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Objective Generic preference-based HRQOL assessments used expressly for economic evaluation have not been examined in pediatric Crohn’s disease (CD) and ulcerative colitis (UC). The objective was to further assess the construct validity of preference-based HRQOL measures in pediatric IBD by comparing the Child Health Utility 9 Dimensions (CHU9D) and Health Utilities Index (HUI) to the disease-specific IMPACT-III and to the generic PedsQL in children with CD and with UC. Methods The CHU9D, HUI, IMPACT-III and/or PedsQL were administered to Canadian children aged 6 to 18 years with CD and UC. CHU9D total and domain utilities were calculated using adult and youth tariffs. HUI total and attribute utilities were determined for the HUI2 and HUI3. Total scores for IMPACT-III and PedsQL were determined. Spearman correlations were calculated between generic preference-based utilities and the IMPACT-III and PedsQL scores. Results The questionnaires were administered to 157 children with CD and 73 children with UC. Moderate to strong correlations were observed between the CHU9D, HUI2, HUI3 and the disease-specific IMPACT-III or generic PedsQL. As hypothesized, domains with similar constructs demonstrated stronger correlations, such as the Pain and Well-being domains. Conclusions While all questionnaires were moderately correlated with the IMPACT-III and PedsQL questionnaires, the CHU9D using youth tariffs and the HUI3 were most strongly correlated and would be suitable choices to generate health utilities for children with CD or UC for the purpose of economic evaluation of treatments in pediatric IBD.

Case-control studies have shown that patients with Crohn's disease (CD) have a microbial composition different from healthy individuals. Although the causes of CD are unknown, epidemiologic studies suggest that diet is an important contributor to CD risk, potentially via modulation of bacterial composition and gut inflammation. We hypothesized that long-term dietary clusters (DCs) are associated with gut microbiome compositions and gut inflammation. Our objectives were to identify dietary patterns and assess whether they are associated with alterations in specific gut microbial compositions and subclinical levels of gut inflammation in a cohort of healthy first-degree relatives (FDRs) of patients with CD.As part of the Genetic, Environmental, Microbial (GEM) Project, we recruited a cohort of 2289 healthy FDRs of patients with CD. Individuals provided stool samples and answered a validated food frequency questionnaire reflecting their habitual diet during the year before sample collection. Unsupervised analysis identified 3 dietary and 3 microbial composition clusters.DC3, resembling the Mediterranean diet, was strongly associated with a defined microbial composition, with an increased abundance of fiber-degrading bacteria, such as Ruminococcus, as well as taxa such as Faecalibacterium. The DC3 diet was also significantly associated with lower levels of subclinical gut inflammation, defined by fecal calprotectin, compared with other dietary patterns. No significant associations were found between individual food items and fecal calprotectin, suggesting that long-term dietary patterns rather than individual food items contribute to subclinical gut inflammation. Additionally, mediation analysis demonstrated that DC3 had a direct effect on subclinical inflammation that was partially mediated by the microbiota.Overall, these results indicated that Mediterranean-like dietary patterns are associated with microbiome and lower intestinal inflammation. This study will help guide future dietary strategies that affect microbial composition and host gut inflammation to prevent diseases.

Purpose Health utilities are challenging to ascertain in children and have not been studied in pediatric Crohn’s disease (CD) and ulcerative colitis (UC). The objective was to assess discriminative validity by comparing utilities elicited using the Child Health Utility-9 Dimension (CHU9D) to the Health Utilities Index (HUI) across multiple disease activity scales in pediatric UC and CD. Methods Preference-based instruments were administered to 188 children with CD and 83 children with UC aged 6 to 18 years. Utilities were calculated using CHU9D adult and youth tariffs, and HUI2 and HUI3 algorithms in children with inactive (quiescent) and active (mild, moderate, and severe) disease. Differences between instruments, tariff sets and disease activity categories and were tested statistically. Results In CD and UC, all instruments detected significantly higher utilities for inactive compared to active disease (p Conclusion CHU9D and HUI discriminated between levels of disease activity in CD and UC regardless of the clinical scale used, with the CHU9D youth tariff most often displaying the lowest utilities for worse health states. Distinct utilities for different IBD disease activity states can be used in health state transition models evaluating the cost-effectiveness of treatments for pediatric CD and UC.

IntroductionEarly relapse in Crohn’s disease (CD) is associated with a more severe disease course. The microbiome plays a crucial role, yet strategies targeting the microbiome are underrepresented in current guidelines. We hypothesise that early manipulation of the microbiome will improve clinical response to standard-of-care (SOC) induction therapy in patients with a relapse-associated microbiome profile. We describe the protocol of a pilot study assessing feasibility of treatment allocation based on baseline faecal microbiome profiles.Methods and analysisThis is a 52-week, multicentre, randomised, controlled, open-label, add-on pilot study to test the feasibility of a larger multicontinent trial evaluating the efficacy of adjuvant antibiotic therapy in 20 paediatric patients with mild-to-moderate-CD (10Ethics and disseminationThis study was approved by METC-AMC and CCMO (Netherlands) and IWK Health Centre (Canada). The first version of this protocol was approved by North Carolina Children’s Hospital (USA), Wolfson Medical Centre (Israel). The FDA (USA), Health Canada and Ministry of Health (Israel) have reviewed and approved the protocol. Results will be published in international peer-reviewed journals and summaries will be provided to the funders and participants.Trial registration numberNCT04186247.

Data on pediatric inflammatory bowel disease (IBD)-associated indirect and out-of-pocket (OOP) costs are limited. We aimed to estimate indirect (lost work hours and productivity) and OOP pediatric IBD-associated costs in Canada.In a nation-wide cross-sectional analysis, caregivers of children with IBD were invited to complete a questionnaire on lost work hours and OOP costs related to IBD in the 4 weeks prior to the survey. Participants were reinvited to periodically answer the same questionnaire every 3-9 months for 2 years. Lost productivity was calculated using the Human Capital method. Costs were reported in 2018 inflation-adjusted Canadian dollars. Predictors of high cost users (top 25%) were examined using binary logistic regression.Consecutive 243 (82 incident cases) of 262 (92.7%) approached participants completed the first survey with a total of 450 surveys longitudinally completed over 2 years. The median annual indirect cost per patient was $5966 (IQR $1809-$12,676), with $5721 (IQR $1366-$11,545) for Crohn's disease (CD) and $7007 (IQR $2428-$14,057) for ulcerative colitis (UC) ( P = 0.11). The annual median per patient OOP costs were $4550 with $4550 for CD and $5038 for UC ( P = 0.53). Longer travel distance to clinic was associated with higher OOP costs (odds ratio = 4.55; Plt; 0.0001; 95% confidence interval: 1.99-10.40).Indirect and OOP IBD-associated costs are substantial and more likely to affect families living in remote communities.

The TUMMY-UC is a Patient Reported Outcome (PRO) measure for pediatric ulcerative colitis (UC) with an observer RO (obsRO) version for children8 years. It includes eight items selected by concept elicitation interviews. We aimed to finalize the TUMMY-UC by cognitive interviews (stage-2) and to evaluate the index for its psychometric properties (stage-3).The TUMMY-UC items were first finalized during 129 cognitive debriefing interviews. Then, in a prospective-multicenter validation study, 84 children who either underwent colonoscopy or provided stool for calprotectin completed the TUMMY-UC and various measures of disease activity. Assessments were repeated after 7 and 21 days for evaluating reliability and responsiveness.During stage-2, the items were formatted with identical structure to ensure conceptual equivalence, and weighted based on ranking of importance. In stage-3, the TUMMY-UC total score had excellent reliability in repeated assessments (intraclass correlation coefficient [ICC], 0.90 [95%CI 0.84-0.94]). It also had moderate to strong correlations with all constructs of disease activity: r=0.70 with UC endoscopic index of severity, r=0.63 with IMPACT questionnaire, r=0.43 with calprotectin, r=0.80 with the PUCAI, r=0.75 with global assessment of disease activity and r=0.46 with C-reactive protein (all p0.015). The index had excellent discrimination of disease activity with a score9 defining remission (AUROC=0.95 (95%CI 0.93-0.99)). The ΔTUMMY-UC showed high responsiveness and differentiated well between children who experienced changed from those with no change.The TUMMY-UC, constructed from PRO and ObsRO versions, is a reliable, valid and responsive index, which can be now used in practice and clinical trials.

Background & Aims Increased intestinal permeability has been associated with Crohn’s disease (CD), but it is not clear whether it is a cause or result of the disease. We performed a prospective study to determine whether increased intestinal permeability is associated with future development of CD. Methods We assessed the intestinal permeability, measured by the urinary fractional excretion of lactulose-to-mannitol ratio (LMR) at recruitment in 1420 asymptomatic first-degree relatives (6–35 years old) of patients with CD (collected from 2008 through 2015). Participants were then followed up for a diagnosis of CD from 2008 to 2017, with a median follow-up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017. We used the Cox proportional hazards model to evaluate time-related risk of CD based on the baseline LMR. Results An abnormal LMR (>0.03) was associated with a diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64–5.63; P = 3.97 × 10–4). This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62; 95% CI, 1.051–2.50; P = .029). Conclusions Increased intestinal permeability is associated with later development of CD; these findings support a model in which altered intestinal barrier function contributes to pathogenesis. Abnormal gut barrier function might serve as a biomarker for risk of CD onset.

Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer’s patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.

Introduction:. Daily pain experiences are a common feature of pediatric inflammatory bowel disease (IBD), which can negatively influence their health-related quality of life (HRQOL). A holistic, family systems approach is needed to further our understanding of daily pain experiences in youth with IBD and their influence on youth's HRQOL. Objectives:. The study's objectives were to (1) provide a detailed description of daily pain experiences in youth with IBD, (2) investigate the relative contribution of family functioning and pain in explaining youth's HRQOL, and (3) explore differences in parental and youth perspectives. Methods:. Sixty youth with IBD (8–17 years) and a parent completed questionnaires to assess family functioning, HRQOL, and pain experiences within the past week. A subsample of 16 youth completed an online diary (7 days) about their pain experiences. Results:. When including any pain experiences, higher youth-reported family satisfaction and lower pain intensity were related to better HRQOL, whereas higher parent-reported family cohesion and satisfaction indirectly related to youth HRQOL through lower pain intensity. When only accounting for abdominal pain, pain intensity related negatively with HRQOL, and only parent-reported cohesion showed an indirect relation with HRQOL through pain intensity. Diary data revealed large heterogeneity: abdominal pain, described as cramping, sharp, and/or stinging was most frequent, but other pain symptoms (eg, back pain and headache) often co-occurred. Conclusion:. The findings provide a rich picture of the daily pain experiences of youth with IBD and underscore the importance of a family systems approach to understand how family functioning and pain symptoms influence HRQOL.

BackgroundPrevious retrospective studies of paediatric ulcerative colitis have had limited ability to describe disease progression and identify predictors of treatment response. In this study, we aimed to identify characteristics associated with outcomes following standardised therapy after initial diagnosis.MethodsThe PROTECT multicentre inception cohort study was based at 29 centres in the USA and Canada and included paediatric patients aged 4-17 years who were newly diagnosed with ulcerative colitis. Guided by the Pediatric Ulcerative Colitis Activity Index (PUCAI), patients received initial standardised treatment with mesalazine (PUCAI 10-30) oral corticosteroids (PUCAI 35-60), or intravenous corticosteroids (PUCAI ≥65). The key outcomes for this analysis were week 12 corticosteroid-free remission, defined as PUCAI less than 10 and taking only mesalazine, and treatment escalation during the 12 study weeks to anti-tumour necrosis factor α (TNFα) agents, immunomodulators, or colectomy among those initially treated with intravenous corticosteroids. We identified independent predictors of outcome through multivariable logistic regression using a per-protocol approach. This study is registered with ClinicalTrials.gov, number NCT01536535.FindingsPatients were recruited between July 10, 2012, and April 21, 2015. 428 children initiated mesalazine (n=136), oral corticosteroids (n=144), or intravenous corticosteroids (n=148). Initial mean PUCAI was 31·1 (SD 13·3) in children initiating with mesalazine, 50·4 (13·8) in those initiating oral corticosteroids, and 66·9 (13·7) in those initiating intravenous corticosteroids (p

Background & Aims: Up to 30% of patients with Crohn's disease (CD) require surgery within the first 5 years from diagnosis. We investigated the recent risk of bowel surgery in an inception cohort of pediatric patients with CD and whether early use of biologics (tumor necrosis factor antagonists) alters later disease course. Methods: We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group registry on 1442 children (age, ó16 y) diagnosed with CD from January 2002 through December 2014. Data were collected at diagnosis, 30 days following diagnosis, and then quarterly and during hospitalizations for up to 12 years. Our primary aim was to determine the 10-year risk for surgery in children with CD. Our secondary aim was to determine whether early use of biologics (

BACKGROUND Corticosteroids continue to play a central role in induction of remission in active Crohn's disease. However, their use comes at a price of significant adverse effects when used repeatedly or for extended periods. Newer corticosteroid agents with limited systemic bioavailability offer a tantalizing option, if they can be shown to be efficacious and safer than conventional corticosteroids. Budesonide is the main alternative corticosteroid currently available in an enteric formulation. OBJECTIVES To evaluate the effectiveness of oral budesonide for the treatment of acute flares of Crohn's disease. A secondary but important endpoint was to evaluate the adverse effect profile. SEARCH STRATEGY The following sources were used to search the literature for potentially relevant papers and trials. 1. A computer-assisted search of the on-line bibliographic database MEDLINE from 1986 onwards. 2. Hand searching the reference lists of trials and review articles identified by means of the computer- assisted search. 3. Proceedings from major gastrointestinal meetings were manually searched from 1990 onwards. 4. Contact with the relevant pharmaceutical companies that have been involved in the development of budesonide. SELECTION CRITERIA Potentially relevant articles were reviewed in an independent unblinded fashion by two authors to determine if they met the criteria specified below: 1) STUDY POPULATION: Patients of any age with acutely active Crohn's disease, as defined by a CDAI > 150. 2) METHODOLOGY: Randomized double blind controlled trials comparing budesonide to a control treatment. Patients in the control arm may have received placebo, conventional corticosteroids, 5-aminosalicylic acid or sulfasalazine. 3) OUTCOME MEASURES: Clinical remission was the outcome measure of interest. The definition of remission was usually a CDAI < 150 by 8 to 16 weeks of therapy. DATA COLLECTION AND ANALYSIS Eligible articles were reviewed in duplicate and the results of the primary research trials were abstracted onto specially designed data extraction forms. The proportion of patients achieving remission in the active treatment and control groups of each study were derived from the data provided in the original research papers. Where possible, data were broken down based on site of disease or other strata used by the individual trials. STATISTICAL ANALYSIS Data extracted from the original research articles were converted, where necessary, into individual 2 x 2 tables (remission versus no remission x budesonide versus control) for each of the individual studies. Where available, individual 2 x 2 tables for strata within studies were also used. The presence of significant heterogeneity among studies was tested for using the chi-square test. Because this is a relatively insensitive test for the presence of heterogeneity, a p-value of 0.10 was regarded as statistically significant. Where p < 0.10 the data from the individual studies were still combined but the pooled results were interpreted with caution. The 2 x 2 tables were synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel. A fixed effects model was used for the pooling of data. The analysis was performed initially by combining data from all trials to estimate the response rate to budesonide therapy. The analysis was also performed by combining only studies with comparable control groups. MAIN RESULTS Eight studies were deemed eligible for review. EFFICACY Budesonide was superior to placebo for induction of remission with a pooled odds ratio for the two placebo-controlled trials of 2.85 (95% CI 1.67 - 4.87). A single trial comparing budesonide with mesalamine demonstrated an odds ratio of 2.80 (95% CI 1.50 - 5.20) in favour of budesonide over mesalamine for induction of remission in active Crohn's disease. However, budesonide was inferior to conventional corticosteroids (prednisone or prednisolone) for induction of remission with a pooled odds ratio for the five trials of 0.69 (95% CI 0.51 - 0.95). SAFETY The two trials comparing budesonide versus placebo (Greenberg 1994; Tremaine 2002) showed no difference between study groups for proportion of reported corticosteroid-related adverse effects with the pooled odds ratio for both trials of 0.98 (95% CI 0.58 - 1.67). Five trials comparing budesonide versus prednisone showed the budesonide study group had fewer reported corticosteroid-related adverse effects than the prednisone study group (pooled odds ratio was 0.38 (95% CI 0.28 - 0.53). AUTHORS' CONCLUSIONS With disease in the ileum or ascending colon, budesonide offers an effective therapy which is somewhat less efficacious but with fewer adverse effects than conventional corticosteroids (e.g. prednisone, prednisolone, or 6-methylprednisolone).