circulating miRNAs as non-invasive biomarkers in pediatric patients with celiac disease. In addition, we examine the effect of a gluten-free diet on the expression of these miRNAs in serum of CD patients. The expression pattern of miR-21 and miR-31 was estimated in serum of 25 untreated CD patients (recently diagnosed), 25 treated CD patients (on gluten-free diet) and 20 healthy controls using qRT-PCR. Our results demonstrated the significant up-regulation of microRNA-21 in the untreated celiac patients in comparison with the treated group and healthy controls. Moreover, miR-31 expression was significantly under-expressed in the untreated celiac patients in comparison with the treated group and healthy controls. Furthermore, the results showed that miR-21 expression level was significantly positively correlated with the tTG IgA auto-antibodies. In conclusion, circulating miRNA-21 and miRNA-31 could serve as potential non-invasive biomarkers for pediatric CD patients.

Methotrexate for the Treatment of Pediatric Crohn's Disease: A Systematic Review and Meta-analysis.

Methotrexate (MTX) is an immunomodulator used for the treatment of pediatric inflammatory bowel disease (IBD). There are currently no RCTs that assess the treatment efficacy of methotrexate within the pediatric IBD patient population. This systematic review and meta-analysis assesses the efficacy of MTX therapy among the existing pediatric literature. A systematic literature search was performed using MEDLINE and the Cochrane library from inception until March 2016. Synonyms for 'pediatric', 'methotrexate' and 'IBD' were utilized as both free text and MESH search terms. The studies included contained clinical remission (CR) rates for MTX treatment of pediatric IBD patients 18 yrs old, as mono- or combination therapy. Case studies with <10 patients were excluded. Quality assessment was performed with the Newcastle-Ottawa Scale. Meta-analysis calculated pooled CR rates. A random-effects meta-analysis with forest plots was performed using R. Fourteen (11 monotherapy, 1 combination therapy, 2 both; n = 886 patients) observational studies were eligible out of 202 studies. No interventional studies were identified. The pooled achieved CR rate for pediatric CD patients on monotherapy within 3-6 months was 57.7% (95% CI 48.2-66.6%), (P =0.22; I2 = 29.8%). The CR was 37.1% (95% CI 29.5-45.5%), (P = 0.20; I2 = 37.4%) for maintenance therapy at 12 months. Sub-analysis could not identify CR differences between MTX administration types, thiopurine exposure. This meta-analysis demonstrated that, over 50% of pediatric Crohn's disease patients induced with methotrexate achieved clinical remission, while 12-month remission rate was only 37%. Prospective controlled interventional trials should assess treatment efficacy among patient subgroups. 10.1093/ibd/izy078_video1izy078.video15774883936001.

Characteristics of Faecal Microbiota in Paediatric Crohn's Disease and Their Dynamic Changes During Infliximab Therapy.

Crohn's disease [CD] is known to be associated with gut microbial dysbiosis. Infliximab [IFX] is increasingly used to treat paediatric CD; however, it is not clear how the gut microbiota is modified during IFX treatment. The aim of this study was to characterise the faecal microbiota community composition in paediatric CD patients and to assess its dynamic changes during IFX therapy. A 16S rRNA sequencing approach was applied to determine the compositions of microbial communities in faecal samples. The composition and function of the faecal microbiota were compared between CD patients and healthy controls. Characteristics of faecal microbiome composition in paediatric CD patients before IFX treatment were represented by a lower biodiversity, a gain in Enterococcus, and a significant loss in multiple short-chain fatty acid [SCFA]-producing bacteria, including Anaerostipes, Blautia, Coprococcus, Faecalibacterium, Lachnospira, Odoribacter, Roseburia, Ruminococcus, and Sutterella. Additionally, alterations were observed in metabolic functions of the gut microbial community in CD. IFX treatment increased the biodiversity of gut microbiota and shifted its composition as well as its functional capabilities in the paediatric CD patients toward a healthy status. However, multiple SCFA-producing taxa were not significantly expanded. The sustained response of paediatric CD patients to IFX was associated with abundance of SCFA-producing bacteria. A lower biodiversity with alterations in the composition and function of faecal microbial community, characterising gut microbial dysbiosis, was observed in Chinese paediatric CD patients. IFX diminished the CD-associated gut microbial dysbiosis but was deficient in increasing certain SCFA-producing taxa.

HLA-DQ2 and -DQ8 haplotypes frequency and diagnostic utility in celiac disease patients of Gaza strip, Palestine

PurposeCeliac disease (CD) diagnosis can be established by serological and small bowel biopsy (SBB), while absence of HLA-DQ2 and -DQ8 haplotypes excludes the disease. The present study aims at evaluating the diagnosis of a representative sample of pediatric and adult CD patients of Gaza strip in light of DQ2 and DQ8 haplotypes expression.MethodsUnrelated CD patients (n = 101) and matched healthy controls (n = 97) were genotyped for DQA1*05, DQB1*02 and DQB1*03:02 alleles by allele-specific real-time PCR. The diagnosis was re-evaluated according to the patient laboratory tests and HLA-DQ genotype.ResultsThe diagnosis of 35 patients who have been managed for CD could not be confirmed. Twenty-five of them were diagnosed upon their clinical presentation only. The remaining were either negative for serological and SBB tests or negative for HLA-DQ haplotypes. The HLA-DQ alleles were negative in 4 SBB and one Anti-EMA positive patients. The frequency of DQ2 and DQ8 haplotypes among the remaining 65 confirmed cases was 70.8 and 15.4%, respectively, compared to 17.5 and 27.8% in the controls. The DQB1*02 allele was the most common in the cases (84.6%) followed by DQA1*05 allele (80%) and DQB1*03:02 allele (20%). The DQA1*05 allele was commonest in the control group (54.6%) followed by DQB1*02 allele (42.3%) and DQB1*03:02 allele (28.9%).ConclusionsAbsence of HLA-DQ2 and HLA-DQ8 genotyping in the workup of patients may result in CD misdiagnosis, particularly in a setting with poor histopathological diagnostic capacity.

The industrial food additive, microbial transglutaminase, mimics tissue transglutaminase and is immunogenic in celiac disease patients.

Microbial transglutaminase (mTg) is capable of cross-linking numerous molecules. It is a family member of human tissue transglutaminase (tTg), and is involved in CD. Despite declarations of the safety of mTg for industrial use, direct evidence for immunogenicity of the enzyme is lacking. The serological activity of mTg, tTg, gliadin complexed mTg (mTg neo-epitope) and gliadin complexed tTg (tTg neo-epitope) were studied in 95 pediatric celiac patients (CD), 99 normal children (NC), 79 normal adults (NA) and 45 children with nonspecific abdominal pain (AP). Sera were tested by ELISAs, detecting IgA, IgG or both IgA and IgG (check): AESKULISA® tTg (tTg), AESKULISA® tTg New Generation (tTg neo-epitope (tTg-neo)), microbial transglutaminase (mTg) and mTg neo-epitope (mTg-neo). Marsh criteria were used for the degree of intestinal injury. Parallel, mTg and tTg neo-epitopes were purified by asymmetric field flow fractionation, confirmed by multi-light-scattering and SDS-PAGE, and analyzed in adult CD and control groups by competition ELISAs. No sequence homology but active site similarity were detected on alignment of the 2 Tgs. Comparing pediatric CD patients with the 2 normal groups: mTg-neo IgA, IgG and IgA+IgG antibody activities exceed the comparable mTg ones (p<0.0001). All mTg-neo and tTg-neo levels were higher (p<0.001). tTg IgA and IgG+IgA were higher than mTg IgA and IgA+IgG (p<0.0001). The levels of tTg-neo IgA/IgG were higher than tTg IgA/IgG (p<0.0001). The sequential antibody activities best reflecting the increased intestinal damage were tTg-neo check>tTg-neo IgA≥mTg-neo IgG>tTg-neo IgG>mTg-neo check>mTg-neo IgA. Taken together, tTg-neo check, tTg-neo IgA and mTg-neo IgG correlated best with intestinal pathology (r2=0.6454, r2=0.6165, r2=0.5633; p<0.0001, p<0.0001, p<0.0001, respectively). Purified mTg-neo IgG and IgA showed an increased immunoreactivity compared to single mTg and gliadin (p<0.001) but similar immunoreactivity to the tTg-neo IgG and IgA ELISA. Using competition ELISA, the mTg neo-epitopes and tTg neo-epitopes have identical outcomes in CD sera both showing a decrease in optical density of 55±6% (p<0.0002). mTg is immunogenic in children with CD and, by complexing to gliadin, its immunogenicity is enhanced. Anti-mTg-neo-epitope IgG antibodies correlate with intestinal damage to a comparable degree as anti-tTg-neo IgA. mTg and tTg display a comparable immunopotent epitope. mTg-neo IgG is a new marker for CD. Further studies are needed to explore the pathogenic potential of anti-mTg antibodies in CD.

Pediatric Crohn's disease, iron deficiency anemia and intravenous iron treatment: a follow-up study

Background and aims: Increasing evidence in adults demonstrates efficacy and safety of IV iron in inflammatory Bowel disease (IBD) associated iron deficiency anemia; however, evidence in pediatric patients is yet scarce and no previous study has included a long follow-up. This study aimed to evaluate safety and efficacy of IV iron (primary end point), and the need of re-treatment (secondary end point), in this setting.Methods: Prospective recruitment (40 months); PCDAI determined before and after treatment; anemia defined according to WHO criteria; IV iron treatment included iron sucrose and ferric carboxymaltose. Primary and secondary endpoints included hemoglobin, serum ferritin, transferrin saturation at baseline and 4-6 weeks after treatment; and the need of re-treatment during the median follow-up period (18 months), respectively.Results: Nineteen patients (median age: 15.5 years) with remissive/mild disease were included. At recruitment, the median hemoglobin was 10.5 g/dl, (median s-ferritin: 20.1 ug/l, median transferrin saturation; 6%) and 4-6 weeks after treatment was 12.7 g/dl. Median hemoglobin according to age groups before vs. after treatment: <12 years:11 vs. 12.0 g/dl; females ≥12 years:9.9 vs. 12.6 g/dl; and males ≥12 years:11.1 vs. 13.3 g/dl. Patients with remissive vs. mild disease had median Hb of 10.5 g/dl vs. 10.6 g/dl, and median s-ferritin: 6.8 ug/dl vs. 43.3 ug/dl, respectively). Nine patients were treated with iron sucrose (median dose 672.6 mg/dl) and 10 patients with ferric carboxymaltose (median dose 811.5 mg/dl). No major adverse reactions occurred. Six patients needed re-treatment after a median 15.5 months period.Conclusions: Our prospective study, concerning pediatric IBD anemia patients with remission/mild disease and a significant follow-up, emphasizes efficacy and safety of IV-iron and the importance of long-term follow-up of iron status.Summary: In pediatric IBD iron anemia, the evidence supporting the efficacy and safety of IV-iron is scare. This prospective study aims to evaluate the safety and efficacy (short and long term) of IV-iron in these patients. Nineteen pediatric CD patients were evaluated before and after IV iron treatment (40-month period).The median Hb before and after IV iron was 10.5 and 12.7 g/dl, respectively. No major adverse reactions were documented. Six patients needed re-treatment (median period of 15.5 months). This study further demonstrates the efficacy and safety of IV iron. It reinforces the importance of long-term follow-up of the iron status in pediatric CD patients.

Altered Fecal Microbiota in Paediatric Inflammatory Bowel Disease.

Several factors support the view of inflammatory bowel disease [IBD] origin in the host responsiveness to intestinal bacteria, although no single bacterial species has been shown as a causative agent in the pathogenesis. Our aim was to analyse the fecal microbiota of paediatric IBD patients at different stages of the disease. In addition, the characteristics of immune response to the bacterial isolates showing very low abundance in IBD were studied. Fecal samples [1-3 samples/child] were collected from 10 paediatric patients with crohn's disease [CD], and 12 with ulcerative colitis [UC] and from 8 healthy children, for polyphasic microbiological analysis (culture, real-time polymerase chain reaction [PCR], and denaturing gradient gel electrophoresis). In addition, in vitro cytokine responses of peripheral blood mononuclear cells to the bacterial isolates, which showed very low abundance in IBD, were studied. Although predominant bacterial diversity was higher in IBD, the numbers of Lachnospiraceae and Coriobacteriaceae bacteria were lower in IBD patients as compared with control children [p < 0.05]. In addition, Ruminococcaceae population diversity was lower in IBD [p < 0.05] and correlated negatively with fecal calprotectin levels. Both abundance and diversity of bifidobacterial populations were lower in children with IBD [p < 0.05], and particularly low numbers of certain bifidobacterial isolates were detected. In CD, we found enhanced up-regulation of interleukin-6 transcripts and impaired RAR-related orphan receptor C response to bifidobacteria, whereas decreased interferon-gamma response was observed in both CD and UC. We demonstrate altered fecal microbiota in paediatric IBD, particularly low numbers and diversity of bifidobacterial populations. Interestingly, immunological response to bifidobacteria differed between paediatric CD patients and control children.

Su1276 Use of Anti-TNF Therapy in Patients With Crohn's Disease Complicated by an Abdominal Phlegmon

when compared to UC patients (29/120, 242%, p < 0.001). The following types of EIM were observed: 37/266 (13.9%) peripheral arthritis / arthralgia (17.8% in CD vs. 9.2% in UC); 5/266 (1.9%) uveitis / iritis (2.7% in CD vs. 0.8% in UC; 26/266 (9.8%) oral aphthous ulcers (12.3% in CD vs. 6.7% in UC); 2/266 (0.8%) ankylosing spondylitis (0.7% in CD vs. 0.9% in UC); 5/266 (1.9%) erythema nodosum (2.7% in CD vs. 0.8% in UC); 2/266 (0.8%) pyoderma gangrenosum (0.7% in CD vs. 0.8% in UC). Conclusion: EIM appear in pediatric IBD patients in similar prevalence when compared to the adult population. As a general rule, EIM are more frequently observed in pediatric CD patients when compared to pediatric UC patients. The most frequent EIM are peripheral arthritis / arthralgia, followed by oral aphthous ulcers.

Methotrexate for maintaining remission in paediatric Crohn's patients with prior failure or intolerance to thiopurines: a multicenter cohort study.

Methotrexate [MTX] is an immunomodulating drug that can be used to maintain remission in patients with Crohn's disease [CD], but data on efficacy and tolerability in children and teenagers are scarce. We evaluated the long-term efficacy and tolerability of MTX monotherapy after thiopurine therapy in paediatric CD patients. A multicenter cohort of paediatric MTX users who stopped thiopurines due to ineffectiveness or intolerance between 2002 and 2012 were included and followed for at least 12 months. Relapse-free use was defined as steroid and biologics-free clinical remission after the introduction of MTX, and included intentional discontinuation of successful therapy before the end of the observation period. A total of 113 patients with CD in remission were followed while on MTX monotherapy, of whom 75 [66%] had failed on thiopurines and 38 [34%] had stopped thiopurines due to side effects. Median age at the introduction of MTX was 14 years [range 7 to 17], and 93% used the subcutaneous route. Kaplan-Meier analysis showed that 52% of the study cohort were still in steroid- and biologics-free remission after 12 months of MTX monotherapy, with a difference that did not reach significance between thiopurine-intolerant and thiopurine-failing patients [p = 0.21, log-rank test]. The findings of this cohort study suggest that MTX is an effective immunomodulator to maintain remission after stopping thiopurines. MTX maintenance should be considered before stepping up to anti-tumor necrosis factor alpha therapy. MTX is probably somewhat more effective in patients who stopped thiopurines due to side effects than in those who failed on thiopurines.

Evaluation of hearing loss in pediatric celiac patients

ObjectivesCeliac disease (CD) is a chronic immune-mediated enteropathy caused by the ingestion of gluten in genetically predisposed individuals. In some reports, sensorineural hearing loss (SNHL) has been identified as an extraintestinal symptom of CD. We aimed to further investigate the possible association between CD and SNHL by examining a greater number of pediatric CD patients. MethodsThe study was carried out from March to September 2014 and included 110 pediatric patients with biopsy-confirmed CD (220 ears) and 41 age- and sex-matched controls (82 ears); participants were evaluated by tympanometry and pure tone audiometry (frequency, 250–8000Hz frequency). ResultsAudiometric bone conduction thresholds were significantly different between the CD patients and the controls (p<0.05), but there were no significant differences in pure tone averages for air conduction (p>0.05). When the results for CD patients were analyzed according to duration of disease (≤36 months and >36 months), a significant difference in bone conduction thresholds (p<0.05) was noted, with significant increments at the later stages of disease. However, this difference was not sufficient to define clinical hearing loss, as the pure tone average thresholds remained below 20dB. ConclusionThese results indicate that subclinical hearing loss may be present in children with CD, which could presage more serious hearing impairments at older ages and later stages of the disease. Hearing screenings should be recommended for children with CD in order to prevent the potentially unfavorable effects of hearing loss on the emotional, behavioral, cognitive, and sensorimotor development of these patients.

Su1293 Diagnosis of Iron Deficiency in Inflammatory Bowel Diseases by Transferrin Receptor-Ferritin Index

course and intestinal surgery. There is a lack of data regarding diagnostic delay in pediatric IBD patients. We aimed to assess the diagnostic delay in pediatric CD and UC patients and to identifiy risk factors for long diagnostic delay. Methods: Data from the Swiss IBD cohort study were analyzed. Patients were recruited from university centers (68%), regional hospitals (14%), and private practices (18%). Data on diagnostic delay was provided by parents and physician questionnaires. Diagnostic delay was further divided into the time interval from first symptoms to the first consultation with the physician (patient-related interval) and the interval from first physician consultation until IBD diagnosis was established (physician related interval). Long diagnostic delay was defined as delay lying above the 75th percentile. Non-normal data are presented as median, interquartile range [IQR] and range. Results: A total of 100 pediatric CD (37% females) patients and 75 pediatric UC patients (56% females) were included. Age at disease onset was 12 [10 14] years in CD and 11 [7 13] years in UC patients. Diagnostic delay in CD was 4 [2 8] (range 0 82) months with the interval from first symptoms to physician visit of 1 [0 3] (range 0 24) months and from physician visit to diagnosis of 3 [1 9] (range 0 82) months. In UC patients the median diagnostic delay was 2 [1 7] (range 0 52) months with an interval from first symptom onset to physician visit of 0 [0 3] (range 0 36) months and from physician visit to diagnosis of 2 [1 4] (range 0 20) months. Diagnostic delay in CD patients was significantly longer than in UC patients (median 4 vs. 2 months, p = 0.011). Long diagnostic delay was defined as period >8 months in CD and >7 months in UC patients. Neither gender, age at diagnosis, disease location, positive IBD family history, nor provenience (rural vs. non-rural) were associated with long diagnostic delay. Conclusions: The median diagnostic delay in pediatric CD and UC patients in Switzerland is 4 and 2 months, respectively. However, one fourth of pediatric CD patients needs >8 months and one fourth of pediatric UC patients needs >7 months from first symptom onset to IBD diagnosis.

Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease

BackgroundCeliac disease (CD) is an autoimmune disorder of the small intestine which is triggered by dietary gluten in genetically predisposed (HLA-DQ2/DQ8 positive) individuals. Only a fraction of HLA-DQ2/DQ8 positive individuals develop CD indicating that other factors have a role in the disorder. Several studies have addressed intestinal microbiota aberrancies in pediatric CD, but the results are inconsistent. Previously, we demonstrated that pediatric CD patients have lower duodenal expression of TLR2 and higher expression of TLR9 as compared to healthy controls (HC) indicating that microbiota may have a role in CD.MethodsWe used bacterial phylogenetic microarray to comprehensively profile the microbiota in duodenal biopsies of CD (n = 10) and HC (n = 9) children. The expression of selected mucosa-associated genes was assessed by qRT-PCR in CD and HC children and in treated CD adults (T-CD, n = 6) on gluten free diet.ResultsThe overall composition, diversity and the estimated microbe associated molecular pattern (MAMP) content of microbiota were comparable between CD and HC, but a sub-population profile comprising eight genus-like bacterial groups was found to differ significantly between HC and CD. In HC, increased TLR2 expression was positively correlated with the expression of tight junction protein ZO-1. In CD and T-CD, the expression of IL-10, IFN-g and CXCR6 were higher as co5mpared to HC.ConclusionsThe results suggest that microbiota and altered expression of mucosal receptors have a role in CD. In CD subjects, the increased expression of IL-10 and IFN-g may have partly resulted from the increased TLR9 expression and signaling.

Su2011 Magnetic Resonance Enterography, Small-Bowel Contrast Ultrasonography and Capsule Endoscopy to Evaluate Small Bowel in Pediatric Crohn's Disease: A Prospective, Blinded, Comparison Trial

Background: Clostridium difficile infection (CDI) is the leading cause of nosocomial diarrhea in the USA and is increasing in prevalence. Evidence from the adult literature has demonstrated that patients with inflammatory bowel disease (IBD) have a higher prevalence of CDI than the general population. There is a paucity of literature regarding CDI in pediatric patients with IBD, which may differ from adults. The prevalence of CDI in hospitalized pediatric IBD patients compared with adult IBD patients is unknown. Aim: To compare the prevalence of CDI in hospitalized pediatric IBD patients, adult IBD patients and hospitalized patients without IBD. Methods: The rates of CDI per 1,000 hospitalizations for patients with and without IBD in the state of Maryland between 1993 and 2011 were examined using the Maryland Health Services Cost Review Commission database. ICD-9-CM codes in any diagnostic position for CDI (008.45), ulcerative colitis (UC; 556) and Crohn's disease (CD; 555) were used to identify hospitalizations. A hospitalization without a code for 555 or 556 was considered a non-IBD hospitalization. Pediatric patients were defined as less than 18 years of age on admission. Incidence rate ratios with robust variances comparing CDI in pediatrics and adults by type of IBD and with patients without IBD were calculated for all years and the most recent year using Stata 11. Results: Among patients with IBD, the rate of CDI was 30.5 per 1,000 hospitalizations compared with 7.8 per 1,000 hospitalizations in patients without IBD (p,0.001). Among adults, the rate of CDI was 3 times greater in IBD hospitalizations than non-IBD hospitalizations (p,0.001) and among pediatric patients, the rate of CDI was over 20 times greater in IBD than non-IBD hospitalizations (p,0.001). In 2011, children with CD had a 2.5 times greater rate of CDI than adults with CD (p,0.001). In 2011, children with UC had a 44% decreased rate of CDI than adults with UC (p=0.01). There was no difference in the rate of CDI between pediatric CD and UC during 1993-2011 (p=0.39). However, in 2011, pediatric CD patients had a 3.5 times greater rate than pediatric UC patients (p,0001). Conclusions: Our study shows that hospitalized children with IBD have a significantly greater prevalence of CDI than hospitalized children without IBD. Moreover, children with CD have a greater rate of CDI during hospitalization than adults with CD, although the opposite is true with UC, potentially suggesting different risk factors for CDI in the pediatric IBD population.

Su2010 The Prevalence of Clostridium difficile Infection in Hospitalized Pediatric and Adult Patients With Inflammatory Bowel Disease

Background: Clostridium difficile infection (CDI) is the leading cause of nosocomial diarrhea in the USA and is increasing in prevalence. Evidence from the adult literature has demonstrated that patients with inflammatory bowel disease (IBD) have a higher prevalence of CDI than the general population. There is a paucity of literature regarding CDI in pediatric patients with IBD, which may differ from adults. The prevalence of CDI in hospitalized pediatric IBD patients compared with adult IBD patients is unknown. Aim: To compare the prevalence of CDI in hospitalized pediatric IBD patients, adult IBD patients and hospitalized patients without IBD. Methods: The rates of CDI per 1,000 hospitalizations for patients with and without IBD in the state of Maryland between 1993 and 2011 were examined using the Maryland Health Services Cost Review Commission database. ICD-9-CM codes in any diagnostic position for CDI (008.45), ulcerative colitis (UC; 556) and Crohn's disease (CD; 555) were used to identify hospitalizations. A hospitalization without a code for 555 or 556 was considered a non-IBD hospitalization. Pediatric patients were defined as less than 18 years of age on admission. Incidence rate ratios with robust variances comparing CDI in pediatrics and adults by type of IBD and with patients without IBD were calculated for all years and the most recent year using Stata 11. Results: Among patients with IBD, the rate of CDI was 30.5 per 1,000 hospitalizations compared with 7.8 per 1,000 hospitalizations in patients without IBD (p,0.001). Among adults, the rate of CDI was 3 times greater in IBD hospitalizations than non-IBD hospitalizations (p,0.001) and among pediatric patients, the rate of CDI was over 20 times greater in IBD than non-IBD hospitalizations (p,0.001). In 2011, children with CD had a 2.5 times greater rate of CDI than adults with CD (p,0.001). In 2011, children with UC had a 44% decreased rate of CDI than adults with UC (p=0.01). There was no difference in the rate of CDI between pediatric CD and UC during 1993-2011 (p=0.39). However, in 2011, pediatric CD patients had a 3.5 times greater rate than pediatric UC patients (p,0001). Conclusions: Our study shows that hospitalized children with IBD have a significantly greater prevalence of CDI than hospitalized children without IBD. Moreover, children with CD have a greater rate of CDI during hospitalization than adults with CD, although the opposite is true with UC, potentially suggesting different risk factors for CDI in the pediatric IBD population.

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

Few studies have compared phenotype and disease course in children and adults with inflammatory bowel disease (IBD). To compare phenotype, treatment and disease course in children (<15 years) and adults (≥18 years) with IBD. Two population-based cohorts comprising paediatric (2001-2006) and adult (2003-2004) patients from Copenhagen County and City were studied. 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. 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.

Strong overexpression of CXCR3 axis components in childhood inflammatory bowel disease

Inflammatory bowel disease (IBD) is a polygenetic disorder. Our group previously showed that a variant within the CXCL9 gene is associated with pediatric Crohn's disease. As CXCL9, CXCL10, and CXCL11 are the 3 ligands to the receptor CXCR3, the aim of this study was to investigate the colonic transcriptional activity of the CXCR3 axis and to perform SNP genotyping of a CXCL11 polymorphism in a large pediatric and adult IBD cohort. mRNA expression of CXCR3, CXCL9, CXCL10, CXCL11, and IL8 was analyzed in colonic biopsies using real-time PCR. CXCL11 rs6817952 nucleotide substitution was determined in 501 German individuals with IBD (336 CD, 165 UC) including 258 children and 243 adults as well as in 231 controls by a TaqMan SNP genotyping assay. CXCR3 axis genes were significantly overexpressed in inflamed colonic tissue of pediatric CD and UC patients. The prevalence of hetero- and homozygous variants of the rs6817952 genotype was higher in pediatric but not in adult CD patients compared with that in controls (P = 0.04). Moreover, carriers of the hetero- and homozygous genotype variants of rs6817952 were at increased risk for UC in all age groups (P = 0.009). Our study provides evidence of the significant overexpression of the CXCR3 axis in active IBD, suggesting it has a role in IBD pathogenesis. The rs6817952 A variant is a risk allele for pediatric CD and UC in all age groups. Therapeutic studies will have to show whether the blockade of chemokine receptors such as CXCR3 can modulate intestinal inflammation in a clinical application.

Infliximab dependency in pediatric Crohnʼs disease: Long-term follow-up of an unselected cohort

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. 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. 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. 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.