The Pediatric Crohn Disease Morbidity Index (PCD-MI): Development of a Tool to Assess Long-Term Disease Burden Using a Data-Driven Approach.

BACKGROUND/OBJECTIVE: Heterogeneity and chronicity of Crohn disease (CD) make prediction of outcomes difficult. To date, no longitudinal measure can quantify burden over a patient's disease course, preventing assessment and integration into predictive modeling. Here, we aimed to demonstrate the feasibility of constructing a data driven, longitudinal disease burden score. METHODS: Literature was reviewed for tools used in assessment of CD activity. Themes were identified to construct a pediatric CD morbidity index (PCD-MI). Scores were assigned to variables. Data were extracted automatically from the electronic patient records at Southampton Children's Hospital, diagnosed from 2012 to 2019 (inclusive). PCD-MI scores were calculated, adjusted for duration of follow up and assessed for variation (ANOVA) and distribution (Kolmogorov-Smirnov). RESULTS: Nineteen clinical/biological features across five themes were included in the PCD-MI including blood/fecal/radiological/endoscopic results, medication usage, surgery, growth parameters, and extraintestinal manifestations. Maximal score was 100 after accounting for follow-up duration. PCD-MI was assessed in 66 patients, mean age 12.5 years. Following quality filtering, 9528 blood/fecal test results and 1309 growth measures were included. Mean PCD-MI score was 14.95 (range 2.2-32.5); data were normally distributed ( P = 0.2) with 25% of patients having a PCD-MI < 10. There was no difference in the mean PCD-MI when split by year of diagnosis, F -statistic 1.625, P = 0.147. CONCLUSIONS: PCD-MI is a calculatable measure for a cohort of patients diagnosed over an 8-year period, integrating a wide-range of data with potential to determine high or low disease burden. Future iterations of the PCD-MI require refinement of included features, optimized scores, and validation on external cohorts.

Pharmacological treatment of gastro-oesophageal reflux in children.

BACKGROUND: Gastro-oesophageal reflux (GOR) is characterised by the regurgitation of gastric contents into the oesophagus. GOR is a common presentation in infancy, both in primary and secondary care, affecting approximately 50% of infants under three months old. The natural history of GOR in infancy is generally of a self-limiting condition that improves with age, but older children and children with co-existing medical conditions can have more protracted symptoms. The distinction between gastro-oesophageal reflux disease (GORD) and GOR is debated. Current National Institute of Health and Care Excellence (NICE) guidelines define GORD as GOR causing symptoms severe enough to merit treatment. This is an update of a review first published in 2014. OBJECTIVES: To assess the effects of pharmacological treatments for GOR in infants and children. SEARCH METHODS: For this update, we searched CENTRAL, MEDLINE, Embase, and Web of Science up to 17 September 2022. We also searched for ongoing trials in clinical trials registries, contacted experts in the field, and searched the reference lists of trials and reviews for any additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any currently-available pharmacological treatment for GOR in children with placebo or another medication. We excluded studies assessing dietary management of GORD and studies of thickened feeds. We included studies in infants and children up to 16 years old. DATA COLLECTION AND ANALYSIS: We used standard methodology expected by Cochrane. MAIN RESULTS: We included 36 RCTs involving 2251 children and infants. We were able to extract summary data from 14 RCTs; the remaining trials had insufficient data for extraction. We were unable to pool results in a meta-analysis due to methodological differences in the included studies (including heterogeneous outcomes, study populations, and study design). We present the results in two groups by age: infants up to 12 months old, and children aged 12 months to 16 years old. Infants Omeprazole versus placebo: there is no clear effect on symptoms from omeprazole. One study (30 infants; very low-certainty evidence) showed cry/fuss time in infants aged three to 12 months had altered from 246 ± 105 minutes/day at baseline (mean +/- standard deviation (SD)) to 191 ± 120 minutes/day in the omeprazole group and from 287 ± 132 minutes/day to 201 ± 100 minutes/day in the placebo group (mean difference (MD) 10 minutes/day lower (95% confidence interval (CI) -89.1 to 69.1)). The reflux index changed in the omeprazole group from 9.9 ± 5.8% in 24 hours to 1.0 ± 1.3% and in the placebo group from 7.2 ± 6.0% to 5.3 ± 4.9% in 24 hours (MD 7% lower, 95% CI -4.7 to -9.3). Omeprazole versus ranitidine: one study (76 infants; very low-certainty evidence) showed omeprazole may or may not provide symptomatic benefit equivalent to ranitidine. Symptom scores in the omeprazole group changed from 51.9 ± 5.4 to 2.4 ± 1.2, and in the ranitidine group from 47 ± 5.6 to 2.5 ± 0.6 after two weeks: MD -4.97 (95% CI -7.33 to -2.61). Esomeprazole versus placebo: esomeprazole appeared to show no additional reduction in the number of GORD symptoms compared to placebo (1 study, 52 neonates; very low-certainty evidence): both the esomeprazole group (184.7 ± 78.5 to 156.7 ± 75.1) and placebo group (183.1 ± 77.5 to 158.3 ± 75.9) improved: MD -3.2 (95% CI -4.6 to -1.8). Children Proton pump inhibitors (PPIs) at different doses may provide little to no symptomatic and endoscopic benefit. Rabeprazole given at different doses (0.5 mg/kg and 1 mg/kg) may provide similar symptom improvement (127 children in total; very low-certainty evidence). In the lower-dose group (0.5 mg/kg), symptom scores improved in both a low-weight group of children (< 15 kg) (mean -10.6 ± SD 11.13) and a high-weight group of children (> 15 kg) (mean -13.6 ± 13.1). In the higher-dose groups (1 mg/kg), scores improved in the low-weight (-9 ± 11.2) and higher-weight groups (-8.3 ± 9.2). For the higher-weight group, symptom score mean difference between the two different dosing regimens was 2.3 (95% CI -2 to 6.6), and for the lower-weight group, symptom score MD was 4.6 (95% CI -2.9 to 12). Pantoprazole: pantoprazole may or may not improve symptom scores at 0.3 mg/kg, 0.6 mg/kg, and 1.2 mg/kg pantoprazole in children aged one to five years by week eight, with no difference between 0.3 mg/kg and 1.2 mg/kg dosing (0.3 mg/kg mean -2.4 ± 1.7; 1.2 mg/kg -1.7 ± 1.2: MD 0.7 (95% CI -0.4 to 1.8)) (one study, 60 children; very low-certainty evidence). There were insufficient summary data to assess other medications. AUTHORS' CONCLUSIONS: There is very low-certainty evidence about symptom improvements and changes in pH indices for infants. There are no summary data for endoscopic changes. Medications may or may not provide a benefit (based on very low-certainty evidence) for infants whose symptoms remain bothersome, despite nonmedical interventions or parental reassurance. If a medication is required, there is no clear evidence based on summary data for omeprazole, esomeprazole (in neonates), H2antagonists, and alginates for symptom improvements (very low-certainty evidence). Further studies with longer follow-up are needed. In older children with GORD, in studies with summary data extracted, there is very low-certainty evidence that PPIs (rabeprazole and pantoprazole) may or may not improve GORD outcomes. No robust data exist for other medications. Further RCT evidence is required in all areas, including subgroups (preterm babies and children with neurodisabilities).

Incidence and Prevalence of Paediatric Inflammatory Bowel Disease Continues to Increase in the South of England.

OBJECTIVE: The incidence of paediatric inflammatory bowel disease (IBD) has been increasing over 25 years; however, contemporary trends are not established and the impact of COVID-19 on case rates is unclear. METHODS: Data from Southampton Children's hospital prospective IBD database were retrieved for 2002-2021. Incidence rates were calculated based on referral area populations and temporal trends analysed. Disease prevalence for those aged <18 years was calculated for 2017-2021. Monoclonal prescriptions were reported. RESULTS: In total, 1150 patients were included (mean age at diagnosis 12.63 years, 40.5% female). An estimated 704 patients had Crohn's disease (61.2%), 385 had ulcerative colitis (33.5%), and 61 had IBD unclassified (5.3%). Overall IBD incidence increased, ß = 0.843, P = 3 × 10 -6 , driven by Crohn's disease, ß = 0.732, P = 0.00024 and ulcerative colitis, ß = 0.816, P = 0.000011. There was no change in IBDU incidence, ß = 0.230, P = 0.33. From 2002-2021, 51 patients were diagnosed <6 years of age, 160 patients aged 6 to <10 years and 939 patients aged 10 to <18 years of age. Increased incidence was observed in patients aged 10 to <18 years of age (ß = 0.888, P = 1.8 × 10 -7 ). There was no significant change in incidence of IBD in <6 years (ß = 0.124, P = 0.57), or 6 to <10 years (ß = 0.146, P = 0.54). IBD prevalence increased by an average of 1.71%/year from 2017 to 2021, ß = 0.979, P = 0.004. The number of new monoclonal prescriptions increased from 6 in 2007 to 111 in 2021. CONCLUSIONS: IBD incidence continues to increase in Southern England. Compounding prevalence and increased monoclonal usage has implications for service provision.

Growth failure is rare in a contemporary cohort of paediatric inflammatory bowel disease patients.

AIM: We assessed growth in a paediatric inflammatory bowel disease (PIBD) cohort. METHODS: Paediatric inflammatory bowel disease patients were eligible if they were diagnosed at Southampton Children's Hospital from 2011 to 2018. Weight and height standard deviation scores (SDS) were retrieved. Mean SDS values, SDS change and anti-TNF status were analysed at diagnosis and during follow-up. RESULTS: Four hundred and ninety patients were included, 313 with Crohn's disease (CD). CD patients presented with mean height SDS -0.13, -0.1 at 1-year, -0.11 at 2-years and -0.03 at 5 years, reflecting preserved linear growth. There was no significant height-SDS change from diagnosis to 5-year follow-up, +0.12, 95%-CI: 0.48 to -0.24. Mean weight-SDS at diagnosis was -0.39, driven by CD patients (-0.65). Mean weight-SDS approached 0 after 1 year and remained at the 50th centile throughout follow-up. Growth in ulcerative colitis was maintained. In multivariable regression males had worse height growth from diagnosis to transition (P = .036). Anti-TNF treatment (P = .013) and surgical resection (P = .005) were also associated with poorer linear growth. Patients treated with anti-TNF therapy had lower height-SDS compared to those never treated with anti-TNF at 1 year (-0.2 vs -0.01, P = .22), 2-years (-0.27 vs -0.01, P = .07) and 5 years (-0.21 vs 0.25, P = .051). CONCLUSION: Height was generally maintained in Crohn's disease, and impaired linear growth was rare in this cohort.

Use of Biosimilars in Pediatric Inflammatory Bowel Disease: An Updated Position Statement of the Pediatric IBD Porto Group of ESPGHAN.

Biologic therapies have changed the outcome of both adult and pediatric patients with Inflammatory Bowel Disease (IBD). In September 2013, the first biosimilar of infliximab was introduced into the pharmaceutical market. In 2015, a first position paper on the use of biosimilars in pediatric IBD was published by the ESPGHAN IBD Porto group. Since then, more data have accumulated for both adults and children demonstrating biosimilars are an effective and safe alternative to the originator. In this updated position statement, we summarize current evidence and provide joint consensus statements regarding the recommended practice of biosimilar use in children with IBD.

Paediatric Endoscopy Global Rating Scale: Development of a Quality Improvement Tool and Results of a National Pilot.

INTRODUCTION AND OBJECTIVES: The endoscopy Global Rating Scale (GRS) is a web-based self-assessment quality improvement (QI) tool that provides a framework for service improvement. Widespread use of the GRS in adult endoscopy services in the United Kingdom (UK) has led to a demonstrable improvement in quality. The adult GRS is not directly applicable to paediatric endoscopy services. The objective of this study is to develop and pilot a paediatric endoscopy Global Rating Scale (P-GRS) as a QI tool. METHODS: Members of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) Endoscopy Working Group collaborated with the Joint Advisory Group on Gastrointestinal Endoscopy (JAG) to develop the P-GRS. After a period of consultation, this was piloted nationally at 9 centres and data were collected prospectively at 2 census points, May and December 2016. RESULTS: The P-GRS mirrors the adult GRS by dividing care into 4 domains and includes 19 standards with several measures that underpin the standards. Eight services completed the online P-GRS return in May 2016 and 6 in December 2016. All pilot sites identified areas that needed improvement and post-pilot reflected on the key challenges and developments. Several positive developments were reported by the pilot sites. CONCLUSIONS: The national pilot helped ensure that the P-GRS developed was relevant to the paediatric endoscopy services. The pilot demonstrated that even in the first year of engaging with this QI tool, services were starting to identify areas that needed improvement, share best practice documents, put in place QI plans, and support greater patient involvement in services.

Endoscopic and Histological Assessment of Paediatric Inflammatory Bowel Disease Over a 3-Year Follow-up Period.

OBJECTIVES: Discrepancies between inflammatory bowel disease (IBD) endoscopic/histological extent are documented at diagnosis. It is unclear whether these differences persist through disease course, with potential impact on categorization and management. We aimed to analyze the progression of disease over a 3-year period. METHODS: Patients younger than 17 years, diagnosed between 2010 and 2013 at Southampton Children's Hospital and followed-up for 3 years were eligible. Primary outcome was disease extent at diagnosis and follow-up. Data are presented as percentage of patients undergoing endoscopy. Paris classification (PC) and PC using histological, rather than endoscopic disease, were determined. RESULTS: One hundred and twenty-five patients were included, 66 boys; Crohn's disease (CD) 74, ulcerative colitis (UC) 40, IBD unclassified (IBDU) 11. All had endoscopy at diagnosis. One hundred and two patients underwent ≥1 repeat endoscopies.Disease extent reduced from diagnosis to first follow-up endoscopy for both endoscopic and histological disease extent (CD/UC/IBDU, all P < 0.00006). Histological extent remained greater than endoscopic in CD with significant differences in stomach, ileum, and large bowel at all follow-up points (P =  < 0.045). Endoscopic matched histological extent in UC/IBDU. Applying a modified PC resulted in significant changes for CD (L3 27.4%-53.2%, P = 0.006, L3 + L4A 21%-50%, P = 0.001, and upper gastrointestinal disease 50%-80.6%, P = 0.0006) but not UC. CD height (-0.37 to -0.25) and weight (-1.09 to -0.19) standard deviation scores increased from diagnosis to follow-up. CONCLUSIONS: Histological disease is greater than endoscopic extent at diagnosis and during follow-up in CD, although not in UC/IBDU. Classification of disease extent in CD should be based on both endoscopic and histological criteria.

Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN.

The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre- and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options.

Endoscopic Versus Histological Disease Extent at Presentation of Paediatric Inflammatory Bowel Disease.

OBJECTIVES: The Paris classification (PC) of paediatric inflammatory bowel disease categorises disease extent and therefore affects treatment decisions. Histological (microscopic) disease extent is not incorporated, and endoscopic (macroscopic) findings may underrepresent disease extent when compared with histological findings; this study compares disease extent at presentation. METHODS: Data were obtained of patients <17 years of age diagnosed with inflammatory bowel disease from 2010 to 2013 at University Hospital Southampton. Data are presented as percentage of patients undergoing endoscopy. PC was performed alongside a modified PC by histological disease location. RESULTS: A total of 172 patients were identified (median age at diagnosis 13.5 years, 115 boys); Crohn disease (CD) 107, ulcerative colitis (UC) 50, inflammatory bowel disease unclassified (IBDU) 15; 159 had undergone upper gastrointestinal (GI) endoscopy, 163 had undergone lower GI endoscopy. Histological disease was more extensive at all points for CD, UC, and IBDU. CD--endoscopic ileal disease in 49% of patients compared with histological disease in 71.3%. Comparing PC--a 10% increase in L3 disease (ileocolonic), a 24% increase in L3 + L4a disease (ileocolonic plus upper GI), and a 27% increase in all of the upper GI involvement if histological disease extent was used. UC--the most common disease location was the rectum (endoscopic 91.5% vs histological 93.6%) and descending colon (endoscopic 89.4% vs histological 95.7%). Comparing PC--a 19% increase in E4 disease (pancolitis) if histological disease extent was used. CONCLUSIONS: These data confirm that histological disease extent is greater than endoscopic disease extent. This should be considered when the PC is used. Further study is needed to elucidate which classification would better predict disease outcome.

Pharmacological treatment of children with gastro-oesophageal reflux.

BACKGROUND: Gastro-oesophageal reflux (GOR) is a common disorder, characterised by regurgitation of gastric contents into the oesophagus. GOR is a very common presentation in infancy in both primary and secondary care settings. GOR can affect approximately 50% of infants younger than three months old (Nelson 1997). The natural history of GOR in infancy is generally that of a functional, self-limiting condition that improves with age; < 5% of children with vomiting or regurgitation continue to have symptoms after infancy (Martin 2002). Older children and children with co-existing medical conditions can have a more protracted course. The definition of gastro-oesophageal reflux disease (GORD) and its precise distinction from GOR are debated, but consensus guidelines from the North American Society of Gastroenterology, Hepatology and Nutrition (NASPGHAN-ESPGHAN guidelines 2009) define GORD as 'troublesome symptoms or complications of GOR.' OBJECTIVES: This Cochrane review aims to provide a robust analysis of currently available pharmacological interventions used to treat children with GOR by assessing all outcomes indicating benefit or harm. SEARCH METHODS: We sought to identify relevant published trials by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 5), MEDLINE and EMBASE (1966 to 2014), the Centralised Information Service for Complementary Medicine (CISCOM), the Institute for Scientific Information (ISI) Science Citation Index (on BIDS-UK General Science Index) and the ISI Web of Science. We also searched for ongoing trials in the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com).Reference lists from trials selected by electronic searching were handsearched for relevant paediatric studies on medical treatment of children with gastro-oesophageal reflux, as were published abstracts from conference proceedings (published in Gut and Gastroenterology) and reviews published over the past five years.No language restrictions were applied. SELECTION CRITERIA: Abstracts were reviewed by two review authors, and relevant RCTs on study participants (birth to 16 years) with GOR receiving a pharmacological treatment were selected. Subgroup analysis was considered for children up to 12 months of age, and for children 12 months to 16 years of age, and for those with neurological impairment. DATA COLLECTION AND ANALYSIS: Trials were critically appraised and data collected by two review authors. Risk of bias was assessed. Meta-analysis data were independently extracted by two review authors, and suitable outcome data were analysed using RevMan. MAIN RESULTS: A total of 24 studies (1201 participants) contributed data to the review. The review authors had several concerns regarding the studies. Pharmaceutical company support for manuscript preparation was a common feature; also, because common endpoints were lacking, study populations were heterogenous and variations in study design were noted, individual drug meta-analysis was not possible.Moderate-quality evidence from individual studies suggests that proton pump inhibitors (PPIs) can reduce GOR symptoms in children with confirmed erosive oesophagitis. It was not possible to demonstrate statistical superiority of one PPI agent over another.Some evidence indicates that H2antagonists are effective in treating children with GORD. Methodological differences precluded performance of meta-analysis on individual agents or on these agents as a class, in comparison with placebo or head-to-head versus PPIs, and additional studies are required.RCT evidence is insufficient to permit assessment of the efficacy of prokinetics. Given the diversity of study designs and the heterogeneity of outcomes, it was not possible to perform a meta-analysis of the efficacy of domperidone.In younger children, the largest RCT of 80 children (one to 18 months of age) with GOR showed no evidence of improvement in symptoms and 24-hour pH probe, but improvement in symptoms and reflux index was noted in a subgroup treated with domperidone and co-magaldrox(Maalox(®) ). In another RCT of 17 children, after eight weeks of therapy. 33% of participants treated with domperidone noted an improvement in symptoms (P value was not significant). In neonates, the evidence is even weaker; one RCT of 26 neonates treated with domperidone over 24 hours showed that although reflux frequency was significantly increased, reflux duration was significantly improved.Diversity of RCT evidence was found regarding efficacy of compound alginate preparations(Gaviscon Infant(®) ) in infants, although as a result of these studies, Gaviscon Infant(®) was changed to become aluminium-free and has been assessed in its current form in only two studies since 1999. Given the diversity of study designs and the heterogeneity of outcomes, as well as the evolution in formulation, it was not possible to perform a meta-analysis on the efficacy of Gaviscon Infant(®) . Moderate evidence indicates that Gaviscon Infant(®) improves symptoms in infants, including those with functional reflux; the largest study of the current formulation showed improvement in symptom control but was limited by length of follow-up.No serious side effects were reported.No RCTs on pharmacological treatments for children with neurodisability were identified. AUTHORS' CONCLUSIONS: Moderate evidence was found to support the use of PPIs, along with some evidence to support the use of H2 antagonists in older children with GORD, based on improvement in symptom scores, pH indices and endoscopic/histological appearances. However, lack of independent placebo-controlled and head-to-head trials makes conclusions as to relative efficacy difficult to determine. Further RCTs are recommended. No robust RCT evidence is available to support the use of domperidone, and further studies on prokinetics are recommended, including assessments of erythromycin.Pharmacological treatment of infants with reflux symptoms is problematic, as many infants have GOR, and little correlation has been noted between reported symptoms and endoscopic and pH findings. Better evidence has been found to support the use of PPIs in infants with GORD, but heterogeneity in outcomes and in study design impairs interpretation of placebo-controlled data regarding efficacy. Some evidence is available to support the use of Gaviscon Infant(®) , but further studies with longer follow-up times are recommended. Studies of omeprazole and lansoprazole in infants with functional GOR have demonstrated variable benefit, probably because of differences in inclusion criteria.No robust RCT evidence has been found regarding treatment of preterm babies with GOR/GORD or children with neurodisabilities. Initiation of RCTs with common endpoints is recommended, given the frequency of treatment and the use of multiple antireflux agents in these children.

Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes.

BACKGROUND: Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group. OBJECTIVE: To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease. DESIGN: DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. RESULTS: Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohn's disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients. CONCLUSION: For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this complex disease.

Pharmacogenomic Assessment of Genes Implicated in Thiopurine Metabolism and Toxicity in a UK Cohort of Pediatric Patients With Inflammatory Bowel Disease.

BACKGROUND: Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity. METHODS: We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15. RESULTS: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes. CONCLUSIONS: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.

This study reports thiopurine-induced toxicity in pediatric patients with inflammatory bowel disease. The findings are presented in the context of genetic variations, focusing on genes implicated in thiopurine drug metabolism, thereby contributing to the missing pharmacogenomic association in patients developing toxicity.

Prediction of Crohn's Disease Stricturing Phenotype Using a NOD2-derived Genomic Biomarker.

BACKGROUND: Crohn's disease (CD) is highly heterogenous and may be complicated by stricturing behavior. Personalized prediction of stricturing will inform management. We aimed to create a stricturing risk stratification model using genomic/clinical data. METHODS: Exome sequencing was performed on CD patients, and phenotype data retrieved. Biallelic variants in NOD2 were identified. NOD2 was converted into a per-patient deleteriousness metric ("GenePy"). Using training data, patients were stratified into risk groups for fibrotic stricturing using NOD2. Findings were validated in a testing data set. Models were modified to include disease location at diagnosis. Cox proportional hazards assessed performance. RESULTS: Six hundred forty-five patients were included (373 children and 272 adults); 48 patients fulfilled criteria for monogenic NOD2-related disease (7.4%), 24 of whom had strictures. NOD2 GenePy scores stratified patients in training data into 2 risk groups. Within testing data, 30 of 161 patients (18.6%) were classified as high-risk based on the NOD2 biomarker, with stricturing in 17 of 30 (56.7%). In the low-risk group, 28 of 131 (21.4%) had stricturing behavior. Cox proportional hazards using the NOD2 risk groups demonstrated a hazard ratio (HR) of 2.092 (P = 2.4 × 10-5), between risk groups. Limiting analysis to patients diagnosed aged < 18-years improved performance (HR-3.164, P = 1 × 10-6). Models were modified to include disease location, such as terminal ileal (TI) disease or not. Inclusion of NOD2 risk groups added significant additional utility to prediction models. High-risk group pediatric patients presenting with TI disease had a HR of 4.89 (P = 2.3 × 10-5) compared with the low-risk group patients without TI disease. CONCLUSIONS: A NOD2 genomic biomarker predicts stricturing risk, with prognostic power improved in pediatric-onset CD. Implementation into a clinical setting can help personalize management.

NOD2 is a well-established risk gene for development of Crohn's disease and stricturing behavior. Here we demonstrate NOD2 can be utilized as a genomic biomarker, stratifying patients into 2 stricturing risk groups. Further refinement using disease location at diagnosis improved risk stratification.

No relation between disease activity measured by multiple methods and REE in childhood Crohn disease.

BACKGROUND AND AIMS: Increased resting energy expenditure (REE) unmatched by dietary intake is implicated as a cause of poor nutrition in childhood inflammatory conditions. Adequate description of disease activity and correction of REE data for body composition are important to reach reliable conclusions about changes in REE associated with disease. The present study aimed to determine the effect of disease activity measured by clinical status, systemic and stool inflammatory markers on REE in children with Crohn disease using appropriate correction for confounding factors. METHODS: Sixty children with Crohn disease were recruited from the regional paediatric gastroenterology unit and studied on 1 occasion. REE was measured by indirect calorimetry. Fat-free mass (FFM) was estimated by skinfold thickness. Disease activity was measured using systemic (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]) and faecal markers of inflammation (lactoferrin, calprotectin) and clinical scores (Paediatric Crohn Disease Activity Index). RESULTS: Using a multiple regression model, there was no significant change in REE from active or inactive disease (ß = 0.03, P = 0.7) nor from CRP (ß = -0.05, P = 0.52), ESR (ß = -0.07, P = 0.43), faecal calprotectin (ß = -0.07, P = 0.38), and faecal lactoferrin (ß = 0.01, P = 0.88). REE/kg FFM was not associated with the Paediatric Crohn Disease Activity Index (r = 0.1, P = 0.44), CRP (r = -0.3, P = 0.84) or ESR (r = 0.12, P = 0.4), faecal calprotectin (r = 0.04, P = 0.97), or faecal lactoferrin (r = 0.02, P = 0.87). CONCLUSIONS: REE corrected for physiologically relevant confounders is not associated with degree of disease activity using clinical tools or systemic and local inflammatory markers, and therefore is an unlikely mechanism for poor nutritional state.

Deleterious Genetic Variation Across the NOD Signaling Pathway Is Associated With Reduced NFKB Signaling Transcription and Upregulation of Alternative Inflammatory Transcripts in Pediatric Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease may arise with inadequate immune response to intestinal bacteria. NOD2 is an established gene in Crohn's disease pathogenesis, with deleterious variation associated with reduced NFKB signaling. We hypothesized that deleterious variation across the NOD2 signaling pathway impacts on transcription. METHODS: Treatment-naïve pediatric inflammatory bowel disease patients had ileal biopsies for targeted autoimmune RNA-sequencing and blood for whole exome sequencing collected at diagnostic endoscopy. Utilizing GenePy, a per-individual, per-gene score, genes within the NOD signaling pathway were assigned a quantitative score representing total variant burden. Where multiple genes formed complexes, GenePy scores were summed to create a "complex" score. Normalized transcript expression of 95 genes within this pathway was retrieved. Regression analysis was performed to determine the impact of genomic variation on gene transcription. RESULTS: Thirty-nine patients were included. Limited clustering of patients based on NOD signaling transcripts was related to underlying genomic variation. Patients harboring deleterious variation in NOD2 had reduced NOD2 (ß = -0.702, P = 4.3 × 10-5) and increased NFKBIA (ß = 0.486, P = .001), reflecting reduced NFKB signal activation. Deleterious variation in the NOD2-RIPK2 complex was associated with increased NLRP3 (ß = 0.8, P = 3.1475 × 10-8) and TXN (ß = -0.417, P = 8.4 × 10-5) transcription, components of the NLRP3 inflammasome. Deleterious variation in the TAK1-TAB complex resulted in reduced MAPK14 transcription (ß = -0.677, P = 1.7 × 10-5), a key signal transduction protein in the NOD2 signaling cascade and increased IFNA1 (ß = 0.479, P = .001), indicating reduced transcription of NFKB activators and alternative interferon transcription in these patients. CONCLUSIONS: Data integration identified perturbation of NOD2 signaling transcription correlated with genomic variation. A hypoimmune NFKB signaling transcription response was observed. Alternative inflammatory pathways were activated and may represent therapeutic targets in specific patients.

Food protein-induced enterocolitis syndrome in the British Isles.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a delayed type of food allergy, most often seen in infancy. We aimed to estimate its incidence, to describe common food triggers and the patient journeys of this rare but serious condition. DESIGN: We undertook a prospective epidemiological survey of FPIES using the British Paediatric Surveillance Unit. SETTING: UK and Ireland. PARTICIPANTS: A survey of all paediatricians over 13 months between January 2019 and February 2020. MAIN OUTCOME MEASURES: 204 cases were reported, 98 (48%) meeting case definition, giving an incidence of 0.006% for England based on 93 cases. RESULTS: 98 patients reported 135 trigger foods, 27% (26 of 98) had multiple food triggers. Common food triggers included cow's milk (24%, 33 of 135), fruits and vegetables (19%, 26 of 135), hen's egg (16%, 22 of 135) and fish (14%, 19 of 135). In 46% (41 of 90), the initial trigger food had been ingested three or more times before diagnosis, with a median diagnostic delay of 7.9 months (3.0, 17.3). Half (50 of 98) were admitted, yet only 5% (5 of 98) received appropriate acute treatment with ondansetron. Most cases were diagnosed by an allergy specialist (74 of 98, 76%), within a median of 7.5 (3.0, 13.3) miles from home. CONCLUSION: The incidence of FPIES was significantly lower than expected across the whole of the British Isles. Most reports were of cases local to specialist allergy centres, with delays in diagnosis. This suggests under-recognition of FPIES in frontline clinical setting where education of healthcare professionals is required to improve recognition, earlier diagnosis and treatment.

Nutrition and inflammatory bowel disease: primary or adjuvant therapy.

PURPOSE OF REVIEW: Our understanding of the importance of nutrition in inflammatory bowel disease (IBD) continues to improve. With increasing evidence or cumulative evidence, this article reviews the current data for the role of nutrition in IBD pathogenesis, disease exacerbation and its use in the treatment of IBD in a clinically relevant context. RECENT FINDINGS: Irritable bowel syndrome and obesity prevalence is rising, and is increasingly being recognized in patients with IBD. Exclusive enteral nutrition remains highly relevant because of its efficacy and superior side-effect profile, even when considered against new pharmacological treatments, but requires patient motivation. We are now beginning to understand the importance of micronutrients such as iron and vitamin D, which may not only alter the bowel flora but also have an immune-modulatory effect. More recently, a prebiotic and probiotic combination has been used in a randomized trial for the treatment of IBD. SUMMARY: Macronutrient and micronutrient assessment should be an essential part of nutritional assessment of all patients with IBD. Although research is needed to further our understanding of the immune-modulatory effects of nutrients and supplements, better and more effective therapies combining nutrition and drug treatments like immune-suppressants should be explored.

Ileal Transcriptomic Analysis in Paediatric Crohn's Disease Reveals IL17- and NOD-signalling Expression Signatures in Treatment-naïve Patients and Identifies Epithelial Cells Driving Differentially Expressed Genes.

BACKGROUND AND AIMS: Crohn's disease [CD] arises through host-environment interaction. Abnormal gene expression results from disturbed pathway activation or response to bacteria. We aimed to determine activated pathways and driving cell types in paediatric CD. METHODS: We employed contemporary targeted autoimmune RNA sequencing, in parallel to single-cell sequencing, to ileal tissue derived from paediatric CD and controls. Weighted gene co-expression network analysis [WGCNA] was performed and differentially expressed genes [DEGs] were determined. We integrated clinical data to determine co-expression modules associated with outcomes. RESULTS: In all, 27 treatment-naive CD [TN-CD], 26 established CD patients and 17 controls were included. WGCNA revealed a 31-gene signature characterising TN-CD patients, but not established CD, nor controls. The CSF3R gene is a hub within this module and is key in neutrophil expansion and differentiation. Antimicrobial genes, including S100A12 and the calprotectin subunit S100A9, were significantly upregulated in TN CD compared with controls [p = 2.61 x 10-15 and p = 9.13 x 10-14, respectively] and established CD [both p = 0.0055]. Gene-enrichment analysis confirmed upregulation of the IL17-, NOD- and Oncostatin-M-signalling pathways in TN-CD patients, identified in both WGCNA and DEG analyses. An upregulated gene signature was enriched for transcripts promoting Th17-cell differentiation and correlated with prolonged time to relapse [correlation-coefficient-0.36, p = 0.07]. Single-cell sequencing of TN-CD patients identified specialised epithelial cells driving differential expression of S100A9. Cell groups, determined by single-cell gene expression, demonstrated enrichment of IL17-signalling in monocytes and epithelial cells. CONCLUSIONS: Ileal tissue from treatment-naïve paediatric patients is significantly upregulated for genes driving IL17-, NOD- and Oncostatin-M-signalling. This signal is driven by a distinct subset of epithelial cells expressing antimicrobial gene transcripts.

Expression profile of the matricellular protein periostin in paediatric inflammatory bowel disease.

The precise role of periostin, an extra-cellular matrix protein, in inflammatory bowel disease (IBD) is unclear. Here, we investigated periostin in paediatric IBD including its relationship with disease activity, clinical outcomes, genomic variation and expression in the colonic tissue. Plasma periostin was analysed using ELISA in 144 paediatric patients and 38 controls. Plasma levels were assessed against validated disease activity indices in IBD and clinical outcomes. An immuno-fluorescence for periostin and detailed isoform-expression analysis in the colonic tissue was performed in 23 individuals. We integrated a whole-gene based burden metric 'GenePy' to assess the impact of variation in POSTN and 23 other genes functionally connected to periostin. We found that plasma periostin levels were significantly increased during remission compared to active Crohn's disease. The immuno-fluorescence analysis demonstrated enhanced peri-cryptal ring patterns in patients compared to controls, present throughout inflamed, as well as macroscopically non-inflamed colonic tissue. Interestingly, the pattern of isoforms remained unchanged during bowel inflammation compared to healthy controls. In addition to its role during the inflammatory processes in IBD, periostin may have an additional prominent role in mucosal repair. Additional studies will be necessary to understand its role in the pathogenesis, repair and fibrosis in IBD.

Genetic Sequencing of Pediatric Patients Identifies Mutations in Monogenic Inflammatory Bowel Disease Genes that Translate to Distinct Clinical Phenotypes.

OBJECTIVES: Monogenic inflammatory bowel disease (IBD) comprises rare Mendelian causes of gut inflammation, often presenting in infants with severe and atypical disease. This study aimed to identify clinically relevant variants within 68 monogenic IBD genes in an unselected pediatric IBD cohort. METHODS: Whole exome sequencing was performed on patients with pediatric-onset disease. Variants fulfilling the American College of Medical Genetics criteria as "pathogenic" or "likely pathogenic" were assessed against phenotype at diagnosis and follow-up. Individual patient variants were assessed and processed to generate a per-gene, per-individual, deleteriousness score. RESULTS: Four hundred one patients were included, and the median age of disease-onset was 11.92 years. In total, 11.5% of patients harbored a monogenic variant. TRIM22-related disease was implicated in 5 patients. A pathogenic mutation in the Wiskott-Aldrich syndrome (WAS) gene was confirmed in 2 male children with severe pancolonic inflammation and primary sclerosing cholangitis. In total, 7.3% of patients with Crohn's disease had apparent autosomal recessive, monogenic NOD2-related disease. Compared with non-NOD2 Crohn's disease, these patients had a marked stricturing phenotype (odds ratio 11.52, significant after correction for disease location) and had undergone significantly more intestinal resections (odds ratio 10.75). Variants in ADA, FERMT1, and LRBA did not meet the criteria for monogenic disease in any patients; however, case-control analysis of mutation burden significantly implicated these genes in disease etiology. DISCUSSION: Routine whole exome sequencing in pediatric patients with IBD results in a precise molecular diagnosis for a subset of patients with IBD, providing the opportunity to personalize therapy. NOD2 status informs risk of stricturing disease requiring surgery, allowing clinicians to direct prognosis and intervention.