Background: Diet plays a critical role in development and progression of Crohn’s disease (CD). Dietary indices are important tools to evaluate diet quality and dietary inflammatory potential, and we investigated the associations of it with pediatric CD. Method: A cross-sectional study including 144 children with CD (122 with clinically active and 22 with quiescent disease) and 57 healthy controls 6-18 years of age was conducted. Dietary intake was estimated using three 24-h dietary recalls. Diet quality was assessed using the Healthy Eating Index (HEI)-2015, alternate Mediterranean diet (aMed) score and modified Children-Dietary Inflammatory Index (mC-DII). Results: Children with active CD had lower total HEI-2015 and aMed scores than healthy controls. A similar pro-inflammatory mC-DII score was found across the three groups. A higher mC-DII score in patients with CD was associated with higher intake of refined sugars, saturated fats and proteins, and lower intake of whole grains and dairy. Fiber intake was significantly lower in children with active CD (median fiber DRI: 37.0 [22.6-48.3] vs 41.2 [34.1-49.1] vs 45.8 [35.7-62.0], P <0.001). Conclusions: Using three dietary indices to evaluate diet quality, both children with CD and healthy children in North America consume a poor-quality, pro-inflammatory diet low in fiber, but the quality and fiber content are significantly lower in children with active CD. Future randomized controlled trials are required to evaluate the effect of the change in diet and secondarily dietary quality scores on the risk and progression of pediatric CD.

Background and Aims Epidemiological studies have suggested an association between the inflammatory potential of dietary patterns and Crohn's disease (CD). However, the relationships of these inflammatory dietary determinants with the microbiome remain largely unknown. In this cross-sectional study, we evaluate the association between the inflammatory potential of habitual diet, as assessed by the modified Children-Dietary Inflammatory Index (mC-DII), and the fecal microbiome and metabolome of children with CD in comparison to healthy children.Methods A cross-sectional study including 51 children with CD between 6 and 18 years of age and 50 healthy controls was conducted. Dietary inflammatory potential was measured using the mC-DII, and diet quality was assessed by the Healthy Eating Index (HEI)-2015 and alternate Mediterranean Eating Index (aMed). The microbiome was analyzed using shotgun metagenomic sequencing and untargeted metabolomic analysis.Results A poor-quality, pro-inflammatory diet, with similar mC-DII, HEI-2015, and aMed scores, was found across healthy children and children with CD. In children with active disease, a pro-inflammatory diet was associated with decreased diversity, increased virulence potential, and expansion of the Proteobacteria phylum dominated by Escherichia coli (E. coli) spp. A positive correlation between E. coli relative abundance and mC-DII was associated with a low intake of a cluster composed of fibers, vitamins, and minerals with anti-inflammatory potential. A negative association between metabolites of fatty acid metabolism and HEI was found.Conclusions In total, our results suggest that a pro-inflammatory diet may potentiate hallmarks of the inflammation-associated dysbiosis in CD and highlight the need for microbiome-targeted dietary interventions optimizing the anti-inflammatory potential of habitual diet in the management of pediatric CD.

OBJECTIVES:Real-world data on ustekinumab for the treatment of pediatric Crohn's disease (CD) are limited. This study sought to evaluate the effectiveness, long-term durability, and safety of ustekinumab in the treatment of children with CD. METHODS:A retrospective longitudinal cohort study of children with CD treated with ustekinumab from two large centers between 2015 and 2020 was performed. The primary outcome was frequency of steroid-free clinical remission at 1 year. Secondary outcomes included time to steroid-free clinical remission, frequency of clinical and biochemical remission, drug escalation and discontinuation, serum level data, and adverse events. Standard descriptive and comparative statistics were performed. Logistic regression was used to identify factors associated with steroid-free remission at 1 year. Kaplan-Meier curves were used to visualize time-to-event relationships for outcomes. RESULTS:A total of 101 patients were included. Median follow-up time on ustekinumab was 16.6 months (interquartile range [IQR]: 8.71-31.2) with drug failure in 28% at 1 year. Fifty-nine patients were in steroid-free clinical remission at 1 year. Higher baseline disease activity (odds ratio [OR]: 0.91 (95% confidence interval [CI]: 0.84-0.97), p = 0.01) and stricturing/penetrating disease phenotype (OR: 0.14 (95% CI: 0.03-0.65), p = 0.02) were associated with decreased likelihood of steroid-free clinical remission at 1-year. Ustekinumab drug escalation occurred in 70% of patients, and after escalation, 50 (70%) achieved clinical remission, and 49 (69%) achieved steroid-free remission at the last follow-up. Adverse events were rare and did not require therapy discontinuation. CONCLUSIONS:Ustekinumab is effective and safe in the treatment of children with CD. Escalation of therapy occurs frequently but results in sustained durability.

Cross-sectional imaging is increasingly used for both initial diagnosis and long-term monitoring of Crohn’s disease. The quantitative morphology of the terminal ileum may predict treatment response. We aimed to identify baseline qualitative and quantitative imaging features that are associated with clinical and radiologic treatment response in a large cohort of children with Crohn’s disease. This was a retrospective study of the RISK cohort study in pediatric Crohn’s disease. This multicenter study included 1,136 children <18 years from 28 sites in North America. Subjects enrolled with newly diagnosed Crohn’s disease who underwent endoscopy with baseline and follow-up CT or MRI were considered for this study. Exclusion criteria were incomplete data or surgical resection prior to follow-up imaging. Imaging analysis included assessing a qualitative terminal ileum (TI) categorical score based on SAR-AGA consensus definitions ((1) normal, (2) inflammation only without luminal narrowing, (3) inflammation with luminal narrowing, or (4) stricture with pre-stenotic dilation ≥3 cm) and quantitative measurements (maximum bowel wall thickness and maximum/minimum lumen diameter). Two endpoints were considered: (1) clinical response (off corticosteroids and quiescent Physician Global Assessment at follow-up imaging) and (2) CT and MRI response (follow-up imaging normalization). Multivariable logistic regression analyses were developed for each endpoint. Ninety-six subjects were included. Clinical response endpoint was achieved in 38

OBJECTIVES:Bone health is at risk in children with inflammatory bowel disease (IBD). This study examined the prevalence and predictors of low bone mineral density (BMD) in a cohort of children and young adults with IBD. METHODS:This single-center retrospective study included patients with IBD, ages 3.5-22 years, with completed dual x-ray absorptiometry (DXA) scans from 2006 to 2019. Demographic, clinical, and laboratory data were collected. Logistic regression analysis identified predictors associated with low BMD (Z-scores ≤ -2 standard deviations [SDs]) for three outcomes. In an overlapping IBD cohort with available genetic data between 2002 and 2019 (n = 378), genetic risk for diminished bone health was calculated using published polygenic risk scores generated from genome-wide association studies based on DXA or heel ultrasound speed of sound (SOS). Linear regression analysis examined associations of low BMD and genetic risk. RESULTS:Low BMD prevalence was 7% in our cohort (n = 600) based on spine bone mineral apparent density (BMAD), which best accounts for growth delays. Median (interquartile range [IQR]) spine BMAD Z-score was -0.37 SD (-1.11 to 0.35). Predictors of low BMAD included lower BMI Z-score (odds ratio [OR]: 0.67, p value: 0.02) and decreased height Z-score (OR: 0.6, p value: 0.005). Of those with longitudinal data (n = 118), low BMI (OR: 0.44, p value: <0.001) and steroid use (OR: 3.42, p value: 0.01) were associated with suboptimal bone health (Z-scores ≤ -1SD). In the cohort with genetic data, heel genomic SOS (β [standard error] = 0.17 [0.35], p ≤ 0.01) was associated with BMD. CONCLUSIONS:Lower BMI should prompt DXA monitoring in pediatric IBD. Genetic predisposition may identify an at-risk subpopulation.

Abstract Background Following ileocecal resection (ICR) for Crohn’s disease (CD), recurrence is frequent even in the biologic era. Gut microbiota is involved in this setting and a few adult studies have suggested that bacterial recolonization after surgery may predict recurrence. Given the inherent risk of postoperative recurrence associated with age and disease duration, studies investigating the role of the gut microbiota in predicting relapse in children undergoing ICR appears critical. We aimed to identify changes in the mucosal microbiome associated with, and predictive of, endoscopic CD recurrence within the first year post-ICR in a paediatric population. Methods Microbiota composition (16S rDNA sequencing) was assessed from ileal and colonic mucosa at the time of ICR and later during endoscopic evaluation from above and below the surgical anastomosis in 33 patients (26 with paired samples) prospectively recruited at a tertiary care paediatric IBD center. Results The study included 33 children (mean age 16±2.7 years) undergoing ICR. At the time of ileo-colonoscopy, 9 (35%) patients had endoscopic recurrence (Rutgeerts’ score≥ i2). ICR strongly modified the gut mucosal microbiota composition with significant changes in β-diversity (R2= 0.03, PERMANOVA test, p=0.01). Bacterial recolonization post-ICR differed according to recurrence status (Figure 1). Post-operatively, recurrence was associated with an increase in Fusobacterium, Dialister genera and in members of the Lachnospiraceae family, and a decrease in Faecalibacterium, Lactobacillus genera and members of the Streptococcaceae family. Microbiota colonizing the neoterminal ileum and subanastomotic colon differed in children with recurrence and showed, compared to remission, elevated and reduced bacterial abundance of the Enterobacter (q=0.1) and Ruminococcaceae (q=0.05) families in colonic samples respectively while the ileal mucosa exhibited profound depletion in Faecalibacterium (q=0.01). Postoperative colonic mucosal relative abundance of Enterobacteriaceae (q=0.06) and Ruminococcaceae (q=0.06) correlated positively and negatively with length of intestinal resection. At the time of surgery, several bacterial taxa able to predict relapse were identified (Figure 2). Conclusion Predicting postoperative CD relapse remains challenging, although several clinical risk factors of recurrence have been identified. Our study demonstrates that bacterial recolonization following ICR might pave the way towards remission or recurrence. Our results highlight, for the first time in a paediatric population, target species that may help clinicians to better define patients at risk of relapse and allow precise modulations of the overall microbial ecosystem towards remission pattern.

Abstract Background A seroproteomic index (i.e. the serum index) corresponds to 13 protein markers, including CRP, combined as a multianalyte assay with a score range 0-100 where higher score is associated with higher probability of endoscopic activity in adult CD. We aimed to evaluate its performances in pediatric CD. Methods Children with CD were enrolled from two separate cohorts. Cohort 1 enrolled CD from multiple centers in the United States (n=118) and cohort 2, was multinational (n=160). A simple endoscopic score for CD (SESCD) was collected (<3 points indicate endoscopic healing) with a blood specimen. Clinical disease status was measured using the Harvey Bradshaw index (HBI, cohort 1) or pediatric CD activity index (PCDAI, cohort 2) (PCDAI<10 or HBI<5 indicate clinical remission). Fecal calprotectin (FC) was collected in 180 patients from both cohorts. Serum specimens were processed in Prometheus Laboratories, San Diego, CA. Statistical analysis consisted of linear regression analysis, calculation of receiver operating characteristics curves (ROC) with area under the curve (AUC), sensitivity, specificity, Odds ratio (OR). Results In the 278 enrolled children (median age 14 years [IQR: 12-16 years], 46% females), median SESCD was 5 points (IQR: 0-12 points, 63% with endoscopic active disease); median CRP was 2.5 mg/L (IQR: 0.3-8.4 mg/L), median FC was 592 µg/g (IQR: 135-1147 µg/g) and median serum index was 33 (IQR: 17-60 points). AUROC analysis yielded significantly better area under ROC curve (AUROC, 0.87±0.03) for FC than the serum index (0.78±0.04) and CRP (0.77±0.04) (p<0.05) in distinguishing endoscopic active disease from endoscopic healing. There was a 9-fold higher likelihood of endoscopic active disease with serum index above 32 points (OR= 8.95 [95%CI: 5.02,15.96] p<0.001) with 70% sensitivity and 79% specificity (PPV=85%; NPV=61% at 63% pretest) (Table). In multivariate analysis EHI above 32 points (aOR= 3.00 [95%CI: 1.25, 4.76] p=0.043), active clinical disease (aOR= 2.01 [95%CI: 0.85, 4.76] p=0.114), FC>250 µg/g (aOR= 5.61 [95%CI: 2.4,13.09] p<0.01) and CRP above 3 mg/L (aOR=2.09 [95%CI: 0.9-4.85])(p=0.08) associated with active endoscopic disease) (Figure). In the subset with clinical remission (n=158), or CRP below 3 mg/L (n=136), or FC levels below 250 µg/g (n=116), EHI above 32 points was still associated with higher likelihood of endoscopic disease (OR=5.4 [95%CI: 2.6,11.1], OR= 6.8 [95%CI: 2.9,15.8], and OR=4.0 [95%CI: 1.3,12.8], respectively) (p<0.05) (Figure). Conclusion These data support the association of the serum index with endoscopic outcome in pediatric CD patients.

Importance The profile of gastrointestinal (GI) tract outcomes associated with the postacute and chronic phases of COVID-19 in children and adolescents remains unclear. Objective To investigate the risks of GI tract symptoms and disorders during the postacute (28-179 days after documented SARS-CoV-2 infection) and the chronic (180-729 days after documented SARS-CoV-2 infection) phases of COVID-19 in the pediatric population. Design, Setting, and Participants This retrospective cohort study was performed from March 1, 2020, to September 1, 2023, at 29 US health care institutions. Participants included pediatric patients 18 years or younger with at least 6 months of follow-up. Data analysis was conducted from November 1, 2023, to February 29, 2024. Exposures Presence or absence of documented SARS-CoV-2 infection. Documented SARS-CoV-2 infection included positive results of polymerase chain reaction analysis, serological tests, or antigen tests for SARS-CoV-2 or diagnosis codes for COVID-19 and postacute sequelae of SARS-CoV-2. Main Outcomes and Measures GI tract symptoms and disorders were identified by diagnostic codes in the postacute and chronic phases following documented SARS-CoV-2 infection. The adjusted risk ratios (ARRs) and 95% CI were determined using a stratified Poisson regression model, with strata computed based on the propensity score. Results The cohort consisted of 1 576 933 pediatric patients (mean [SD] age, 7.3 [5.7] years; 820 315 [52.0%] male). Of these, 413 455 patients had documented SARS-CoV-2 infection and 1 163 478 did not; 157 800 (13.6%) of those without documented SARS-CoV-2 infection had a complex chronic condition per the Pediatric Medical Complexity Algorithm. Patients with a documented SARS-CoV-2 infection had an increased risk of developing at least 1 GI tract symptom or disorder in both the postacute (8.64% vs 6.85%; ARR, 1.25; 95% CI, 1.24-1.27) and chronic (12.60% vs 9.47%; ARR, 1.28; 95% CI, 1.26-1.30) phases compared with patients without a documented infection. Specifically, the risk of abdominal pain was higher in COVID-19–positive patients during the postacute (2.54% vs 2.06%; ARR, 1.14; 95% CI, 1.11-1.17) and chronic (4.57% vs 3.40%; ARR, 1.24; 95% CI, 1.22-1.27) phases. Conclusions and Relevance In this cohort study, the increased risk of GI tract symptoms and disorders was associated with the documented SARS-CoV-2 infection in children or adolescents during the postacute or chronic phase. Clinicians should note that lingering GI tract symptoms may be more common in children after documented SARS-CoV-2 infection than in those without documented infection.

Dysbiosis is associated with pediatric and adult-onset inflammatory bowel disease (IBD), but the role of dysbiosis and the microbiome in very early onset IBD (VEO-IBD) has not yet been described. Here, we aimed to demonstrate the impact of age and inflammation on microbial community structure using shotgun metagenomic sequencing in children with VEO-IBD, pediatric-onset IBD, and age-matched pediatric healthy controls (HC) observed longitudinally over the course of 8 weeks. We found disease-related differences in alpha and beta diversity between HC and children with IBD or VEO-IBD. Using a healthy microbial maturity index modeled from HC across the age range to characterize their gut microbiota, we found that children with pediatric-onset IBD and VEO-IBD had lower maturity than their age-matched HC groups, suggesting a disease effect on the microbial community. In addition, patients with pediatric IBD had significantly lower maturity than those with VEO-IBD, who had more heterogeneity at the youngest ages, highlighting differences in these two cohorts that were not captured in standard comparisons of alpha and beta diversity. These results demonstrate that young age and inflammation independently impact microbial community structure. However, the effect is not additive in the youngest patients, likely because of the heterogeneous and dynamic stool microbiome in this population.

To advance personalized medicine in pediatric Crohn’s disease (CD), we aimed to explore the utility of serological biomarkers in predicting response to anti-tumor necrosis factor (TNF). Children with CD were enrolled at initiation of anti-TNF and followed prospectively at 4 and 12 months thereafter, as well as at last follow-up. At baseline, 10 serological markers of the “PROMETHEUS® IBD sgi Diagnostic test” were measured, including pANCA, ASCA IgG and IgA, anti-CBir1, anti-OmpC, anti-A4-Fla2, anti-Fla-X, SAA, ICAM-1 and VCAM-1. The primary outcome was sustained steroid-free remission (SSFR, i.e. clinical remission without steroids at both 4 and 12 months) and the secondary outcome was primary non-response (PNR). Of the 72 included children (mean age, 12.8 ± 3.1 years; median disease duration, 6.4 months [IQR 2.5–17.3]), 42 (58

Abstract Background DEVELOP is a multi-center, global, prospective, observational, longitudinal registry of long-term safety of infliximab (and other treatments) in paediatric patients (pts) with inflammatory bowel disease (IBD) <18 years (yrs) at diagnosis. Over the course of follow-up, many pts required changes in therapy. Ustekinumab (UST) is approved for treatment of Crohn’s disease (CD) in adults and is currently being evaluated for safety/efficacy in paediatric pts. This report focuses on assessment of safety of UST in paediatric pts with CD from DEVELOP. Methods Data included paediatric pts treated with UST from 31 May 2007 through 30 June 2022; data are collected every 6 months. The analyzed population included: all paediatric pts (all pts), pts weighing <40kg (<40kg group), and pts weighing ≥40kg (≥40kg group). Assessments included medical and treatment history, UST exposure, adverse events (AEs), serious AEs (SAEs), CD-related SAEs leading to hospitalization, IBD surgeries, serious and opportunistic infections, malignancies, and deaths. Results A total of 150 pts received UST (49.3% females); 31 in the <40kg group and 119 in the ≥40kg group (Table 1). Most treated pts (92.0%) were 12-17yrs. The majority (91%) of pts were initially dosed with UST every 8 weeks (q8w); at the last known dose, 64% received UST q8w and 22% q4w. Mean (SD) age of initial UST exposure was 15yrs (2.19). Prior IBD surgery was reported in 65.3% pts. The majority of pts (98%) had prior biologic therapy and 72% received ≥2 biologics prior to UST. Overall, 37/150 (24.7%) of pts discontinued UST during follow-up, with a mean (SD) time to discontinuation of 16.7 (17.00) months; 84/150 (56.0%) were exposed to UST for ≥24 months. Rates (events/100 pt-yrs) of AEs were higher in the ≥40kg group (177.62) than in the <40kg group (101.27). Rates of SAEs were slightly lower among the ≥40kg group (25.42) vs <40kg (32.67). There were no SAEs related to infusion or injection site reactions. Rates of serious infections and CD-related hospitalizations were low and similar between groups, and rates of IBD-related surgeries were similar between groups (Figure 1). One malignancy (malignant carcinoid tumor) was reported in a female (18yrs) in the ≥40kg group with a history of prior therapy with vedolizumab, methotrexate, and 6-MP. No deaths or opportunistic infections were reported. Conclusion The safety profile observed for this off-label use of UST in paediatric CD pts in DEVELOP was similar to that of the treated adult population, despite most paediatric pts having prior biologic exposure. No new safety signals are identified in this paediatric population.

Abstract OBJECTIVE The intestinal microbiota plays a pivotal role in the inflammation associated with inflammatory bowel disease (IBD) through their interaction with the mucosal immune system. Prebiotic interventions using inulin-type fructans increase faecal and mucosal bifidobacteria as well as butyrate producing bacteria in healthy volunteers. The aim of this study was to assess the effect of a two-month oligofructose-enriched inulin (OI) supplementation on the microbiome composition, metabolome of children with IBD with subclinical disease activity. DESIGN We performed a single-center, double-blind, placebo-controlled trial at the Children’s Hospital of Philadelphia. Participants included children, 6–21 years old, with subclinical active colonic IBD as defined by a fecal calprotectin level between 50 and 500 μg/g and clinical remission. Participants were randomly assigned 1:1 to consume prebiotic OI or maltodextrin placebo for 8 weeks. Fecal and rectal swabs samples were collected at baseline, week 4, 8 and 16 for fecal calprotectin, microbiome profiling (shotgun metagenomic sequencing) and matching metabolomics (liquid chromatography tandem mass spectrometry). RESULTS The study randomized 68 patients, and 59 were included in the efficacy analyses. The global fecal and mucosal microbiome composition was significantly altered by prebiotic intake and specific inulin-induced increase in relative abundance of Bifidobacterium and Anaerostipes in the fecal samples were identified at week 4 (Figure 1). Two months after discontinuation of OI, the microbial composition of both groups returned to baseline levels. Fecal metabolite profiles were not altered during the 8-week intervention. A negative correlation was observed between calprotectin levels and the relative abundance of Bifidobacterium [q=0.08] and butyrate producer Anaerostipes [q=0.017] (Figure 2). Outcome analysis of inulin-induced change in calprotectin level during the intervention is pending. CONCLUSIONS Dietary intervention with prebiotic OI causes short term alterations in the microbiome of children with IBD characterized by an enrichment of Bifidobacterium and butyrate producer Anaerostipes. These results open new perspectives for development of microbiome-targeted dietary interventions in pediatric IBD. JB received the Crohn’s and Colitis Foundation Career Development Award # 693867 for this study. Figure 1 Selective effect of prebiotic supplementation on microbiome composition Figure 2 Correlation between calprotectin level and inulin-induced microbiome shift A negative correlation between fecal calprotectin level and inulin-induced change in relative abundance of Bifidobacterium [q= 0.08] and Anaerostipes [q=0.017] was observed during the 8-week intervention.

Importance:The profile of gastrointestinal (GI) outcomes that may affect children in post-acute and chronic phases of COVID-19 remains unclear. Objective:To investigate the risks of GI symptoms and disorders during the post-acute phase (28 days to 179 days after SARS-CoV-2 infection) and the chronic phase (180 days to 729 days after SARS-CoV-2 infection) in the pediatric population. Design:We used a retrospective cohort design from March 2020 to Sept 2023. Setting:twenty-nine healthcare institutions. Participants:A total of 413,455 patients aged not above 18 with SARS-CoV-2 infection and 1,163,478 patients without SARS-CoV-2 infection. Exposures:Documented SARS-CoV-2 infection, including positive polymerase chain reaction (PCR), serology, or antigen tests for SARS-CoV-2, or diagnoses of COVID-19 and COVID-related conditions. Main Outcomes and Measures:Prespecified GI symptoms and disorders during two intervals: post-acute phase and chronic phase following the documented SARS-CoV-2 infection. The adjusted risk ratio (aRR) was determined using a stratified Poisson regression model, with strata computed based on the propensity score. Results:Our cohort comprised 1,576,933 patients, with females representing 48.0% of the sample. The analysis revealed that children with SARS-CoV-2 infection had an increased risk of developing at least one GI symptom or disorder in both the post-acute (8.64% vs. 6.85%; aRR 1.25, 95% CI 1.24-1.27) and chronic phases (12.60% vs. 9.47%; aRR 1.28, 95% CI 1.26-1.30) compared to uninfected peers. Specifically, the risk of abdominal pain was higher in COVID-19 positive patients during the post-acute phase (2.54% vs. 2.06%; aRR 1.14, 95% CI 1.11-1.17) and chronic phase (4.57% vs. 3.40%; aRR 1.24, 95% CI 1.22-1.27). Conclusions and Relevance:In the post-acute phase or chronic phase of COVID-19, the risk of GI symptoms and disorders was increased for COVID-positive patients in the pediatric population.