Biomarkers predicting the effect of anti-TNF treatment in paediatric and adult inflammatory bowel disease.

OBJECTIVES: Paediatric and adult inflammatory bowel disease (pIBD, aIBD) patients may lose response to anti-tumour necrosis factor (TNF) treatment within the first year. Adult-extrapolated weight-based dosing is incorrect in children, due to age-related pharmacokinetic differences. We investigated biomarkers for initial and maintenance of response to infliximab (IFX) or adalimumab (ADA), comparing pIBD and aIBD patients. METHODS: In this prospective, observational study, pIBD (n = 24) and aIBD (n = 21) patients were included when initiating anti-TNF. Escalation from standard dosing and continued anti-TNF at 12 and 18 months were assessed. Biomarkers included clinical laboratory parameters, faecal calprotectin (FCP) and IFX trough levels (TLs). Plasma proteomics was performed in pIBD. RESULTS: During our study, treatment escalation (in clinical loss of response) occurred more common in pIBD versus aIBD (p = 0.02). We established that IFX therapy escalation in pIBD patients was not due to low infliximab levels. We identified 9 pro-inflammatory proteins that were elevated in patients losing response. CONCLUSION: Anti-TNF exposure-response relationship may be different in pIBD versus aIBD. No biomarkers for maintained response were identified, but 9 inflammatory proteins were of interest as potential predictors for loss of response in pIBD.

Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function.

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb(-/-) anti-inflammatory macrophages ameliorated colitis induction by WT CD4(+) T cells in Rag2(-/-)Il10rb(-/-) mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.

Prediction of thiopurine failure in pediatric Crohn's disease: pediatric IBD Porto group of ESPGHAN.

BACKGROUND: Maintaining of remission early in the disease course of Crohn's disease (CD) is essential and has major impact on the future prognosis. This study aimed to identify baseline predictors to develop model allowing stratification of patients who will not benefit from long-term azathioprine (AZA) treatment and will require more intensive therapy. METHODS: This study was designed to develop clinical prediction rule using retrospective data analysis of pediatric CD patients included in prospective inception cohort. Clinical relapse was defined as necessity of re-induction of remission. Sequence of Cox models was fitted to predict risk of relapse. RESULTS: Out of 1190 CD patients from 13 European centers, 441 were included, 50.3% patients did not experience clinical relapse within 2 years of AZA treatment initiation. Median time to relapse was 2.11 (CI 1.59-2.46) years. Of all the tested parameters available at diagnosis, six were significant in multivariate analyses: C-reactive protein (p = 0.038), body mass index Z-score >0.8 SD (p = 0.002), abnormal sigmoid imaging (p = 0.039), abnormal esophageal endoscopy (p = 0.005), ileocolonic localization (p = 0.023), AZA dose in specific age category (p = 0.031). CONCLUSIONS: Although the possibility of predicting relapse on AZA treatment appears limited, we developed predictive model based on six baseline parameters potentially helpful in clinical decision. IMPACT: The possibility of predicting relapse on AZA treatment appears to be possible but limited. We identified six independent predictors available at diagnosis of early AZA/6-MP treatment failure in pediatric CD patients. Using combination of these factors, a model applicable to clinical practice was created. A web-based tool, allowing estimation of individual relapse risk in pediatric CD patients on a particular therapeutic regimen, has been developed.

Validation and Reference Scores of the Transition Readiness Assessment Questionnaire in Adolescent and Young Adult IBD Patients.

OBJECTIVES: Transition readiness can predict a successful transition from pediatric to adult care. This study aimed to validate and develop age-dependent reference scores for the (Dutch version of) Transition Readiness Assessment Questionnaire (TRAQ), in adolescents and young adults (AYAs) with inflammatory bowel disease (IBD). METHODS: TRAQ has 20 items (score 1-5) distributed over 5 domains (total sum score 100) and is completed by AYAs. Following the COnsensus-based Standards for the selection of health Measurement INstruments methodology, we conducted the translation, back-to back translation, pretesting, and validation of the final Dutch version of TRAQ (TRAQ-NL) questionnaire. We used a Rasch model for structural validation, hypothesis testing for construct validity, and Cronbach alpha to demonstrate reliability. Reference scores were calculated using percentiles. RESULTS: Two hundred fifty TRAQ questionnaires were evaluated in 136 AYAs with IBD [56% Crohn disease, 58% male, median age 17.5 years (range 15.7-20.4)]. The overall mean item score was 3.87 (range 1.45-5). With good reliability (Cronbach alpha 0.87), TRAQ-NL discriminated well between knowledge levels, especially in the lower levels. Transition readiness was defined as low, moderate, adequate, or excellent in patients with TRAQ percentile scores (PC) <25th (<3.375 mean item score), 25th-50th (3.375-3.9), 50th-90th (3.91-4.7), or >90th (>4.7). Younger patients, concomitant illness, fewer visits to the transition clinic, and parental dependence were associated with significantly lower TRAQ scores. CONCLUSION: TRAQ(-NL) is reliable and valid, with age-dependent PC to identify (in)adequate transfer readiness. TRAQ can now be more easily used as a patient-reported outcome measure to monitor transition readiness longitudinally in routine care for AYAs IBD patients.

First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn's disease: an open-label multicentre randomised controlled trial.

OBJECTIVE: In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment. DESIGN: In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis. RESULTS: 100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004). CONCLUSIONS: FL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02517684).

Rotterdam Transition Test: A Valid Tool for Monitoring Disease Knowledge in Adolescents With Inflammatory Bowel Disease.

OBJECTIVES: Disease knowledge is important in adolescents with inflammatory bowel disease (IBD) transitioning to adult care. We developed an IBD-specific knowledge questionnaire, the Rotterdam Transition Test (RTT), and aimed to validate this tool. METHODS: This is a prospective longitudinal validation study. The RTT has 25 open questions on IBD, medication, lifestyle, and transition to adult care. A scoring model was developed, and inter-rater agreement was assessed. Using a Rasch model, we determined the difficulty and performance of the questions. Cronbach alpha was used to demonstrate reliability. Patient factors (age, disease, education, medication use, illness acceptance, and independence) were correlated to RTT score. RESULTS: A total of 207 RTTs were evaluated in 111 adolescent IBD patients. The scoring model showed a kappa score of >0.61 for all questions. Reliability with Cronbach alpha was good (0.81). Mean total result of the RTT was 58% (girls) and 55% (boys) of maximal score.The RTT discriminated well between the different levels of knowledge. Knowledge scores increased in patients who did repeated RTTs during the transition period. Male sex, low educational level, disease acceptance issues, and dependence on parents associated with a significantly lower total RTT score. Prednisone use within 3 months and treatment without biologics associated with significantly higher RTT scores. Disease activity was not a significant factor. CONCLUSIONS: The RTT is a reliable and valid tool to assess IBD knowledge. The RTT can be used to detect and discuss knowledge gaps in adolescents with IBD transitioning to adult healthcare.

Evaluation of exclusive enteral nutrition and corticosteroid induction treatment in new-onset moderate-to-severe luminal paediatric Crohn's disease.

To induce remission in luminal paediatric Crohn's disease (CD), the ESPGHAN/ECCO guideline recommends treatment with exclusive enteral nutrition (EEN) or oral corticosteroids. In newly diagnosed moderate-to-severe paediatric CD patients, we determined the proportion of patients in which EEN or corticosteroids induced remission and maintained remission on azathioprine monotherapy. We included patients from the "TISKids" study assigned to the conventional treatment arm. Patients were aged 3-17 years and had new-onset, untreated luminal CD with weighted paediatric CD activity index (wPCDAI) > 40. Induction treatment consisted of EEN or oral corticosteroids; all received azathioprine maintenance treatment from start of treatment. The primary outcome of this study was endoscopic remission defined as a SES-CD score < 3 without treatment escalation at week 10. Secondary outcomes included proportion of patients without treatment escalation at week 52. In total, 27/47 patients received EEN and 20/47 corticosteroids. At baseline, patient demographics and several inflammation parameters were similar between the two treatment groups. At 10 weeks, clinical remission rates were 7/23 (30%) for EEN and 7/19 (37%) for corticosteroids (p = 0.661). Twenty-nine of 47 consented to endoscopy at 10 weeks, showing endoscopic remission rates without treatment escalation in 2/16 (13%) of EEN-treated patients and in 1/13 (8%) of corticosteroid-treated patients (p = 1.00). At week 52, 23/27 (85%) EEN-treated patients received treatment escalation (median 14 weeks) and 13/20 (65%) corticosteroid-treated patients (median 27 weeks), p = 0.070.Conclusion: In children with moderate-to-severe newly diagnosed CD, induction treatment with EEN or CS regularly is insufficient to achieve endoscopic remission without treatment escalation at week 10. Trial registration number: NCT02517684 What is Known: • Endoscopic remission is associated with a low risk of disease progression. • FL-IFX was superior to conventional treatment in achieving and maintaining remission in paediatric patients with moderate-to-severe CD the first year from diagnosis. What is New: • In children with newly diagnosed moderate-to-severe CD, clinical remission rates and endoscopic remission rates without treatment escalation at week 10 were 30% and 13% after EEN and 37% and 8% after corticosteroid induction treatment. • The current treatment target was often not achieved by either EEN or corticosteroid induction treatment after bridging to azathioprine.

Health outcomes of 1000 children born to mothers with inflammatory bowel disease in their first 5 years of life.

OBJECTIVE: The aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes. DESIGN: We performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies. RESULTS: We included 1000 children born to 626 mothers (381 (61%) Crohn's disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) had intrauterine exposure to anti-tumour necrosis factor-α (anti-TNF-α) (60 with concomitant thiopurine) and 240 (24%) were exposed to thiopurine monotherapy. The 564 children (56%) not exposed to anti-TNF-α and/or thiopurine served as control group. There was no association between adverse long-term health outcomes and in utero exposure to IBD treatment. We did find an increased rate of intrahepatic cholestasis of pregnancy (ICP) in case thiopurine was used during the pregnancy without affecting birth outcomes and long-term health outcomes of children. All outcomes correspond with the general age-adjusted population. CONCLUSION: In our study, we found no association between in utero exposure to anti-TNF-α and/or thiopurine and the long-term outcomes antibiotic-treated infections, severe infections needing hospital admission, adverse reactions to vaccinations, growth failure, autoimmune diseases and malignancies.

Development and Validation of the Mucosal Inflammation Noninvasive Index For Pediatric Crohn's Disease.

BACKGROUND & AIMS: Mucosal healing (MH) has become a goal of therapy for Crohn's disease (CD), but frequent endoscopies are not feasible. We aimed to develop and validate a non-invasive index to assess mucosal inflammation in children with CD. METHODS: We collected data from the multi-center prospective ImageKids study, in which children with CD underwent ileocolonoscopy with magnetic resonance enterography. We investigated the association of pediatric CD activity index (PCDAI) items and laboratory test results with the simple endoscopic score for CD (SESCD). We used these data in a blended mathematical judgmental clinimetric approach to develop a weighted categorized index to identify children with CD who have MH, which we called the MINI index. We validated the index using data from 3 independent patient cohorts. The derivation and validation cohorts included 154 and 168 children, respectively (age 14.1 ± 2.5 years and 14.2 ± 3.9 years), of whom 16% and 36% had MH (defined as SESCD<3). RESULTS: In multivariable models, the stooling item of the PCDAI, erythrocyte sedimentation rate, and level of fecal calprotectin were associated with SESCD (all P < .05). We added data on level of C-reactive protein to develop the MINI index. MINI scores below 8 identified children with MH with 88% sensitivity and 85% specificity in the derivation cohort and with 84% sensitivity and 87% specificity in the validation cohorts. Ninety percent of the patients in the validation cohort with scores of 8 or more had active mucosal inflammation, yet 78% of patients with scores below 8 had MH. Scores below 6 increase the positive predictive value to 86%. CONCLUSIONS: We developed an index to non-invasively assess mucosal inflammation in children with CD. This index, identifies children with MH with high sensitivity and specificity. The added benefit of MINI over measurement of fecal calprotectin was small but significant, especially for patients with concentrations of fecal calprotectin from 100 to 599 µg/g. ClinicalTrials.gov no: NCT01881490.

Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Infliximab in Pediatric Inflammatory Bowel Disease: A Systematic Review and Revised Dosing Considerations.

OBJECTIVES: Infliximab (IFX), a monoclonal antibody directed against tumor necrosis factor alpha is a potent treatment option for inflammatory bowel disease (IBD). Dosing regimens in children are extrapolated from adult data using a fixed, weight-based dose, which is often not adequate. While clinical trials have focused on safety and efficacy, there is limited data on pharmacokinetic characteristics and immunogenicity of IFX in children. The objective was to provide a systematic overview of current literature on pharmacokinetic and immunogenicity of IFX in children with IBD, to assess the validity of current adult to pediatric dosing extrapolation. METHODS: A literature search identified publications up to October 2018. Eligibility criteria were study population consisting of children and/or adolescents with IBD, report of IFX trough levels and/or antibodies-to IFX, full text article or abstract, article in English, and original data. RESULTS: Initial electronic search yielded 2360 potentially relevant articles, with 1831 remaining after removal of duplicates. An additional search yielded another 202 potentially relevant articles. Of the 2033 retrieved articles, 2000 articles were excluded based on title, abstract, or eligibility criteria. Clearance of IFX was increased in young children and children with extensive disease, leading to lower trough levels after extrapolated dosing of 5 mg/kg, antibodies-to IFX emergence, and subsequent reduced efficacy. CONCLUSIONS: Adult to pediatric weight-based dosing extrapolation is often inadequate. We provide several considerations for optimal dosing of IFX in children and adolescents with IBD.

Vedolizumab Trough Levels in Children With Anti-Tumor Necrosis Factor Refractory Inflammatory Bowel Disease.

OBJECTIVES: Inflammatory bowel disease (IBD) can be successfully treated with vedolizumab. Studies in adult IBD patients have shown that differences in response to vedolizumab may be related to variability in vedolizumab trough levels, but in children with pediatric-onset IBD data regarding vedolizumab trough levels are not available. Thus far, the role of trough levels in pediatric-onset IBD treatment remains unclear. We aimed to investigate predictors of vedolizumab trough levels in pediatric-onset IBD patients. METHODS: Data from anti-tumor necrosis factor refractory pediatric-onset IBD patients who received vedolizumab were collected retrospectively. Vedolizumab trough levels were measured in serum samples collected before each infusion. A linear mixed model was conducted to analyze factors that influence trough levels. RESULTS: Twenty-six pediatric-onset IBD patients (14 ulcerative colitis [UC]), 9 Crohn Disease [CD], 3 IBD-unclassified [IBD-U]) received 258 vedolizumab infusions. Mean vedolizumab trough level at week 6 was 29.9 µg/mL (SD 17.8), and 11.5 µg/mL (SD 4.9) during maintenance therapy. CD patients had significantly lower trough levels than IBD-U patients (ß 15.2; 95% confidence interval [CI] -1.1 to 29.2; P = 0.036). Higher fecal calprotectin (ß -0.009; 95% CI -0.02 to -0.003; P = 0.007) and C-reactive protein levels (ß -0.4; 95% CI -0.72 to -0.04; P = 0.027) were associated with lower trough levels, whereas shortening of time between infusions led to higher trough levels (ß -0.77; 95% CI -0.9 to 0.64; P < 0.001). CONCLUSIONS: In this group of pediatric-onset IBD patients, trough levels were significantly lower in CD patients compared with UC/IBD-U patients. Higher levels of inflammatory markers were associated with lower vedolizumab trough levels.

Psychological Outcomes of a Cognitive Behavioral Therapy for Youth with Inflammatory Bowel Disease: Results of the HAPPY-IBD Randomized Controlled Trial at 6- and 12-Month Follow-Up.

Youth with inflammatory bowel disease (IBD) often experience psychological difficulties, such as anxiety and depression. This randomized controlled study tested whether a 3-month disease-specific cognitive behavioral therapy (CBT) in addition to standard medical care versus standard medical care only was effective in improving these youth's psychological outcomes. As this study was aimed at prevention, we included 70 youth (10-25 years) with IBD and symptoms of subclinical anxiety and/or depression, and measured psychological outcomes at 6- and 12-month follow-up. In general, participants in both groups showed improvements in anxiety, depression, health-related quality of life, social functioning, coping, and illness perceptions, sustained until 12 months follow-up. Overall, we found no differences between those receiving additional CBT and those receiving standard medical care only. We assume that this can be explained by the perceived low burden (both somatically and psychologically) or heightened awareness of psychological difficulties and IBD. ClinicalTrials.gov NCT02265588.

Azithromycin and metronidazole versus metronidazole-based therapy for the induction of remission in mild to moderate paediatric Crohn's disease : a randomised controlled trial.

OBJECTIVE: Crohn's disease (CD) pathogenesis associated with dysbiosis and presence of pathobionts in the lumen, intracellular compartments and epithelial biofilms. Azithromycin is active in all three compartments. Our goal was to evaluate if azithromycin-based therapy can improve response and induce remission compared with metronidazole alone in paediatric CD. DESIGN: This blinded randomised controlled trial allocated children 5-18 years with 1012.5 or remission using intention to treat analysis. RESULTS: 73 patients (mean age 13.8±3.1 years) were enrolled, 35 to group 1 and 38 to group 2. Response and remission rates at week 8 were identical 23/35 (66%) in group 1 and 17/38 (45%) and 15/38 (39%) in group 2 (P=0.07 and P=0.025, respectively). The needed to treat for remission was 3.7. Faecal calprotectin declined significantly in group 1 (P=0.003) but not in group 2 (p=0.33), and was lower at week 8 (P=0.052). Additional therapy was required in 6/35(17%) from group 1 versus 16/38(42%) in group 2 (P=0.027) by week 8. Among 12 failures in group 2, open-label azithromycin led to remission in 10/12 (83%). CONCLUSIONS: The combination of azithromycin and metronidazole failed to improve response but was superior for induction of remission and reduction in calprotectin. TRIAL REGISTRATION NUMBER: NCT01596894.

Weibel-Palade Body Localized Syntaxin-3 Modulates Von Willebrand Factor Secretion From Endothelial Cells.

OBJECTIVE: Endothelial cells store VWF (von Willebrand factor) in rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs). WPB exocytosis is coordinated by a complex network of Rab GTPases, Rab effectors, and SNARE (soluble NSF attachment protein receptor) proteins. We have previously identified STXBP1 as the link between the Rab27A-Slp4-a complex on WPBs and the SNARE proteins syntaxin-2 and -3. In this study, we investigate the function of syntaxin-3 in VWF secretion. APPROACH AND RESULTS: In human umbilical vein endothelial cells and in blood outgrowth endothelial cells (BOECs) from healthy controls, endogenous syntaxin-3 immunolocalized to WPBs. A detailed analysis of BOECs isolated from a patient with variant microvillus inclusion disease, carrying a homozygous mutation in STX3(STX3-/-), showed a loss of syntaxin-3 protein and absence of WPB-associated syntaxin-3 immunoreactivity. Ultrastructural analysis revealed no detectable differences in morphology or prevalence of immature or mature WPBs in control versus STX3-/- BOECs. VWF multimer analysis showed normal patterns in plasma of the microvillus inclusion disease patient, and media from STX3-/- BOECs, together indicating WPB formation and maturation are unaffected by absence of syntaxin-3. However, a defect in basal as well as Ca2+- and cAMP-mediated VWF secretion was found in the STX3-/- BOECs. We also show that syntaxin-3 interacts with the WPB-associated SNARE protein VAMP8 (vesicle-associated membrane protein-8). CONCLUSIONS: Our data reveal syntaxin-3 as a novel WPB-associated SNARE protein that controls WPB exocytosis.

Self-efficacy did not predict the outcome of the transition to adult care in adolescents with inflammatory bowel disease.

AIM: It can be difficult for adolescents with inflammatory bowel disease (IBD) to make the transition from paediatric to adult care. We studied the outcomes of this process and defined what constituted a successful transition. METHODS: In 2008, 50 adolescents who attended our IBD transition clinic completed IBD-yourself, a self-efficacy questionnaire that we had previously developed and validated. We approached the subjects in 2014, two to six years after they transferred to adult care, and 35 agreed to take part in the current study. The outcome of transition was assessed by our newly developed Transition Yourself Score. In addition, the relationship between self-efficacy and the outcome of the transition was measured. RESULTS: The mean age of the patients was 21.8 years, and 69% suffered from Crohn's disease. The transition process was successful in 63% of cases, moderately successful in 31% and failed in 6%. A successful transition was associated with effective use of medication and clinical remission at the time of transfer, but could not be predicted by self-efficacy. The Transition Yourself Score will be validated in future studies. CONCLUSION: Nearly two-thirds (63%) of the adolescents who attended the IBD transition clinic had a successful transition to adult care.

Illness Perceptions and Depression Are Associated with Health-Related Quality of Life in Youth with Inflammatory Bowel Disease.

BACKGROUND: In youth with inflammatory bowel disease (IBD), health-related quality of life (HRQOL) has been shown to be affected by individual disease factors and specific psychological factors. The innovative aim of this study is to examine the combined impact of psychological factors (illness perceptions, cognitive coping, anxiety, and depression) on HRQOL, over and above the associations of demographic and disease factors with HRQOL in youth with IBD. METHOD: Data on clinical disease activity, illness perceptions, cognitive coping, anxiety, depression, and HRQOL were prospectively collected in 262 consecutive youth (age 10-20, 46.6% male) with confirmed IBD. Multiple linear regression analyses tested the associations of demographic, disease, and psychological variables with HRQOL in separate groups for Crohn's disease (CD; N = 147) and ulcerative colitis and IBD unclassified (UC/IBD-U; N = 115), using age-specific validated instruments. RESULTS: In both disease groups, more negative illness perceptions (ß = - .412; ß = - .438, p < .001) and more depression (ß = - .454; ß = - .279, p < .001) were related to lower HRQOL. In the UC/IBD-U group, more anxiety was related to lower HRQOL (ß = - .201, p = .001). The model with the psychological variables explained a large and significant amount of variance in both groups: 74% and 83%, respectively (p < .001). CONCLUSION: In 10-20-year-old IBD patients, negative illness perceptions and depression were significantly and more strongly associated with lower HRQOL than demographic and disease factors. Thus, it is important to integrate psychological factors in the treatment for IBD patients. To improve HRQOL in young IBD patients, psychological interventions should be targeted at negative illness perceptions and depression.

Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as a biomarker of CFTR function.

Forskolin-induced swelling (FIS) of intestinal organoids from individuals with cystic fibrosis (CF) measures function of the cystic fibrosis transmembrane conductance regulator (CFTR), the protein mutated in CF.We investigated whether FIS corresponds with clinical outcome parameters and biomarkers of CFTR function in 34 infants diagnosed with CF. Relationships with FIS were studied for indicators of pulmonary and gastrointestinal disease.Children with low FIS had higher levels of immunoreactive trypsinogen (p=0.030) and pancreatitis-associated protein (p=0.039), more often had pancreatic insufficiency (p<0.001), had more abnormalities on chest computed tomography (p=0.049), and had lower z-scores for maximal expiratory flow at functional residual capacity (p=0.033) when compared to children with high FIS values. FIS significantly correlated with sweat chloride concentration (SCC) and intestinal current measurement (ICM) (r= -0.82 and r=0.70, respectively; both p<0.001). Individual assessment of SCC, ICM and FIS suggested that FIS can help to classify individual disease severity.Thus, stratification by FIS identified subgroups that differed in pulmonary and gastrointestinal outcome parameters. FIS of intestinal organoids correlated well with established CFTR-dependent biomarkers such as SCC and ICM, and performed adequately at group and individual level in this proof-of-concept study.

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.

Effectiveness of Disease-Specific Cognitive Behavioral Therapy on Anxiety, Depression, and Quality of Life in Youth With Inflammatory Bowel Disease: A Randomized Controlled Trial.

Objective: To evaluate the effectiveness of a disease-specific cognitive behavioral therapy (CBT) protocol on anxiety and depressive symptoms and health-related quality of life (HRQOL) in adolescents and young adults with inflammatory bowel disease (IBD). Method: A parallel group randomized controlled trial was conducted in 6 centers of (pediatric) gastroenterology. Included were 70 patients and young adults (10-25 years) with IBD and subclinical anxiety and/or depressive symptoms. Patients were randomized into 2 groups, stratified by center: (a) standard medical care (care-as-usual [CAU]) plus disease-specific manualized CBT (Primary and Secondary Control Enhancement Training for Physical Illness; PASCET-PI), with 10 weekly sessions, 3 parent sessions, and 3 booster sessions (n = 37), or (b) CAU only (n = 33). Primary analysis concerned the reliable change in anxiety and depressive symptoms after 3 months (immediate posttreatment assessment). Exploratory analyses concerned (1) the course of anxiety and depressive symptoms and HRQOL in subgroups based on age, and (2) the influence of age, gender, and disease type on the effect of the PASCET-PI. Results: Overall, all participants improved significantly in their anxiety and depressive symptoms and HRQOL, regardless of group, age, gender, and disease type. Primary chi-square tests and exploratory linear mixed models showed no difference in outcomes between the PASCET-PI (n = 35) and the CAU group (n = 33). Conclusions: In youth with IBD and subclinical anxiety and/or depressive symptoms, preliminary results of immediate post-treatment assessment indicated that a disease-specific CBT added to standard medical care did not perform better than standard medical care in improving psychological symptoms or HRQOL. ClinicalTrials.gov: NCT02265588.

The impact of Narcotrend™ EEG-guided propofol administration on the speed of recovery from pediatric procedural sedation-A randomized controlled trial.

BACKGROUND: Propofol is often used for procedural sedation in children undergoing gastrointestinal endoscopy. Reliable assessment of the depth of hypnosis during the endoscopic procedure is challenging. Processed electroencephalography using the Narcotrend Index can help titrating propofol to a predefined sedation level. AIMS: The aim of this trial was to investigate the impact of Narcotrend Index-guided titration of propofol delivery on the speed of recovery. METHODS: Children, aged 12-17 years, undergoing gastrointestinal endoscopy under procedural sedation, had propofol delivered via target controlled infusion either based on Narcotrend Index guidance (group NI) or standard clinical parameters (group C). Sedation was augmented with remifentanil in both study groups. The primary endpoint of this study was to compare the speed of fulfilling discharge criteria from the operating room between study groups. Major secondary endpoints were propofol consumption, discharge readiness from the recovery room, hypnotic depth as measured by the Narcotrend Index, and adverse events. RESULTS: Of the 40 children included, data were obtainable from 37. The time until discharge readiness from the operating room was shorter in group NI than in group C, with a difference between medians of 4.76 minutes [95%CI 2.6 to 7.4 minutes]. The same accounts for recovery room discharge times; difference between medians 4.03 minutes [95%CI 0.81 to 7.61 minutes]. Propofol consumption and the percentage of EEG traces indicating oversedation were higher in group C than in group NI. There were no significant adverse events in either study group. CONCLUSION: Narcotrend Index guidance of propofol delivery for deep sedation in children aged 12-17 years, underdoing gastrointestinal endoscopy results in faster recovery, less drug consumption, and fewer episodes of oversedation than dosing propofol according to clinical surrogate parameters of depth of hypnosis. The results of this study provide additional evidence in favor of the safety profile of propofol/remifentanil for procedural sedation in adequately selected pediatric patients.