Effectiveness of strategies to suppress antibodies to infliximab in pediatric inflammatory bowel disease.

OBJECTIVES: Antibodies to infliximab (ATIs) are associated with loss of response in children with inflammatory bowel disease (IBD). We aimed to describe the effectiveness of strategies for treatment modification following ATI development in pediatric IBD: (1) treatment escalation; and (2) switching to another anti-TNF agent. METHODS: This multicenter retrospective study included children with IBD (4-18 years) on infliximab. Therapeutic drug monitoring (TDM) < 6 months and corticosteroid-free remission following each strategy were evaluated for low ATI titers (≤30 AU/mL) and high ATI titers (>30 AU/mL). RESULTS: Anti-infliximab antibodies were detected in 52/288 patients (18%) after a median of 15.3 months. Three of 52 ATI-positive patients were excluded due to alternative treatments. Of the remaining 49 patients, 19 had low titers and 30 had high titers. Of 19 low-ATIs, 16 (84%) underwent treatment escalation with infliximab (IFX). Of 13 patients with TDM available, seven (54%) achieved ATI suppression at subsequent TDM and 12 (92%) at any time point. Among 30 patients with high-ATIs, 17 (57%) continued with IFX; immunomodulators were started in seven patients. Of 14 patients with TDM, seven (50%) achieved ATI suppression at subsequent TDM and 10 (71%) at any time point. At 24 months of follow-up, 73% of low-ATI patients and 50% of high-ATI patients could continue with IFX without steroids. Thirteen of 30 high-ATI patients (43%) switched to another anti-TNF agent, of whom 54% and 46% had clinical response at 6 and 24 months, respectively. CONCLUSIONS: Dose optimization and/or adding an immunomodulator seem effective in suppressing low ATI titers. This strategy could also be considered in high ATI titers before switching.

Co-Development of Three Dietary Indices to Facilitate Dietary Intake Assessment of Pediatric Crohn's Disease Patients.

Literature on dietary behaviours of the pediatric Crohn's Disease (CD) population and the relationship between dietary intake and CD activity is limited. Three dietary indices were developed and tested to conduct dietary pattern analysis in pediatric patients with CD consuming a free diet following remission induction via exclusive enteral nutrition (n = 11). Index scores underwent descriptive and inferential analysis. The mean adjusted scores (out of 100) for the Pediatric Western Diet Index, Pediatric Prudent Diet Index, and Pediatric-Adapted 2010 Alternate Healthy Eating Index (PA2010-AHEI) were 29.82 ± 15.22, 34.25 ± 15.18, and 51.50 ± 11.69, respectively. The mean Western-to-Prudent ratio was 0.94 ± 0.55. A significant correlation (r = -0.71) and relationship (F[1, 9] = 9.04, P < 0.05, R2 = 0.501) between the Western-to-Prudent ratio and PA2010-AHEI was found. The results suggest participants were not following a Western or Prudent diet, and were consuming foods not captured by the indices. More research is needed to describe dietary intake of individuals with CD, validate dietary indices in diverse samples, and explore the utility of these indices in CD assessment and treatment. The co-authors hope this work will stimulate/inspire subsequent interprofessional, dietitian-led research on this topic.

Metabolome Changes With Diet-Induced Remission in Pediatric Crohn's Disease.

BACKGROUND & AIMS: The Crohn's disease (CD) exclusion diet (CDED) plus partial enteral nutrition (PEN) and exclusive enteral nutrition (EEN) both induce remission in pediatric CD. CDED+PEN is better tolerated and able to sustain remission. We characterized the changes in fecal metabolites induced by CDED+PEN and EEN and their relationship with remission. METHODS: A total of 216 fecal metabolites were measured in 80 fecal samples at week (W) 0, W6, and W12, of children with mild to moderate CD in a prospective randomized trial comparing CDED+PEN vs EEN. The metabolites were measured using liquid chromatography coupled to mass spectrometry. Metagenome Kyoto Encyclopedia of Genes and Genomes Orthology analysis was performed to investigate the differential functional gene abundance involved in specific metabolic pathways. Data were analyzed according to clinical outcome of remission (W6_rem), no remission (W6_nr), sustained remission (W12_sr), and nonsustained (W12_nsr) remission. RESULTS: A decrease in kynurenine and succinate synthesis and an increase in N-α-acetyl-arginine characterized CDED+PEN W6_rem, whereas changes in lipid metabolism characterized EEN W6_rem, especially reflected by lower levels in ceramides. In contrast, fecal metabolites in EEN W6_nr were comparable to baseline/W0 samples. CDED+PEN W6_rem children maintained metabolome changes through W12. In contrast, W12_nsr children in the EEN group, who resumed a free diet after week 6, did not. The metabolome of CDED+PEN differed from EEN in the purine, pyrimidine, and sphingolipid pathways. A significant differential abundance in several genes involved in these pathways was detected. CONCLUSION: CDED+PEN- and EEN-induced remission are associated with significant changes in inflammatory bowel disease-associated metabolites such as kynurenine, ceramides, amino acids, and others. Sustained remission with CDED+PEN, but not EEN, was associated with persistent changes in metabolites. CLINICALTRIALS: gov, Number NCT01728870.

Assessing Disease Activity in Pediatric Crohn's Disease Using Ultrasound: The Pediatric Crohn Disease Intestinal Ultrasound Score.

OBJECTIVES: Currently, there is no consensus on how to score Crohn disease (CD) activity assessed by intestinal ultrasound (IUS) in children. This study aimed to design an easy-to-use IUS score for disease activity in pediatric CD. METHODS: Children undergoing ileo-colonoscopy for CD assessment underwent IUS the day before ileo-colonoscopy, assessed with simple endoscopic score for CD (SES-CD). IUS features were compared to the SES-CD on segmental level. Multiple regression analyses, separately for terminal ileum (TI) and colon, were done to assess predictors of disease activity and to develop a model. RESULTS: In 74 CD patients (median 15 years, 48% female), 67 TI and 364 colon segments were assessed. Based on receiver operating characteristics curves, bowel wall thickness (BWT) was categorized into low [1 point: 2-3 mm (TI) and 1.6-2 mm (colon)], medium [2 points: 3.0-3.7 mm (TI) and 2.0-2.7 mm (colon)], and high [3 points: >3.7 mm (TI) and >2.7 mm (colon)]. In TI, only BWT was retained in the model [high BWT: odds ratio (OR) 11.50, P < 0.001]. In colon, BWT (high BWT: OR 8.63, P < 0.001) and mesenteric fat (1 point: OR 3.02, P < 0.001) were independent predictors. A pediatric Crohn disease IUS score (PCD-US) cut-off of 1 resulted in a sensitivity of 82% (95% confidence interval, CI: 65%-93%) and 85% (95% CI: 80%-89%) and a cut-off of 3 in a specificity of 88% (72%-97%) and 92% (87%-96%) for TI and colon, respectively. Inter-observer agreement was moderate for TI and colon ( K : 0.42, K : 0.49, respectively). CONCLUSIONS: The PCD-US score is an easy-to-use and reliable score to detect or rule out CD activity on segmental level in children. External validation is needed before applying this score in clinical practice.

Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140.

BACKGROUND: SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn's disease (CD), suggesting a role in inflammation. RESULTS: We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal mucosa. CONCLUSIONS: This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

Influence of timing of maternal antibiotic administration during caesarean section on infant microbial colonisation: a randomised controlled trial.

OBJECTIVE: Revised guidelines for caesarean section (CS) advise maternal antibiotic administration prior to skin incision instead of after umbilical cord clamping, unintentionally exposing the infant to antibiotics antenatally. We aimed to investigate if timing of intrapartum antibiotics contributes to the impairment of microbiota colonisation in CS born infants. DESIGN: In this randomised controlled trial, women delivering via CS received antibiotics prior to skin incision (n=20) or after umbilical cord clamping (n=20). A third control group of vaginally delivering women (n=23) was included. Faecal microbiota was determined from all infants at 1, 7 and 28 days after birth and at 3 years by 16S rRNA gene sequencing and whole-metagenome shotgun sequencing. RESULTS: Compared with vaginally born infants, profound differences were found in microbial diversity and composition in both CS groups in the first month of life. A decreased abundance in species belonging to the genera Bacteroides and Bifidobacterium was found with a concurrent increase in members belonging to the phylum Proteobacteria. These differences could not be observed at 3 years of age. No statistically significant differences were observed in taxonomic and functional composition of the microbiome between both CS groups at any of the time points. CONCLUSION: We confirmed that microbiome colonisation is strongly affected by CS delivery. Our findings suggest that maternal antibiotic administration prior to CS does not result in a second hit on the compromised microbiome. Future, larger studies should confirm that antenatal antibiotic exposure in CS born infants does not aggravate colonisation impairment and impact long-term health.

Utilization of Antitumor Necrosis Factor Biologics in Very Early Onset Inflammatory Bowel Disease: A Multicenter Retrospective Cohort Study From North America.

BACKGROUND: Research on the utilization and effectiveness of antitumor necrosis factor (TNF) biologics in children with very early onset inflammatory bowel disease (VEOIBD) is urgently needed. Here we describe anti-TNF use and durability in a multicenter cohort. METHODS: We performed a retrospective cohort study of patients diagnosed with VEOIBD (<6 years) between 2008 and 2013 at 25 North American centers. We performed chart abstraction at diagnosis and 1, 3, and 5 years after diagnosis. We examined the rate of initiation and durability of infliximab and adalimumab and evaluated associations between treatment durability and the following covariates with multivariate Cox proportional hazard regression: age at diagnosis, sex, disease duration, disease classification, and presence of combined immunomodulatory treatment versus monotherapy. RESULTS: Of 294 children with VEOIBD, 120 initiated treatment with anti-TNF therapy and 101 had follow-up data recorded [50% Crohn disease (CD), 31% ulcerative colitis (UC), and 19% IBD unclassified (IBD-U)]. The cumulative probability of anti-TNF treatment was 15% at 1 year, 30% at 3 years, and 45% at 5 years from diagnosis; 56 (55%) were treated between 0 and 6 years old. Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years. The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children. Children with UC/IBD-U had lower durability than those with CD (hazard ratio [HR] 0.17; 95% confidence interval [CI], 0.06-0.51; P = 0.001). CONCLUSIONS: Utilization and durability of anti-TNF in VEOIBD is relatively high and comparable with older children. Having Crohn disease (compared with UC/IBD-U) is associated with greater durability.

Adverse Events of Thiopurine Therapy in Pediatric Inflammatory Bowel Disease and Correlations with Metabolites: A Cohort Study.

BACKGROUND: In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity. AIMS: We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival. METHODS: We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient. RESULTS: Of 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase. CONCLUSIONS: Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities.

Dietary Therapies Induce Rapid Response and Remission in Pediatric Patients With Active Crohn's Disease.

BACKGROUND & AIMS: Dietary therapies based on exclusion of usual dietary elements induce remission in children with Crohn's disease (CD), whereas re-exposure induces rebound inflammation. We investigated whether a short trial of dietary therapy, to identify patients with and without a rapid response or remission on the diet (DiRe), can be used to predict success or failure of long-term dietary therapy. METHODS: We collected data from the multicenter randomized trial of the CD exclusion diet (CDED). We analyzed data from 73 children with mild to moderate CD (mean age, 14.2 ± 2.7 y) randomly assigned to groups given either exclusive enteral nutrition (EEN, n = 34) or the CDED with 50% (partial) enteral nutrition (n = 39). Patients were examined at baseline and at weeks 3 and 6 of the diet. Remission was defined as CD activity index scores below 10 and response was defined as a decrease in score of 12.5 points or clinical remission. Inflammation was assessed by measurement of C-reactive protein. RESULTS: At week 3 of the diet, 82% of patients in the CDED group and 85% of patients in the EEN group had a DiRe. Median serum levels of C-reactive protein had decreased from 24 mg/L at baseline to 5.0 mg/L at week 3 (P < .001). Among the 49 patients in remission at week 6, 46 patients (94%) had a DiRe and 81% were in clinical remission by week 3. In multivariable analysis, remission at week 3 increased odds of remission by week 6 (odds ratio, 6.37; 95% CI, 1.6-25; P = .008) whereas poor compliance reduced odds of remission at week 6 (odds ratio, 0.75; 95% CI, 0.012-0.46; P = .006). CONCLUSIONS: For pediatric patients with active CD, dietary therapies (CDED and EEN) induce a rapid clinical response (by week 3). Identification of patients with and without a rapid response to diet might help identify those who, with compliance, will be in clinical remission by week 6 of the diet. ClinicalTrials.gov no: NCT01728870.

SuRF: A new method for sparse variable selection, with application in microbiome data analysis.

In this article, we present a new variable selection method for regression and classification purposes, particularly for microbiome analysis. Our method, called subsampling ranking forward selection (SuRF), is based on LASSO penalized regression, subsampling and forward-selection methods. SuRF offers major advantages over existing variable selection methods in terms of both sparsity of selected models and model inference. We provide an R package that can implement our method for generalized linear models. We apply our method to classification problems from microbiome data, using a novel agglomeration approach to deal with the special tree-like correlation structure of the variables. Existing methods arbitrarily choose a taxonomic level a priori before performing the analysis, whereas by combining SuRF with these aggregated variables, we are able to identify the key biomarkers at the appropriate taxonomic level, as suggested by the data. We present simulations in multiple sparse settings to demonstrate that our approach performs better than several other popularly used existing approaches in recovering the true variables. We apply SuRF to two microbiome datasets: one about prediction of pouchitis and another for identifying samples from two healthy individuals. We find that SuRF can provide a better or comparable prediction with other methods while controlling the false positive rate of variable selection.

Withdrawal of Combination Immunotherapy in Paediatric Inflammatory Bowel Disease-An International Survey of Practice.

OBJECTIVES: To assess current practices around the use of combination immunosuppression in paediatric inflammatory bowel disease (PIBD) with a focus on the subsequent withdrawal process. METHODS: A web-based, 43-question survey. RESULTS: Surveys were completed by 70 paediatric gastroenterologists (PGs) from 27 nations across Europe, North America, Oceania and Asia from 62 centres covering approximately 15,000 PIBD patients (median of 200 patients [interquartile range (IQR) 130-300] per centre). Routine use of co-immunosuppression was significantly higher with infliximab (IFX) versus adalimumab (ADL) ([61/70, 87.1%] compared with [23/70, 32.9%]; P < 0.01). Thiopurines (azathioprine [AZA] or 6-mercaptopurine) were the preferred option overall for co-immunosuppression. They were favoured with either IFX or ADL (76% and 77%, respectively) and in both ulcerative colitis (UC) and Crohn disease (CD) (84% and 69%) compared with methotrexate (MTX).Immunomodulators were the preferred choice as the initial drug to be withdrawn from the combination therapy rather than anti-tumour necrosis factor-alpha (anti-TNFα) therapy (59/67, 88% [P < 0.01]). The most common withdrawal time was after 6-12 months, with this decision usually based on clinical assessment rather than a scheduled withdrawal time (51/67, 76% vs 16/67, 24%). Indicators of mucosal healing and therapeutic drug monitoring results tended to be the most important "clinical factors" in the withdrawal decision (P = 0.05). CONCLUSION: Most PG's favour initial withdrawal of immunomodulator (usually thiopurines) rather than biologic therapy in the step-down process, usually after 6-12 months based on sustained clinical remission. This survey precedes an in-depth, multicentre study of clinical outcomes of withdrawal of co-immunosuppression in PIBD.

Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND: It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups. METHODS: The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists). RESULTS: We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries. CONCLUSIONS: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.

Teaching Families of Children with Celiac Disease about Gluten-Free Diet Using Distributed Education: a Pilot Study.

Introduction: Treatment of celiac disease is a strict life-long gluten-free diet (GFD). The GFD is complex, and counseling by a dietitian is essential. The number of new referrals for GFD education has increased. We studied the feasibility of GFD teaching using distributed education.Methods: The IWK Health Center in Halifax is the only tertiary-care pediatric hospital in the 3 Maritime provinces with GFD experienced dietitians. Families travel long distances to attend teaching sessions. Families outside the Halifax area were offered to participate in the 2.5-hour education sessions held once a month via live videoconference link at their regional hospitals. All participants were surveyed with a 10-item questionnaire assessing the content and delivery and usefulness of information.Results: Over a 6-month period, 39 families attended the sessions, 21 locally and 18 at distributed sites across the Maritimes. The survey was completed by 26 participants (67%). All participants at both sites strongly agreed or agreed that their setting was good for learning and the information provided was easy to understand. There were no significant differences between the 2 groups on any individual questions in the 2 domains assessed (all P > 0.06).Conclusions: Distributed education on GFD is feasible and as effective as in person education. It affords convenience and savings to families by reducing travel costs.

Crohn's Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled Trial.

BACKGROUND & AIMS: Exclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn's disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier. METHODS: We performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestlé) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7 to 12 (stage 2) (n = 40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7 to 12 (n = 38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed; 16S ribosomal RNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 (pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week 12. RESULTS: Four patients withdrew from the study because of intolerance by 48 hours, 74 patients (mean age 14.2 ± 2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (P = .002; odds ratio for tolerance of CDED and PEN, 13.92; 95% confidence interval [CI] 1.68-115.14). At week 6, 30 (75%) of 40 children given CDED plus PEN were in corticosteroid-free remission vs 20 (59%) of 34 children given EEN (P = .38). At week 12, 28 (75.6%) of 37 children given CDED plus PEN were in corticosteroid-free remission compared with 14 (45.1%) of 31 children given EEN and then PEN (P = .01; odds ratio for remission in children given CDED and PEN, 3.77; CI 1.34-10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria. CONCLUSION: CDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD. Clinicaltrials.gov no: NCT01728870.

Clinical disease activity and endoscopic severity correlate poorly in children newly diagnosed with Crohn's disease.

BACKGROUND AND AIMS: Treatment goals in Crohn's disease (CD) have evolved to target mucosal healing. There is now a drive to determine if noninvasive measures can adequately identify the attainment and persistence of this goal. Currently, data describing the relationship between clinical indices and endoscopic appearance in pediatric CD are sparse. Our aim was to compare endoscopic severity with the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) in children with newly diagnosed CD. METHODS: All children aged ≤17 years newly diagnosed with CD enrolled in an inception cohort at sites of the Canadian Children Inflammatory Bowel Disease Network were eligible. Clinical disease activity at presentation was evaluated by the wPCDAI and conventional biochemical parameters. Severity of disease at ileocolonoscopy was assessed by the simple endoscopic score for CD (SES-CD), with segmental subscores noted. We evaluated the association of SES-CD and disease activity markers using the Pearson test of correlation, the Spearman rank coefficient, and linear regression models. RESULTS: Two hundred eighty patients from 11 centers were included in the analysis. The median wPCDAI score was 60 (interquartile range, 40-80; 53% severe). Median SES-CD was 16 (interquartile range 10-22; 51% severe). The wPCDAI correlated weakly with SES-CD (r = .39, P < .001). Examination of the individual components that contribute to the wPCDAI demonstrated weak correlation with the SES-CD for all items apart from stooling (moderate correlation, r = .50, P < .001). Routine blood tests did not correlate well with the SES-CD. In regression models, variation in clinical symptoms accounted for most of the variation in both the wPCDAI and SES-CD, with no additional benefit from routine blood tests. CONCLUSIONS: In children with newly diagnosed CD, wPCDAI correlates poorly with endoscopic disease activity. As treatment paradigms evolve to target mucosal healing, clinical markers should not be used in isolation to determine disease activity.

Nutrition in Pediatric Inflammatory Bowel Disease: A Position Paper on Behalf of the Porto Inflammatory Bowel Disease Group of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND AND AIMS: A growing body of evidence supports the need for detailed attention to nutrition and diet in children with inflammatory bowel disease (IBD). We aimed to define the steps in instituting dietary or nutritional management in light of the current evidence and to offer a useful and practical guide to physicians and dieticians involved in the care of pediatric IBD patients. METHODS: A group of 20 experts in pediatric IBD participated in an iterative consensus process including 2 face-to-face meetings, following an open call to Nutrition Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition Porto, IBD Interest, and Nutrition Committee. A list of 41 predefined questions was addressed by working subgroups based on a systematic review of the literature. RESULTS: A total of 53 formal recommendations and 47 practice points were endorsed with a consensus rate of at least 80% on the following topics: nutritional assessment; macronutrients needs; trace elements, minerals, and vitamins; nutrition as a primary therapy of pediatric IBD; probiotics and prebiotics; specific dietary restrictions; and dietary compounds and the risk of IBD. CONCLUSIONS: This position paper represents a useful guide to help the clinicians in the management of nutrition issues in children with IBD.

Infliximab Monotherapy vs Combination Therapy for Pediatric Crohn's Disease Exhibit Similar Pharmacokinetics.

BACKGROUND: The use of concomitant azathioprine may improve efficacy and pharmacokinetic (PK) properties of infliximab (IFX) but is also associated with an increased risk of adverse events. Proactive therapeutic drug monitoring (pTDM) of IFX monotherapy is an alternative strategy to improve PK. The aim of this study was to evaluate whether IFX with an immunomodulator (combo) has PK benefits over IFX-pTDM (mono) in pediatric Crohn's disease (CD). METHODS: This PK analysis included pediatric CD patients who started either IFX combo (TISKids study) or IFX mono with pTDM (REFINE cohort). Combo and mono IFX trough levels (TLs) and antibodies-to-infliximab were assessed at infusion 3, 4, and 5. A population PK model was built to compare IFX PK outcomes (clearance [CL], TLs and cumulative exposure) between combo and mono groups at infusion 4 and 5. Clinical response and steroid-free clinical remission (SFCR) was assessed at infusion 4 and 5. RESULTS: This study included 128 pediatric CD patients (66 mono and 62 combo). At infusion 5, there was no significant difference between mono and combo median TLs 4.1 µg/mL (2.1, 7.8) vs 5.9 µg/mL (3.2, 9.4; P = .14) or median CL 0.26 L/d (0.21, 0.32) vs 0.26 L/d (0.21, 0.33; P = .81). Mono patients had a lower SFCR rate at infusion 5 (53% [31 of 59] vs 80% [32 of 40]; P = .01). Clinical response rates were significantly higher among combo than mono patients at both infusion 4 and 5. CONCLUSIONS: This study suggests that there are no PK differences (TLs and CL) between combo and mono therapy in pediatric CD patients who started IFX.

This study compared the pharmacokinetics of infliximab combination therapy with azathioprine vs infliximab with proactive therapeutic drug monitoring as monotherapy among pediatric patients with Crohn's disease within the first 22 weeks. No pharmacokinetic differences were found between monotherapy and combination therapy.

The gastrointestinal antibiotic resistome in pediatric leukemia and lymphoma patients.

Introduction: Most children with leukemia and lymphoma experience febrile neutropenia. These are treated with empiric antibiotics that include ß-lactams and/or vancomycin. These are often administered for extended periods, and the effect on the resistome is unknown. Methods: We examined the impact of repeated courses and duration of antibiotic use on the resistome of 39 pediatric leukemia and lymphoma patients. Shotgun metagenome sequences from 127 stool samples of pediatric oncology patients were examined for abundance of antibiotic resistance genes (ARGs) in each sample. Abundances were grouped by repeated courses (no antibiotics, 1-2 courses, 3+ courses) and duration (no use, short duration, long and/or mixed durationg) of ß-lactams, vancomycin and "any antibiotic" use. We assessed changes in both taxonomic composition and prevalence of ARGs among these groups. Results: We found that Bacteroidetes taxa and ß-lactam resistance genes decreased, while opportunistic Firmicutes and Proteobacteria taxa, along with multidrug resistance genes, increased with repeated courses and/or duration of antibiotics. Efflux pump related genes predominated (92%) among the increased multidrug genes. While we found ß-lactam ARGs present in the resistome, the taxa that appear to contain them were kept in check by antibiotic treatment. Multidrug ARGs, mostly efflux pumps or regulators of efflux pump genes, were associated with opportunistic pathogens, and both increased in the resistome with repeated antibiotic use and/or increased duration. Conclusions: Given the strong association between opportunistic pathogens and multidrug-related efflux pumps, we suggest that drug efflux capacity might allow the opportunistic pathogens to persist or increase despite repeated courses and/or duration of antibiotics. While drug efflux is the most direct explanation, other mechanisms that enhance the ability of opportunistic pathogens to handle environmental stress, or other aspects of the treatment environment, could also contribute to their ability to flourish within the gut during treatment. Persistence of opportunistic pathogens in an already dysbiotic and weakened gastrointestinal tract could increase the likelihood of life-threatening blood borne infections. Of the 39 patients, 59% experienced at least one gastrointestinal or blood infection and 60% of bacteremia's were bacteria found in stool samples. Antimicrobial stewardship and appropriate use and duration of antibiotics could help reduce morbidity and mortality in this vulnerable population.