Pediatric Inflammatory Bowel Disease Patients Research Articles

Effectiveness of Switching to Subcutaneous Infliximab in Pediatric Inflammatory Bowel Disease Patients on Intravenous Maintenance Therapy.

No real-world data are available on subcutaneous infliximab (SC-IFX) in pediatric inflammatory bowel disease (PIBD). We report a single-center cohort experience of an elective switching program from biosimilar intravenous infliximab to SC-IFX, 120 mg fortnightly, as maintenance. Clinical and laboratory data were collected for 7 patients with infliximab trough levels collected prior and at 6 and 40 weeks after the switch. High treatment persistence was registered with a single patient discontinuing the treatment due to high IFX antibodies, already present before switching. All patients remained in clinical remission with no significant changes in laboratory markers and median infliximab trough levels (12.3 µg/mL at baseline; 13.9 and 14.0 µg/mL at 6 and 40 weeks respectively). No newly-developed IFX antibodies were detected and no adverse reactions or rescue therapies were recorded. Our real-world data support the feasibility of an elective switch to SC-IFX in PIBD as maintenance with potential advantages concerning medical resources and patient satisfaction.

Safety and Efficacy of Fecal Microbiota Transplantation in Treatment of Inflammatory Bowel Disease in the Pediatric Population: A Systematic Review and Meta-Analysis

Background and Aims: Fecal microbiota transplantation (FMT) has been increasingly studied in the inflammatory bowel disease (IBD) population. However, most studies have focused on the adult population, and the safety and efficacy of FMT in a pediatric population is less well understood. This systematic review and meta-analysis investigates the safety and efficacy of FMT in a pediatric IBD population. Methods: A comprehensive literature search of publications published prior to 30 June 2022 was undertaken. Safety data, IBD-related outcomes, and microbiome analysis were obtained from these studies when accessible. Individual estimates of each study were pooled, and sensitivity analysis was conducted. Results: Eleven studies satisfied our eligibility criteria. The calculated pooled rate of adverse events was 29% (95% confidence interval [CI]: 15.0%, 44.0%; p < 0.001; I2 = 89.0%, Q = 94.53), and the calculated pooled rate of serious adverse events was 10% (95% confidence interval [CI]: 6.0%, 14.0%; p = 0.28; I2 = 18.0%, Q = 9.79). One month after FMT, clinical response was achieved in 20/34 (58.8%) pediatric IBD patients, clinical remission was achieved in 22/34 (64.7%), and both clinical response and remission were achieved in 15/34 (44.1%) pediatric IBD patients. Conclusions: FMT can be a safe and effective treatment in the pediatric IBD population and may demonstrate improved safety and efficacy in the pediatric population compared to the adult population. However, our results are limited by a lack of established protocol as well as long-term follow-up for FMT in a pediatric IBD population.

Physical Training and Healthy Diet Improved Bowel Symptoms, Quality of Life, and Fatigue in Children With Inflammatory Bowel Disease.

Physical activity programs have been suggested as adjunctive therapy in adult inflammatory bowel disease (IBD) patients. We assessed the effects of a 12-week lifestyle intervention in children with IBD. This study was a randomized semi-crossover controlled trial, investigating a 12-week lifestyle program (3 physical training sessions per week plus personalized healthy dietary advice) in children with IBD. Endpoints were physical fitness (maximal and submaximal exercise capacity, strength, and core stability), patient-reported outcomes (quality of life, fatigue, and fears for exercise), clinical disease activity (fecal calprotectin and disease activity scores), and nutritional status (energy balance and body composition). Change in maximal exercise capacity (peak VO 2 ) was the primary endpoint; all others were secondary endpoints. Fifteen patients (median age 15 [IQR: 12-16]) completed the program. At baseline, peak VO 2 was reduced (median 73.3% [58.8-100.9] of predicted). After the 12-week program, compared to the control period, peak VO 2 did not change significantly; exercise capacity measured by 6-minute walking test and core-stability did. While medical treatment remained unchanged, Pediatric Crohn's Disease Activity Index decreased significantly versus the control period (15 [3-25] vs 2.5 [0-5], P = 0.012), and fecal calprotectin also decreased significantly but not versus the control period. Quality of life (IMPACT-III) improved on 4 out of 6 domains and total score (+13 points) versus the control period. Parents-reported quality of life on the child health questionnaire and total fatigue score (PedsQoL Multidimensional Fatigue Scale) also improved significantly versus the control period. A 12-week lifestyle intervention improved bowel symptoms, quality of life, and fatigue in pediatric IBD patients.

Letter to the Editor in Response to: Hypersensitivity Reaction to Ustekinumab in Pediatric and Young Adult Inflammatory Bowel Disease Patients: A Case Series.

We would like to thank Dr. Sunny et al (1) for their important contribution on hypersensitivity reactions to intravenous ustekinumab. They report 6 patients who had infusion reactions to intravenous dosing of ustekinumab, 4 of whom subsequently tolerated subcutaneous dosing. We report an additional 4 cases of these reactions (Table 1). Our patients experienced similar hypersensitivity symptoms. After treatment of hypersensitivity reactions, all 4 successfully completed their intravenous infusions without further reaction, and each tolerated subsequent subcutaneous dosing of ustekinumab. Our patients did not undergo testing for ethylenediaminetetraacetic acid (EDTA) sensitivity. TABLE 1. - Case series Patient A B C D Onset of reaction (min) 3 5 1 1 Rash/flushing X X X X Shortness of breath X X Oxygen desaturation X X Nausea X X Dizziness X Cough X X X Scratchy throat X Duration of SQ UST use 2 doses ~12 mo May 2021–present April 2022–present Reason for discontinuation Lack of response/low drug level Found XIAP deletion, underwent bone marrow transplant - - SQ = subcutaneous; UST = ustekinumab. It is crucial that providers are aware that continued treatment with ustekinumab may be an option despite initial hypersensitivity reaction to the intravenous infusion. Most pediatric patients starting ustekinumab have failed or had adverse events with more standard therapies and have limited remaining therapeutic options. Knowing that patients who have a reaction to the intravenous induction dose may still tolerate subcutaneous ustekinumab may prevent hasty discontinuation and allow more patients to continue ustekinumab for inflammatory bowel disease treatment. We emphasize the importance of the authors’ initial contribution and provide further evidence by documenting 4 additional pediatric patients who tolerated consequent subcutaneous ustekinumab dosing. Additional research is needed to understand the physiology of these reactions, determine proactively which patients are at risk, and differentiate who can continue the medication safely. The chart review of these patients was approved by the University of Michigan IRB.

Safety and Durability of Accelerated Infliximab Dosing Strategies in Pediatric IBD: A Single Center, Retrospective Study.

Infliximab (IFX) is commonly used to treat children with inflammatory bowel disease (IBD). We previously reported that patients with extensive disease started on IFX at a dose of 10 mg/kg had greater treatment durability at year one. The aim of this follow-up study is to assess the long-term safety and durability of this dosing strategy in pediatric IBD. We performed a retrospective single-center study of pediatric IBD patients started on IFX over a 10-year period. Two hundred ninety-one patients were included (mean age = 12.61, 38% female) with a follow-up range of 0.1-9.7 years from IFX induction. One hundred fifty-five (53%) were started at a dose of 10 mg/kg. Only 35 patients (12%) discontinued IFX. The median duration of treatment was 2.9 years. Patients with ulcerative colitis ( P ≤ 0.01) and patients with extensive disease ( P = 0.01) had lower durability, despite a higher starting dose of IFX ( P = 0.03). Adverse events (AEs) were observed to occur at a rate of 234 per 1000 patient-years. Patients with a higher serum IFX trough level (≥20 µg/mL) had a higher rate of AEs ( P = 0.01). Use of combination therapy had no impact on risk of AEs ( P = 0.78). We observed an excellent IFX treatment durability, with only 12% of patients discontinuing therapy over the observed timeframe. The overall rate of AEs was low, the majority being infusion reactions and dermatologic conditions. Higher IFX dose and serum trough level> 20 µg/mL were associated with higher risk of AEs, the majority being mild and not resulting in cessation of therapy.

Diet prevents the expansion of segmented filamentous bacteria and ileo-colonic inflammation in a model of Crohn’s disease

BackgroundCrohn’s disease (CD) is associated with changes in the microbiota, and murine models of CD-like ileo-colonic inflammation depend on the presence of microbial triggers. Increased abundance of unknown Clostridiales and the microscopic detection of filamentous structures close to the epithelium of TnfΔARE mice, a mouse model of CD-like ileitis pointed towards segmented filamentous bacteria (SFB), a commensal mucosal adherent bacterium involved in ileal inflammation.ResultsWe show that the abundance of SFB strongly correlates with the severity of CD-like ileal inflammation in two mouse models of ileal inflammation, including TnfΔARE and SAMP/Yit mice. SFB mono-colonization of germ-free TnfΔARE mice confirmed the causal link and resulted in severe ileo-colonic inflammation, characterized by elevated tissue levels of Tnf and Il-17A, neutrophil infiltration and loss of Paneth and goblet cell function. Co-colonization of SFB in human-microbiota associated TnfΔARE mice confirmed that SFB presence is indispensable for disease development. Screening of 468 ileal and colonic mucosal biopsies from adult and pediatric IBD patients, using previously published and newly designed human SFB-specific primer sets, showed no presence of SFB in human tissue samples, suggesting a species-specific functionality of the pathobiont. Simulating the human relevant therapeutic effect of exclusive enteral nutrition (EEN), EEN-like purified diet antagonized SFB colonization and prevented disease development in TnfΔARE mice, providing functional evidence for the protective mechanism of diet in modulating microbiota-dependent inflammation in IBD.ConclusionsWe identified a novel pathogenic role of SFB in driving severe CD-like ileo-colonic inflammation characterized by loss of Paneth and goblet cell functions in TnfΔARE mice. A purified diet antagonized SFB colonization and prevented disease development in TnfΔARE mice in contrast to a fiber-containing chow diet, clearly demonstrating the important role of diet in modulating a novel IBD-relevant pathobiont and supporting a direct link between diet and microbial communities in mediating protective functions.8ntX7JCRAmgBnFgN24WWkMVideo

Clinical outcomes in pediatric inflammatory bowel disease patients: a systematic review of prospective studies.

We studied response and remission rates in children and adolescents with inflammatory bowel disease whose real-world data were collected prospectively. A systematic literature search was performed in MEDLINE, Embase, and the Improve Care Now registry from inception until March 17, 2022. Inclusion criteria were prospective studies with patients <18years at diagnosis (M0) and minimum follow-up of 1year (M12) mentioning disease phenotype and disease activity. Exclusion criteria were (i) reporting disease activity only at diagnosis, (ii) retrospective studies, and (iii) outcome limited to steroid-free remission. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines and the Newcastle-Ottawa scale were applied. Proportions between groups were compared using a chi-square test (α=0.05). The search yielded 394 records and 7 inclusions with a sample size ranging from 33 to 390 patients (total population: 888) and a median follow-up of 1-5years. Proportions of disease activity differed between M0 and M12 (P<0.0001) with more inactive (χ2 =5.5) and less moderate-to-severe disease (χ2 =23) at M12. Interestingly, disease activity after 1year did not differ globally (P=0.53). Proportions of disease activity in Crohn's disease only and limited to Belgium significantly differed from baseline after 5years (P<0.0001 for evolution) but not between 1- and 5-year follow-up (P=0.94). The few available prospective cohorts reported a significant decrease in disease activity after 1year, with no global differences. Proportions of disease activity did not differ between 1- and 5-year follow-up in the Belgian Crohn's disease cohort, suggesting stable disease activity.

Identification of FCN1 as a novel macrophage infiltration-associated biomarker for diagnosis of pediatric inflammatory bowel diseases

BackgroundThe incidence of pediatric inflammatory bowel disease (PIBD) has been steadily increasing globally. Delayed diagnosis of PIBD increases the risk of complications and contributes to growth retardation. To improve long-term outcomes, there is a pressing need to identify novel markers for early diagnosis of PIBD.MethodsThe candidate biomarkers for PIBD were identified from the GSE117993 dataset by two machine learning algorithms, namely LASSO and mSVM-RFE, and externally validated in the GSE126124 dataset and our PIBD cohort. The role of ficolin-1 (FCN1) in PIBD and its association with macrophage infiltration was investigated using the CIBERSORT method and enrichment analysis of the single-cell dataset GSE121380, and further validated using immunoblotting, qRT-PCR, and immunostaining in colon biopsies from PIBD patients, a juvenile murine DSS-induced colitis model, and THP-1-derived macrophages.ResultsFCN1 showed great diagnostic performance for PIBD in an independent clinical cohort with the AUC of 0.986. FCN1 expression was upregulated in both colorectal biopsies and blood samples from PIBD patients. Functionally, FCN1 was associated with immune-related processes in the colonic mucosa of PIBD patients, and correlated with increased proinflammatory M1 macrophage infiltration. Furthermore, single-cell transcriptome analysis and immunostaining revealed that FCN1 was almost exclusively expressed in macrophages infiltrating the colonic mucosa of PIBD patients, and these FCN1+ macrophages were related to hyper-inflammation. Notably, proinflammatory M1 macrophages derived from THP-1 expressed high levels of FCN1 and IL-1β, and FCN1 overexpression in THP-1-derived macrophages strongly promoted LPS-induced activation of the proinflammatory cytokine IL-1β via the NLRP3-caspase-1 axis.ConclusionsFCN1 is a novel and promising diagnostic biomarker for PIBD. FCN1+ macrophages enriched in the colonic mucosa of PIBD exhibit proinflammatory phenotypes, and FCN1 promotes IL-1β maturation in macrophages via the NLRP3-caspase-1 axis.

Serum leucine-rich alpha-2 glycoprotein and calprotectin in children with inflammatory bowel disease: A multicenter study in Japan.

Serum leucine-rich alpha-2 glycoprotein (LRG) and calprotectin have been studied as disease activity markers in adults with inflammatory bowel disease (IBD). We evaluated them in pediatric IBD patients. Subjects under 17years old undergoing care at 11 Japanese pediatric centers were retrospectively assigned to 3 groups representing Crohn's disease (CD), ulcerative colitis (UC), and normal controls (NC) with irritable bowel syndrome or no illness. Serum LRG and calprotectin were measured using commercial enzyme-linked immunosorbent assay kits. We enrolled 173 subjects, including 74 with CD, 77 with UC, and 22 NC. Serum LRG concentrations in active CD (median, 200μg/mL) were significantly greater than in remission (81μg/mL; P<0.001) or NC (69μg/mL; P<0.001). Serum calprotectin concentrations in active CD (2941ng/mL) also were significantly greater than in remission (962ng/mL; P<0.05) or NC (872ng/mL; P<0.05). Serum LRG concentrations in active UC (134μg/mL) were significantly greater than in remission (65μg/mL; P<0.01) but not significantly greater than in NC (69μg/mL); serum calprotectin concentrations in active UC (1058ng/mL) were not significantly different from those in remission (671ng/mL) or NC (872ng/mL). In receiver operating characteristic analyses of LRG, calprotectin, C-reactive protein, and erythrocyte sedimentation rate for ability to distinguish active IBD from remission, CD and UC showed areas under receiver operating characteristic curves for LRG (0.77 and 0.70, respectively), exceeding those for calprotectin, C-reactive protein, or erythrocyte sedimentation rate. In pediatric IBD, serum LRG may better reflect disease activity than serum calprotectin, particularly in CD.

A199 BIOFILMS IN THE APPENDIX AND OTHER NON-INFLAMED SECTIONS OF THE COLON IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASES

Abstract Background Biofilms, aggregated bacteria colonizing the extracellular polymeric substances matrix, are associated with the mucosa of inflammatory bowel diseases (IBD) patients with some studies showing a mean density of the mucosal biofilms 2-fold higher in IBD patients than in controls. The appendix, which is a highly immune organ, seems to be involved in IBD pathogenesis. Purpose In this study we aimed to evaluate biofilms in the appendix and other non-inflamed regions of the colon in pediatric IBD patients. We hypothesized that biofilms composed of pathobionts in these sections could drive inflammation in IBD patients. Method Tissues from the appendix, peri-appendicular region, cecum, and ascending colon (ASC), collected from the resected colons of 9 pediatric IBD patients and one pediatric non-IBD patient, preserved in methanol Carnoy’s solution were processed and paraffin embedded. Combined fluorescence in situ hybridization (FISH) for biofilms (probe: EUB338) and immunofluorescence (IF) mucin staining (MUC2) identified biofilms and their location. Biofilm formation capacity of culturable bacteria (identified through 16S DNA Sanger sequencing) from these sections was measured. Interleukin (IL)-8 (pro-inflammatory chemokine) and IL-10 (anti-inflammatory cytokine) expressions were assessed by tissue qPCR. Result(s) FISH demonstrated biofilms in these sections, in close proximity to epithelial cells. We used a biofilm formation assay to assess the ability of the identified bacteria from these sections to form biofilms, illustrating their potential to colonize and evade host defense and potential antibiotics. We found that Enterococcus avium has a significantly higher ability to form biofilms than the negative control. IL-8 and IL-10 both had the highest expression level in the appendix and peri-appendicular region and the lowest in the ASC among all the patients, suggesting an active immune response. Mechanistic experiments are in progress to investigate the type of bacteria involved in the biofilms and their effects on the gut barrier integrity. Conclusion(s) Biofilms adjacent to the epithelium, especially in the appendix and peri-appendix, could interact with or invade epithelial cells. The elevated chemokine transcript level in the appendix could reflect the recruitment of immune cells to this section following bacterial invasion, resulting in the activation of the immune system. Identifying the bacteria involved in the biofilms and clarifying their characteristics will aid us in developing novel microbe-altering treatment strategies or personalized medicine. Disclosure of Interest None Declared

A171 INTESTINAL INTERFERON-LAMBDA RECEPTOR 1 EXPRESSION AND RESPONSES ARE SIGNIFICANTLY DECREASED IN PEDIATRIC INFLAMMATORY BOWEL DISEASE PATIENTS

Abstract Background While interferon-lambdas (IFN-λs) were initially discovered for their role in antiviral immunity at mucosal barriers such as the lung and gut, there are many unanswered questions for how IFN-λs uniquely dampen inflammatory immune responses. In mouse colitis models, IFN-λs were shown to play a significant role in promoting epithelial barrier integrity and mucosal healing. Microbes present in the gut naturally induce IFN-λs, but how chronic inflammation, such as in patients with inflammatory bowel diseases (IBD), affects IFN-λ biology has not been well studied, especially in humans. Purpose Here, we tested the hypothesis that children with active, more severe IBD would present with lower intestinal IFN-λR levels and IFN-λ responses which could contribute to IBD pathology through exacerbated inflammation, decreased mucosal healing and impaired barrier function. Method We screened 14 novel antibodies to find the optimal clone that accurately stains the unique IFN-λ receptor subunit (IFN-λR1) protein in human intestinal tissue and IFN-λR1 levels were quantified by immunohistochemistry and flow cytometry in biopsy samples from children without IBD, Crohn’s disease, or ulcerative colitis (n=35 total). Fresh patient biopsies (ascending colon or terminal ileum) were also treated in media +/- IFN-λ for 24hrs using our novel ex vivo biopsy assay and changes in gene expression were quantified by RT-qPCR. Intestinal washes were also collected and microbes profiled by shotgun metagenomics. Result(s) We identified 2 new antibodies that accurately stained human cell lines and immune cells known to express IFN-λR1 protein (gut epithelial cells and B cells). We found that IFN-λ receptor (IFN-λR) levels are significantly reduced in gut epithelial and immune cells within pediatric IBD intestinal tissue, even at non-inflamed sites (p&amp;lt;0.01, 30-50% reduction) and this was even more pronounced when comparing moderate/severe disease compared to children with no disease activity. This led to lower IFN-λ responsiveness in IBD compared to non-IBD biopsies when investigating IFN-stimulated gene expression (p&amp;lt;0.05, up to 7-fold reduction). Paired patient gut microbe analyses identified specific species that correlated with changes in IFN-λ receptor expression. Conclusion(s) Together, our findings demonstrate pediatric IBD patients may be less able to induce critical IFN-λ-mediated antimicrobial responses and protective anti-inflammatory pathways. This work supports the goal to restore and promote IFN-λ responses as a novel therapeutic strategy for pediatric IBD. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Children's Hospital Research Institute of Manitoba Disclosure of Interest None Declared

Psychosocial Considerations in Ostomy Surgery for Pediatric IBD Patients.

David, Jennie G.; Michel, Hilary K.; Dotson, Jennifer L.; Nwomeh, Benedict C.; Boyle, Brendan; Donegan, Amy; Maltz, Ross M.; McKillop, Hannah N.; Mackner, Laura Author Information

Venous Thromboembolism Prophylaxis in Pediatric Inflammatory Bowel Disease Patients Hospitalized With a Central Line.

Patients hospitalized with inflammatory bowel disease (IBD) have increased risk of venous thromboembolism (VTE). The aim of this study was to determine whether the adoption of a VTE protocol would change rates of medical VTE prophylaxis (low molecular weight heparin) in patients with IBD and a central venous catheter (CVC), while subsequently decreasing the incidence of VTE in this population. A protocol for VTE prophylaxis in IBD was established in March of 2018. Every patient hospitalized with an IBD flare and central venous access from March 2013 to March 2020 was identified. Study data, including patient demographics, rates of Doppler ultrasound (US), and rates of VTE were collected using International Classification of Diseases (ICD)-10 codes, CPT codes, and chart review retrospectively. Determination of an IBD flare was based on physician global assessment. Groups were compared with independent-sample t tests and chi-squared tests. A total of 313 hospitalizations across 187 different patients were identified that met criteria including IBD and central venous access. VTE prophylaxis increased from 5.24% (n = 12) prior to the intervention to 63.10% (n = 53) after the intervention [chi-square (1, N = 313) = 125.0192, P < 0.001]. Rate of Doppler US increased from 9.17% (n = 21) prior to the intervention to 17.86% (n = 15) after the intervention [chi-square (1, N = 313) = 4.5562, P < 0.05]. Diagnosis of VTE increased from 0.87% (n = 2) prior to the intervention to 7.14% (n = 6) after the intervention [chi-square (1, N = 313) = 9.6992, P < 0.01]. There were no significant differences in the demographic characteristics pre- versus post-intervention. Rates of Doppler US and VTE prophylaxis use increased significantly after implementation of a VTE protocol. Rates of VTE diagnosis also increased, though we suspect this may be due to missed diagnoses prior to implementation of the protocol and increased risk awareness after the protocol was established.

The Use of the Perioperative Nutrition Score in Postoperative Pediatric Inflammatory Bowel Disease Patients

Background and objectivesPreoperative malnutrition is associated with increased postoperative morbidity. The perioperative nutrition score (PONS) was developed to identify patients at risk of malnutrition. We sought to assess the correlation between preoperative PONS and postoperative outcomes in pediatric inflammatory bowel disease (IBD) patients. MethodsWe performed a retrospective cohort study of IBD patients, less than 21 years of age, who underwent elective bowel resection between June 2018 and November 2021. Patients were divided based upon whether they met PONS criteria. The primary outcome was postoperative surgical site infections. Results96 patients were included. Sixty-one patients (64%) met at least one PONS criteria, while 35 patients (36%) met none. PONS positive patients more frequently received preoperative TPN supplementation (p < .001). There was no difference in preoperative oral nutritional supplementation between groups. Patients that screened positive for PONS had a longer hospital stay (p = .002), more readmissions (p = .029), and more surgical site infections (p = .002). ConclusionsOur data highlight the prevalence of malnutrition in the pediatric IBD population. Patients who screened positive had worse postoperative outcomes. Further, very few of these patients received preoperative optimization with oral nutritional supplementation. There is a need for standardization of nutritional evaluation to improve preoperative nutritional status and postoperative outcomes. Level of EvidenceIII. Type of StudyRetrospective Cohort.

Clinical Course of Very Early-Onset Inflammatory Bowel Disease.

Data on the phenotypes and disease outcomes of very early-onset inflammatory bowel disease (VEO-IBD) are limited. The aims of this study were to describe the clinical features, outcomes, and treatment response of VEO-IBD patients and to compare them with later-onset pediatric inflammatory bowel disease (P-IBD) patients. All consecutive patients aged 0-6 years who were diagnosed with Crohn disease (CD), ulcerative colitis, or IBD unclassified (IBD-U) at 2 academic hospitals from 2010 to March 2021 were included. They were compared to sex-matched IBD patients aged 6-17 years. Two hundred thirty-two patients were included, 78 (34%) with VEO-IBD and 154 (66%) with P-IBD. IBD-U was the most common diagnosis in the VEO-IBD group compared to P-IBD (28% vs 3%, P < 0.001), while CD was predominant in older children (27% vs 52%, P < 0.001). The VEO-IBD group showed lower rates of clinical remission after induction with steroids compared to older children (82% vs 93%, P = 0.01), higher rates of steroid resistance (14% vs 5%, P = 0.02), and steroid dependence (27% vs 8%, P < 0.001). The number of patients who started anti-tumor necrosis factor (TNF)-α agents was similar between the groups. Anti-TNF-α retention was lower in the VEO-IBD group at 1 and 2 years (59% vs 85%, P = 0.003; 16% vs 55%, P < 0.001, respectively). Surgical risk appeared to be higher for VEO-IBD (32% vs 14%, P < 0.001). When compared to P-IBD patients, patients with VEO-IBD may have a more severe disease course, a poorer response to steroids and anti-TNF-α agents, and require more frequent surgical procedures.

Cytomegalovirus Infection Is Associated With Adverse Outcomes Among Hospitalized Pediatric Patients With Inflammatory Bowel Disease.

Adults with inflammatory bowel disease (IBD) are at increased risk of developing cytomegalovirus (CMV) colitis, which is associated with adverse outcomes. Similar studies in pediatric IBD patients are lacking. We analyzed non-overlapping years of National Inpatient Sample (NIS) and Kids Inpatient Database (KID) between 2003 and 2016. We included all patients < 21 years with a diagnosis of Crohn's disease (CD) or ulcerative colitis (UC). Patients with coexisting CMV infection during that admission were compared with patients without CMV infection for outcome measures such as in-hospital mortality, disease severity, and healthcare resource utilization. We analyzed a total of 254,839 IBD-related hospitalizations. The overall prevalence rate of CMV infection was 0.3% with an overall increasing prevalence trend, P < 0.001. Approximately two-thirds of patients with CMV infection had UC, which was associated with almost 3.6 times increased risk of CMV infection (confidence interval (CI): 3.11 to 4.31, P < 0.001). IBD patients with CMV had more comorbid conditions. CMV infection was significantly associated with increased odds of in-hospital mortality (odds ratio (OR): 3.58; CI: 1.85 to 6.93, P < 0.001) and severe IBD (OR: 3.31; CI: 2.54 to 4.32, P < 0.001). CMV-related IBD hospitalizations had increased length of stay by 9 days while incurring almost $65,000 higher hospitalization charges, P < 0.001. The prevalence of CMV infection is increasing in pediatric IBD patients. CMV infections significantly corelated with increased risk of mortality and severity of IBD leading to prolonged hospital stay and higher hospitalization charges. Further prospective studies are needed to better understand the factors leading to this increasing CMV infection.

P451 Early infliximab trough levels in paediatric IBD patients predict sustained remission

Abstract Background Therapeutic drug monitoring (TDM) is an approach to improve treatment effectiveness of anti-TNF therapy in Inflammatory Bowel Disease (IBD), but timing and threshold trough levels (TL) are still subject of investigation, especially in paediatric populations. The aims of our study were (1) to analyse induction – and post-induction infliximab TLs (respectively after 6 and 14 weeks) to predict sustained biochemical and clinical remission between 6 and 12 months in paediatric patients with IBD, and (2) to define paediatric threshold TLs at these timepoints. Methods We performed a retrospective study in 70 anti-TNF naïve paediatric IBD patients from two centres who were treated with an induction scheme of 5 mg/kg on 0, 2 and 6 weeks, and subsequently every approximately 8 weeks. We measured infliximab TLs at week 6 and 14 combined with (non)-invasive markers for disease activity. Patients were in sustained biochemical and clinical remission when they were asymptomatic and had normalised CRP and faecal calprotectin between 6 and 12 months after initiating therapy. Receiver operating characteristic (ROC) analysis was used to determine infliximab TL thresholds that best predicted sustained biochemical remission. Results Median infliximab TL at 6 and 14 weeks were higher for children in sustained remission versus children who were not (TL6 p=0.028 and TL14 p=0.028). Area under the ROC curve (AUROC) for infliximab TL6 and TL14 to predict sustained biochemical remission was 0.68 (95% Confidence Interval [CI] 0.53-0.83) and 0.67 (95%CI 0.53-0.82), respectively (Figure 1 and 2). The optimal infliximab thresholds were 13.2 mg/L and 6.9 mg/L for TL6 and TL14, respectively, yielding a sensitivity and specificity of 70% and 68% for TL6 and 57% and 76% for TL14. Figure 1 ROC curve of infliximab trough level at 6 weeks for predicting sustained remission between 6 months to 12 months. Figure 2 ROC curve of infliximab trough level at 14 weeks for predicting sustained remission between 6 months to 12 months. Conclusion In children with IBD treated with a regular infliximab induction scheme, infliximab TLs at week 6 and 14 both predicted sustained clinical and biochemical remission between 6 and 12 months after initiating therapy. TDM and early dose optimization may improve infliximab effectiveness and drug survival.

P069 Elevated adaptive immune responses to multiple Lachnospiraceae bacterial flagellins in therapy-naïve pediatric CD patients are associated with distinct immune pathology.

Abstract Background In inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), CD4+ T cell-responses to unknown microbial antigens drive intestinal inflammation. Both hypo- or hyperactive anti-microbial innate immunity may underlie these pathogenic T-cell responses. Previously, IgG and T-cell responses to Lachnospiraceae flagellins were detected in spontaneously colitic mice with an innate immune defect and adult CD patients with complicated disease. However, whether these IgG responses occur in therapy-naïve pediatric patients and whether they relate to hypo- or hyperresponsiveness is unknown. We hypothesize that, at diagnosis, a subgroup of pediatric CD patients has elevated anti-Lachnospiraceae flagellin IgG and concomitant inflammatory flagellin-specific T-cell responses associating with insufficient anti-microbial innate immunity. Methods Plasma IgG reactivity to 20 flagellins from Lachnospiraceae that colonize mouse and human gut was measured in therapy-naïve pediatric IBD patients (CD n=49; UC n=16), non-IBD (n=12) and age-matched healthy controls (HC n=17). CD patients were divided in two groups: ‘flagellin-hi’ (elevated IgG to 11-20 flagellins) and ‘flagellin-lo’ (elevated IgG to 0-10 flagellins), whose immunological and clinical profiles were compared. Results The proportion of flagellin-hi patients was higher in CD (41%) compared to UC (6%), non-IBD (8%) and HC (6%). In CD patients, clinical disease activity score, CRP and ESR did not relate to flagellin reactivity. Compared to flagellin-lo patients, flagellin-hi patients had increased frequencies of inflammatory gut-homing (CD38+CD62Lneg) circulating CD4+ T cells. Crucially, flagellin-hi patients had high frequencies of circulating flagellin-specific CD4+ T cells. Although high anti-flagellin IgG reactivity associated with increased flagellin-specific- and gut-homing- T-cell frequencies in the circulation, it associated with very limited immune cell infiltration, epithelial damage and phosphorylated NFκB in colonic biopsies on histology. Moreover, the plasma concentration of EN-RAGE, a neutrophil-derived protein, was decreased in flagellin-hi compared -lo patients. Conclusion In sum, a subgroup of pediatric therapy-naïve CD patients has high IgG responses to Lachnospiraceae-derived flagellins. While these flagellin-hi patients have higher frequencies of circulating gut-homing and flagellin-specific CD4+ T cells, they have lower colonic histological disease activity and NFκB activation, possibly suggesting insufficient innate immune cell activation and/or infiltration. Together, our data raise the question whether the enhanced anti-Lachnospiraceae adaptive immune response in a subgroup of CD patients may be driven by insufficient local innate immunity.

DOP11 A novel diagnostic serum protein signature for paediatric Inflammatory Bowel Disease: A discovery and validation study in two independent inception cohorts

Abstract Background A diagnostic delay is common in paediatric inflammatory bowel disease (PIBD) and is associated with impaired outcomes. Therefore, we aimed to identify and validate a diagnostic protein signature of PIBD in blood. Methods Using the Proximity Extension Assay technology (Olink Proteomics®), we assayed plasma proteins in an inception cohort of treatment-naïve paediatric patients referred to Uppsala University Children's Hospital, Sweden for suspected IBD and validated findings in an independent population-based paediatric inception cohort, i.e., the Norwegian IBSEN III cohort. Diagnosis was based on the ESPGHAN/Porto criteria. The false discovery rate approach was applied, and q-values were reported. Multivariable analyses and supervised machine learning were used to identify a diagnostic protein signature, and its performance was compared to clinically established biomarkers. Results The Swedish discovery cohort included 58 PIBD patients and 36 symptomatic controls without any discernible evidence of IBD, and the validation cohort 79 PIBD patients and 37 symptomatic controls (Table 1). In total, 154 proteins were included in the final analysis. Univariable analyses identified 26 differentially regulated proteins for PIBD versus symptomatic controls in the discovery cohort (q&amp;lt;0.05), and 15 of these were validated in IBSEN III. Using regularized regression, we identified a model of 31 proteins that distinguished PIBD from symptomatic controls in the discovery cohort (area under the curve (AUC) = 0.87; 95%CI: 0.79-0.93). The relative contribution of each protein is shown in Figure 1. The diagnostic capacity of the protein signature (AUC=0.83; 95% CI: 0.75-0.90) outperformed high sensitivity C-reactive protein (hsCRP) (AUC=0.72; 95%CI: 0.63-0.82) in the validation cohort (p=0.01, Figure 2). Similar results were obtained from our random forest models. Only 76/116 children in the validation cohort provided a stool sample. Among these children, the diagnostic capacity of the protein signature (AUC=0.81; 95%CI 0.70-0.90) was slightly lower than faecal Calprotectin (FCP) (AUC=0.93; 95%CI 0.86-0.98) (p=0.014). To assess the clinical relevance of the novel protein signature, we evaluated its capacity to rule out IBD compared to increased hsCRP (&amp;gt;5.0 mg/L) in the validation cohort. The protein signature demonstrated a significantly higher negative predictive value (55.3%) compared to increased hsCRP (39.5%) (p=0.002). Conclusion We identified and validated a diagnostic protein signature for PIBD in blood that is superior to CRP and has potential for better clinical utility than FCP since faecal samples are difficult to obtain. This signature could be used to guide decisions on referral to endoscopy and facilitate early diagnosis of IBD.

P723 Comparison of the Persistence Rates of Biologic Agents in Paediatric Crohn's Disease Patients (Japanese Paediatric IBD Registry Study)

Abstract Background Biologics are widely used for paediatric Crohn's disease (CD) and are highly effective; however, primary inefficacy and the emergence of secondary inefficacy during long-term use remain challenges. Although it is desirable for biologics used in paediatric patients to be safe and usable long-term, there are few detailed reports on the comparison of persistence rates of biologics in paediatric patients. Methods This was a multicentre prospective cohort study using a web-based registry system in Japan that was performed between October 2012 and March 2020. New paediatric inflammatory bowel disease patients diagnosed at less than 18 years of age were enrolled from 23 Japanese hospitals. The persistence rates of the first biologics (Infliximab: IFX and Adalimumab: ADA), and the second biologics (IFX, ADA, and Ustekinumab: UST) were analysed. Patients with unknown outcomes were excluded. Results We enrolled 185 patients with CD as the final diagnosis, and 109 (59%) received biologics during the observation period. As the first biologic, IFX was used in 52 (45%) patients, ADA in 52 (45%), UST and Vedolizumab (VED) in one, respectively, and the biologic in one patient was unidentified. The 1-, 3- and 5-year persistence rates of IFX and ADA as the first biologic were 90%, 70% and 61% for IFX, and 80%, 71% and 49% for ADA, respectively (Fig.1), with no statistically significant difference (P=0.31). There was also no statistically significant difference after propensity score matching (P=0.27). Multivariate analysis showed that Paris classification L4a and b were independent risk factors for lower retention of biologics in IFX and ADA. Of the 104 patients whose first biologic was IFX or ADA, 31 patients were treated with a second biologic (IFX: 7, ADA: 6, UST: 15, VED: 2 and unknown: 1). The 1- and 3-year persistence rates of the second biologic were 86% and 51% for IFX; 80% and 80% for ADA and 100% and 100% for UST, respectively (Fig.2). Conclusion The persistence rates of IFX and ADA as first biologics were similar in paediatric patients with CD, and the persistence rates of UST tended to be higher than IFX or ADA as second biologics, although the differences were not statistically significant.