Faculty Bibliography

BACKGROUND AND AIM/OBJECTIVE:Metabolites produced through host-microbe interactions may help associate metabolomic signatures with therapy response. We aimed to assess serum metabolites as predictors of vedolizumab remission in children with IBD. METHODS:VedoKids was a multicenter, prospective cohort study of children initiating vedolizumab at any stage of disease. Serum metabolomic profiling was performed at baseline (W0), week 14 (W14), and week 30 (W30) using quantitative metabolomics based on DI/LC-MS/MS method. Random Forest (RF) models with maximum relevance-minimum redundancy (mRMR) feature selection, integrated clinical and metabolomic features to predict clinical remission at the next time point (ie, week 0 to week 14; week 14 to week 30; week 30 to week 54). RESULTS:One hundred thirty-eight patients were included (mean age 13.6 years), 64 with Crohn disease (CD) and 74 with ulcerative colitis (UC). In CD, models achieved an area under the receiver operating characteristic curve (AUROC) of 0.80 (95% CI, 0.68-0.92) for predicting response to vedolizumab at W14, 0.92 (95% CI, 0.85-0.99) at W30 , and 0.83 (95% CI, 0.72-0.94) at W54. Metabolites appeared among the most important features, notably PC ae C36:4, citric acid, and malic acid. In UC, corresponding AUROC were 0.72 (95% CI, 0.59-0.85) at W14, 0.77 (95% CI, 0.64-0.90) at W30, and 0.90 (95% CI, 0.80-1.00) at W54. LysoPC a C26:1, picolinic acid, and serotonin were among the most important metabolites for prediction. CONCLUSIONS:We identified serum metabolites associated with vedolizumab remission in children with IBD, several of which have been previously linked to IBD pathophysiology.

The prevalence and incidence of Crohn's disease (CD) in pediatric populations have been steadily increasing. Growing evidence suggests that gut microbiomal community differences play a critical role in the pathogenesis of CD. Additionally, the clinical course of patients with CD is unpredictable, making treatment decisions challenging. We investigated the fecal microbiome of newly diagnosed, treatment-naïve pediatric CD patients (n = 43) compared to age- and sex-matched controls with other functional gastrointestinal disorders (n = 139). We also correlated microbial changes with CD disease activity, measured by the Pediatric Crohn's Disease Activity Index (PCDAI). Our results showed that microbial richness and diversity were significantly lower in CD patients. Furthermore, taxonomic analysis revealed an enrichment in pro-inflammatory bacteria (Fusobacteria and Proteobacteria) and depletion in favorable bacteria (Firmicutes and Verrucomicrobia). Higher PCDAI scores were linked to the enrichment of genera harboring pro-inflammatory taxa (Hungatella and Veillonella) and decreased abundance of genera harboring protective taxa (Lachnospiraceae). Our study underscores the potential of fecal microbiome profiling as an effective tool for understanding CD pathogenesis, identifying microbial biomarkers, and predicting disease activity for treatment response. This, in turn, can help to improve personalized treatment and management strategies in pediatric CD.

INTRODUCTION/UNASSIGNED:Evaluating pediatric esophageal motility and structural disorders such as eosinophilic esophagitis (EoE) remains challenging. Conventional modalities are limited in their ability to assess biomechanical properties of the gastrointestinal tract, such as luminal compliance and distensibility. The endoluminal functional lumen imaging probe (FLIP) is a minimally invasive technology that uses impedance planimetry to measure esophageal parameters. Recent studies have shown the utility of FLIP in quantifying esophageal remodeling and fibrostenotic severity. FLIP-derived esophageal distensibility index (DI) is a sensitive marker for subclinical fibrosis and rigidity, often identifying esophageal narrowing not apparent on endoscopy or by symptom assessment alone. We investigated the use of FLIP to capture early esophageal dysfunction in patients with EoE, especially those in clinical remission. METHODS/UNASSIGNED:Retrospective chart review of patients with EoE who underwent EndoFLIP at our institution. EndoFLIP 2.0 Impedance Planimetry System was used via standard protocol. Variables in patients with EoE were compared by unpaired t-test. RESULTS/UNASSIGNED:/mmHg ± 1.4. DISCUSSION/UNASSIGNED:EndoFLIP was able to detect esophageal dysfunction in pediatric patients with EoE as evidenced by an overall low distensibility index. This adjunctive tool appears particularly useful in asymptomatic patients with EoE in clinical and histologic remission, as it may detect residual esophageal dysfunction highlighting the importance of early detection and ongoing therapy.

BACKGROUND:The pharmacokinetics of biologic agents can differ between children and adults with inflammatory bowel disease (IBD), often necessitating modified paediatric dosing strategies. AIMS/OBJECTIVE:To define the exposure-response relationship of vedolizumab in the paediatric IBD VedoKids cohort including the effect of baseline clearance on deep biochemical remission (normal C-reactive protein [CRP]/erythrocyte sedimentation rate [ESR] and steroid-free remission) at 30 weeks, and to use population pharmacokinetic models to find the best matches between adult and paediatric pharmacokinetic profiles. METHODS:We sought a pharmacokinetic model on 312 serum vedolizumab concentrations from 129 children, assisted by a published adult model as a Bayesian prior. We employed the model for exposure-response evaluation and for investigating doses in paediatric patients to match the adult exposure at the labelled dose. RESULTS:At Week 30, 104/129 (81%) children (53% female and 47% Crohn disease) remained on vedolizumab, of whom 39 (31%) in the exposure-response evaluation were in deep biochemical remission. Increased baseline drug clearance was associated with lower deep biochemical remission rates at Week 30 based on ESR/CRP (OR 0.47 [95% CI 0.2-1.05, p = 0.08]) and calprotectin < 100 μg/g (OR 0.13 [95% CI 0.1-0.79, p < 0.05]). Higher weight and lower serum albumin were associated with increased clearance (p < 0.001). Simulation models found that, for children ≤ 30 kg, tiered fixed dosing regimens best matched adult drug concentrations. CONCLUSIONS:Drug clearance was strongly influenced by serum albumin. Baseline clearance predicted deep biochemical remission at Week 30. Further investigation is needed to better understand optimal dosing strategies-especially for lower-weight children receiving vedolizumab.

Celiac disease (CeD) and eosinophilic esophagitis (EoE) are immune-mediated disorders that can occur in the same patient. A retrospective study at a tertiary care hospital was conducted to determine the prevalence of EoE in a pediatric population with CeD and to compare characteristics of patients with both diseases to patients with CeD-only. Among the 148 patients with CeD identified in the study, 11 patients had both CeD and EoE (7.4%). Patients with both CeD and EoE had a higher absolute eosinophil count (per μL) at diagnosis compared to patients with CeD-only (454.1 ± 122.7 vs 231.9 ± 19.4, P = .003). In conclusion, there was a higher proportion of EoE in patients with CeD than would be expected in the general population, suggesting a potential pathophysiological overlap between the 2 diseases. An elevated peripheral absolute eosinophil count may help predict which patients with CeD may additionally have EoE.

BACKGROUND:Scarce data are available on the use of vedolizumab in children with inflammatory bowel disease (IBD). We aimed to evaluate the safety, effectiveness, and dosing of vedolizumab to induce remission of IBD. METHODS:body surface area (up to 300 mg maximum). The primary outcome was steroid-free and exclusive enteral nutrition-free remission at 14 weeks, analysed according to the intention-to-treat principle. Serum samples were taken for analysis of drug concentration and faecal calprotectin at baseline, and at 2, 6, and 14 weeks. Adverse events were recorded in real time and classified as severe or non-severe and related or unrelated to vedolizumab. This study is registered with ClinicalTrials.gov, NCT02862132. FINDINGS/RESULTS:body surface area or 10 mg/kg. 32 (23%) of 142 children reported at least one adverse event, the most common were headache (five [4%]), myalgia (four [3%]), and fever (three [2%]). None of the adverse events were classified as severe, and only two (1%) patients discontinued treatment due to adverse events. INTERPRETATION/CONCLUSIONS:) or weight (10 mg/kg). FUNDING/BACKGROUND:The European Crohn's and Colitis Organization, the European Society for Paediatric Gastroenterology Hepatology and Nutrition, and Takeda.

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS) is a very rare gastric polyposis syndrome characterized by numerous polyps of the gastric fundus and body. We present the unusual case of a 10-year-old Polish-American male with history of eosinophilic esophagitis, who was found to have multiple fundic gland polyps (FGP) with low grade dysplasia on esophagogastroduodenoscopy. Subsequent evaluation including genetic testing confirmed the diagnosis of GAPPS, and after exhaustive multidisciplinary consultation the decision was made to proceed with prophylactic total gastrectomy given the markedly increased risk of gastric adenocarcinoma in GAPPS patients. To our knowledge, this represents the youngest patient diagnosed with GAPPS and the youngest patient who has undergone prophylactic gastrectomy for this disease at age 8 and 10 years, respectively. The pathophysiology, presentation, and treatment of GAPPS in a pediatric patient are discussed.

Background and objectives/UNASSIGNED:Altered gastrointestinal permeability in celiac disease (CD) is mediated by zonulin. The receptor for zonulin is expressed on podocytes. Therefore, we tested the effect of a gluten-free diet (GFD) on albuminuria in pediatric patients with newly diagnosed CD. Methods/UNASSIGNED:We performed a cohort study comparing urinary albumin (μg):creatinine (mg) ratio (ACR) in CD patients vs controls and in response to a GFD. Results/UNASSIGNED:Children with CD (n=46) had higher ACR compared to controls (n=21), 20.2±5.6 versus 8.4±1.1 μg/mg, P=0.16 and exceeded 30 μg/mg (microalbuminuria cut-off) in 7/46 cases. 17 patients had a follow-up assessment (interval 6.1±0.7 months) on a GFD. Baseline ACR was 20.7±5.2 that fell to 10.4±1.5 μg/mg, P=0.035. Conclusion/UNASSIGNED:Children and adolescents with newly diagnosed CD have low-grade albuminuria that is numerically higher than controls and that declined after implementation of a GFD. CD may be associated with reversible defects in the glomerular barrier.

Background/UNASSIGNED:Suicide risk screening is recommended in pediatric care. To date, no previous studies illustrate the implementation of suicide risk screening in pediatric subspecialty care, even though chronic medical conditions are associated with a higher risk of suicide. Methods/UNASSIGNED:A large multidivision pediatric ambulatory clinic implemented annual suicide risk screening. Patients ages 9-21 years participated in suicide risk screening using the Ask Suicide-Screening Questions during the project. A multidisciplinary team employed quality improvement methods and survey-research design methods to evaluate the feasibility and acceptability of the screening process for patients, families, and medical providers. Results/UNASSIGNED:During the quality improvement project period, 1,934 patients were offered screening; 1,301 (67.3%) patients completed screening; 82 patients (6.3% of 1,301 patients) screened positive. The monthly compliance rate held steady at 86% following several Plan-Do-Study-Act cycles of improvement. The survey results demonstrate that providers rated the suicide risk screening process positively; however, a subset of providers indicated that the screening process was out of their scope of practice or impeded their workflow. Conclusions/UNASSIGNED:Suicide risk screening is feasible in pediatric specialty care and can identify at-risk patients. Continued efforts are needed to standardize suicide risk screening practices. Future directions include identifying factors associated with suicide risk in patients in pediatric subspecialty care settings.

Celiac disease affects approximately 1% of the population worldwide. Little is known about environmental factors that may modulate risk in genetically susceptible populations. Persistent organic pollutants (POPs) are known endocrine disruptors and, given the interplay between the endocrine and immune systems, are plausible contributors to celiac disease. The current study aims to elucidate the association between POPs and celiac disease. We conducted a single-site pilot study of 88 patients recruited from NYU Langone's Hassenfeld Children's Hospital outpatient clinic, 30 of which were subsequently diagnosed with celiac disease using standard serology and duodenal biopsy examination. Polybrominated diphenyl ether (PBDEs), perfluoroalkyl substances (PFASs), and p,p'-dichlorodiphenyldichloroethylene (DDE) and HLA-DQ genotype category were measured in blood serum and whole blood, respectively. Multivariable logistic regressions were used to obtain odds ratios for celiac disease associated with serum POP concentrations. Controlling for sex, race, age, BMI, and genetic susceptibility score, patients with higher serum DDE concentrations had 2-fold higher odds of celiac disease (95% CI: 1.08, 3.84). After stratifying by sex, we found higher odds of celiac disease in females with serum concentrations of DDE (OR = 13.0, 95% CI = 1.54, 110), PFOS (OR = 12.8, 95% CI = 1.17, 141), perfluorooctanoic acid (OR = 20.6, 95% CI = 1.13, 375) and in males with serum BDE153, a PBDE congener (OR = 2.28, 95% CI = 1.01, 5.18). This is the first study to report on celiac disease with POP exposure in children. These findings raise further questions of how environmental chemicals may affect autoimmunity in genetically susceptible individuals.