High Body Mass Index and Response to Anti-Tumor Necrosis Factor Therapy in Pediatric Crohn's Disease.

INTRODUCTION: Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). METHODS: The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z -score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. RESULTS: Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 µg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. DISCUSSION: Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

Long-Term Effectiveness and Durability of COVID-19 Vaccination Among Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: COVID-19 vaccination prevents severe disease in most patients with inflammatory bowel disease (IBD), but immunosuppressive medications can blunt serologic response. We followed adults with IBD for >1 year post-COVID-19 vaccination to describe factors associated with SARS-CoV-2 infection after vaccination, evaluate for a protective SARS-CoV-2 antibody level, characterize SARS-CoV-2 antibody persistence, and identify factors associated with humoral immune response durability. METHODS: Using a prospective cohort of COVID-19 immunized adults with IBD, we analyzed factors associated with SARS-CoV-2 infection after vaccination. We evaluated for an association between SARS-CoV-2 antibody level 12 weeks postvaccination and subsequent SARS-CoV-2 infection and assessed for a threshold of protection using receiver-operating characteristic curve analysis. We then conducted a separate analysis evaluating factors associated with persistence of SARS-CoV-2 antibodies 52 weeks postimmunization. RESULTS: Almost half (43%) of 1869 participants developed COVID-19 after vaccination, but most infections were mild, and <1% required hospitalization. Older age and corticosteroid use were associated with a decreased risk of SARS-CoV-2 infection postvaccination (50-59 years of age vs 18-29 years of age: adjusted hazard ratio, 0.57; 95% confidence interval, 0.44-0.74; steroid users vs nonusers: adjusted hazard ratio, 0.58; 95% confidence interval, 0.39-0.87). Most (98%) participants had detectable antibody levels at 52 weeks postvaccination. Antibody levels at 12 weeks and number of vaccine doses were positively associated with higher antibody levels at 52 weeks, while anti-tumor necrosis factor α therapy was negatively associated. CONCLUSIONS: COVID-19 vaccination generates an effective and durable protective response for the vast majority of adults with IBD, including vulnerable populations such as corticosteroid users and older individuals. Patients with IBD benefit from COVID-19 booster vaccination.

Child Health Needs and the Pediatric Gastroenterology Workforce: 2020-2040.

This article is part of an American Board of Pediatrics Foundation-sponsored effort to analyze and forecast the pediatric subspecialty workforce between 2020 and 2040. Herein, an overview of the current pediatric gastroenterology workforce is provided, including demographics, work characteristics, and geographic distribution of practitioners. Brief context is provided on the changing nature of current practice models and the increasing prevalence of some commonly seen disorders. On the basis of a rigorous microsimulation workforce projection model, projected changes from 2020 to 2040 in the number of pediatric gastroenterologists and clinical workforce equivalents in the United States are presented. The article closes with a brief discussion of training, clinical practice, policy, and future workforce research implications of the data presented. This data-driven analysis suggests that the field of pediatric gastroenterology will continue to grow in scope and complexity, propelled by scientific advances and the increasing prevalence of many disorders relevant to the discipline. The workforce is projected to double by 2040, a growth rate faster than most other pediatric subspecialties. Disparities in care related to geography, race, and ethnicity are among the most significant challenges for the years ahead. Changes to training and education, incentives to meet the needs of underserved populations, and new multidisciplinary models for health care delivery will be necessary to optimally meet the volume, diversity, and complexity of children with gastroenterological diseases in the years ahead.

Humoral immune response and safety of SARS-CoV-2 vaccination in very early onset inflammatory bowel disease.

Children with very early onset inflammatory bowel disease (VEO-IBD) may respond differently to coronavirus disease 2019 (COVID-19) immunization compared to healthy children or other patients with IBD. We recruited children with VEO-IBD <6 years of age and younger following receipt of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Demographics, IBD characteristics, medication use, adverse events (AEs) and IBD exacerbations were collected. Blood draws (optional) were obtained for measurement of antireceptor binding domain (RBD) IgG antibodies following vaccination. Of 41 participants, none required emergency department visit or hospitalization due to AE, and only one experienced IBD exacerbation. Detectable antibody was present in 19/19 participants who provided blood sample; 6/7 participants (86%) had durable humoral response 12 months postvaccination. Children with VEO-IBD experience robust humoral immune response to COVID-19 immunization. Severe AEs were rare. These findings provide reassurance that children with VEO-IBD respond well and safely to SARS-CoV-2 vaccination.

Low Rates of Breakthrough COVID-19 Infection After SARS-CoV-2 Vaccination in Patients With Inflammatory Bowel Disease.

We demonstrate low rates of breakthrough coronavirus disease 2019 (COVID-19) infection and mild course of illness following severe acute respiratory syndrome coronavirus 2 vaccination in a large cohort of inflammatory bowel disease patients. Residence in southern United States and lower median anti-receptor binding antibody level were associated with development of COVID-19.

Humoral Immune Response and Safety of SARS-CoV-2 Vaccination in Pediatric Inflammatory Bowel Disease.

INTRODUCTION: Children with inflammatory bowel disease (IBD) may respond differently to COVID-19 immunization as compared with healthy children or adults with IBD. Those younger than 12 years receive a lower vaccine dose than adults. We sought to describe the safety and humoral immune response to COVID-19 vaccine in children with IBD. METHODS: We recruited children with IBD, ages 5-17 years, who received ≥ 2 doses of the BNT162b2 vaccine by a direct-to-patient outreach and at select sites. Patient demographics, IBD characteristics, medication use, and vaccine adverse events were collected. A subset of participants had quantitative measurement of anti-receptor binding domain IgG antibodies after 2-part immunization. RESULTS: Our study population included 280 participants. Only 1 participant required an ED visit or hospitalization because of an adverse event. Of 99 participants who underwent anti-receptor binding domain IgG antibody measurement, 98 had a detectable antibody, with a mean antibody level of 43.0 µg/mL (SD 67) and a median of 22 µg/mL (interquartile range 12-38). In adjusted analyses, older age ( P = 0.028) and antitumor necrosis factor monotherapy compared with immunomodulators alone ( P = 0.005) were associated with a decreased antibody level. Antibody response in patients treated with antitumor necrosis factor combination vs monotherapy was numerically lower but not significant. DISCUSSION: Humoral immune response to COVID-19 immunization in children with IBD was robust, despite a high proportion of this pediatric cohort being treated with immunosuppressive agents. Severe vaccine-related AEs were rare. Overall, these findings provide a high level of reassurance that pediatric patients with IBD respond well and safely to SARS-CoV-2 vaccination.

Implementation of Enhanced Recovery Protocols for Gastrointestinal Surgery in Children: Practical Tools From Key Stakeholders.

INTRODUCTION: We explored patient, caregiver, and provider recommendations for development of a tool kit to implement enhanced recovery protocols (ERPs) for pediatric patients undergoing gastrointestinal surgery. ERPs are widely used for adults to decrease hospital length of stay, hospital costs, and complications while hastening patient recovery after surgery. With limited data available for ERPs among pediatric populations informed modification of adult ERPs is needed to facilitate successful implementation for pediatric surgery. METHODS: Using a qualitative research design, semistructured interviews were conducted with hospital-based teams including surgeons, anesthesiologists, gastroenterologists, nursing, and physician assistants. Four in-person focus groups were held at two pediatric hospitals with patients and caregivers. Codes were developed and applied to interview and focus groups transcripts for structural content analysis. Thematic analysis guided by the Active Implementation Framework, included recommendations that informed ERP implementation tool kit development. RESULTS: Key components of the ERP tool kit included the need for a structured and systematic approach, leadership support from key champions, and buy-in from surgical partners and hospital management. Providers identified the need for multimodal educational materials on ERP elements for staff and patients; use of uniform checklists, care sets and an electronic repository to collect outcome data for quality assurance assessment. Patients and caregivers endorsed expansion of the team to include child-life specialists, nutritionists, and patient-parent supporters to help navigate the surgical experience. CONCLUSIONS: This study is the first to leverage key input from patients, caregivers, and providers to identify practical components for an ERP implementation tool kit for children undergoing gastrointestinal surgery.

A qualitative examination of barriers and facilitators of pediatric enhanced recovery protocol implementation among 18 pediatric surgery services.

BACKGROUND: Enhanced recovery protocols (ERPs) are an evidence-based intervention to optimize post-surgical recovery. Several studies have demonstrated that the use of an ERP for gastrointestinal surgery results in decreased length of stay, shortened time to a regular diet, and fewer administered opioids, while also trending toward lower complication and 30-day readmission rates. Yet, implementation of ERPs in pediatric surgery is lagging compared to adult surgery. The study's purpose was to conduct a theory-guided evaluation of barriers and facilitators to ERP implementation at US hospitals with a pediatric surgery service. METHODS: We conducted semi-structured interviews at 18 hospitals with 48 participants, including pediatric surgeons, anesthesiologists, gastroenterologists, nurses, and physician assistants. Interviews were conducted online, audio-recorded, and transcribed verbatim. To identify barriers and facilitators to ERP implementation, we conducted an analysis using deductive logics based on the five Active Implementation Frameworks (AIFs). RESULTS: Effective practices (usable innovations) were challenged by a lack of compliance to ERP elements, and facilitators were having standardized protocols in place and organization support for implementation. Effective implementation (stages of implementation and implementation drivers) had widespread barriers to implementation across the stages from exploration to full implementation. Barriers included needing dedicated teams for ERP implementation and buy-in from hospital leadership. These items, when present, were strong facilitators of effective implementation, in addition to on-site, checklists, protected time to oversee ERP implementation, and order sets for ERP elements built into the electronic medical record. The enabling context (teams) focused on teams' engagement in ERP implementation and how they collaborated to implement ERPs. Barriers included having surgical team members resistant to change or who were not bought into ERPs in pediatric practice. Facilitators included engaging a multi-disciplinary team and engaging patients and families early in the implementation process. CONCLUSIONS: Barriers to ERP implementation in pediatric surgery highlighted can be addressed through providing guidelines to ERP implementation, team-based support for change management, and protocols for developing an ERP implementation team. Future steps are to apply and evaluate these strategies in a stepped-wedge, cluster randomized trial to increase the implementation of ERPs at these 18 hospitals.

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.

Age- and Sex-Specific Needs for Children Undergoing Inflammatory Bowel Disease Surgery: A Qualitative Study.

INTRODUCTION: The use of enhanced recovery protocols (ERP) is extending to pediatric surgical populations, such as patients with inflammatory bowel diseases (IBDs). Given the variation in age- and sex-specific characteristics of pediatric IBD patients, it is important to understand the unique needs of subgroups, such as male versus female or preadolescent versus older patients, when implementing ERPs. We gathered clinician, patient, and caregiver perspectives on age- and sex-specific needs for children undergoing IBD surgery. METHODS: We used semistructured interviews and focus groups to assess ERP needs and perceived differences in needs between preadolescent (10-13 y), older (14-19 y), male, and female IBD patients. Participants included clinicians, patients who had recent IBD surgery, and patients' caregivers. RESULTS: Forty-eight clinicians, six patients, and eight caregivers participated. Three broad categories of themes emerged: concerns, needs, and experiences related to the (1) surgical care process; (2) continuum of IBD care; and (3) suggestions to make surgical care more patient centered. With regard to surgical care processes, stakeholders reported different communication needs for preadolescent and older children. Key themes about the continuum of IBD care were the need (1) for support from child life specialists and (b) to address young women's health issues. Suggestions to make surgical care more patient centered included providing older children with patient experiences that reflect their perspective as young adults. CONCLUSIONS: The findings highlight the need to adopt a patient-centered approach for ERP use that actively addresses age- and sex-specific factors while engaging patients and caregivers as partners with clinicians to improve surgical care for children with IBD.

Impact of SARS-CoV-2 Vaccination on Inflammatory Bowel Disease Activity and Development of Vaccine-Related Adverse Events: Results From PREVENT-COVID.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 vaccination is recommended for all individuals with inflammatory bowel disease (IBD), including those on immunosuppressive therapies; however, little is known about vaccine safety and efficacy in these patients or the impact of vaccination on IBD disease course. METHODS: We evaluated coronavirus disease 2019 (COVID-19) vaccine-related adverse events (AEs) and the effect of vaccination on IBD disease course among participants in the PREVENT-COVID (Partnership to Report Effectiveness of Vaccination in populations Excluded from iNitial Trials of COVID) study, a prospective, observational cohort study. Localized and systemic reactions were assessed via questionnaire. Disease flare was defined by worsening IBD symptoms and change in IBD medications. Outcomes were stratified by vaccine type and IBD medication classes. RESULTS: A total of 3316 individuals with IBD received at least 1 COVID-19 vaccine. Injection site tenderness (68%) and fatigue (46% dose 1, 68% dose 2) were the most commonly reported localized and systemic AEs after vaccination. Severe localized and systemic vaccine-related AEs were rare. The mRNA-1273 vaccine was associated with significantly greater severe AEs at dose 2 (localized 4% vs 2%, systemic 15% vs 10%; P < .001 for both). Prior COVID-19 infection, female sex, and vaccine type were associated with severe systemic reactions to dose 1, while age <50 years, female sex, vaccine type, and antitumor necrosis factor and vedolizumab use were associated with severe systemic reactions to dose 2. Overall rates (2%) of IBD flare were low following vaccination. CONCLUSIONS: Our findings provide reassurance that the severe acute respiratory syndrome coronavirus 2 vaccine is safe and well tolerated among individuals with IBD, which may help to combat vaccine hesitancy and increase vaccine confidence.

The severe acute respiratory syndrome coronavirus 2 vaccine is safe and well tolerated among individuals with inflammatory bowel disease (IBD). Severe localized and systemic vaccine-related adverse events were rare, and rates of IBD flare were low (2%) following severe acute respiratory syndrome coronavirus 2 vaccination in a cohort of 3316 participants with IBD.

Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study.

BACKGROUND: The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. METHODS: We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. RESULTS: The study population included 269 children (105 [39%] Crohn's disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9-5.2). Most (94%) Crohn's disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn's disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. CONCLUSIONS: Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%-15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population.

A baseline assessment of enhanced recovery protocol implementation at pediatric surgery practices performing inflammatory bowel disease operations.

BACKGROUND: Enhanced recovery protocols (ERPs) have been used to improve patient outcomes and resource utilization after surgery. These evidence-based interventions include patient education, standardized anesthesia protocols, and limited fasting, but their use among pediatric populations is lagging. We aimed to determine baseline recovery practices within pediatric surgery departments participating in an ERP implementation trial for elective inflammatory bowel disease (IBD) operations. METHODS: To measure baseline ERP adherence, we administered a survey to a staff surgeon in each of the 18 participating sites. The survey assessed demographics of each department and utilization of 21 recovery elements during patient encounter phases. Mixed-methods analysis was used to evaluate predictors and barriers to ERP element implementation. RESULTS: The assessment revealed an average of 6.3 ERP elements being practiced at each site. The most commonly practiced elements were using minimally invasive techniques (100%), avoiding intraabdominal drains (89%), and ileus prophylaxis (72%). The preoperative phase had the most elements with no adherence including patient education, optimizing medical comorbidities, and avoiding prolonged fasting. There was no association with number of elements utilized and total number of surgeons in the department, annual IBD surgery volume, and hospital size. Lack of buy-in from colleagues, electronic medical record adaptation, and resources for data collection and analysis were identified barriers. CONCLUSIONS: Higher intervention utilization for IBD surgery was associated with elements surgeons directly control such as use of laparoscopy and avoiding drains. Elements requiring system-level changes had lower use. The study characterizes the scope of ERP utilization and the need for effective tools to improve adoption. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Mixed-methods survey.

Implementing a Novel Quality Improvement-Based Approach to Data Quality Monitoring and Enhancement in a Multipurpose Clinical Registry.

OBJECTIVE: To implement a quality improvement based system to measure and improve data quality in an observational clinical registry to support a Learning Healthcare System. DATA SOURCE: ImproveCareNow Network registry, which as of September 2019 contained data from 314,250 visits of 43,305 pediatric Inflammatory Bowel Disease (IBD) patients at 109 participating care centers. STUDY DESIGN: The impact of data quality improvement support to care centers was evaluated using statistical process control methodology. Data quality measures were defined, performance feedback of those measures using statistical process control charts was implemented, and reports that identified data items not following data quality checks were developed to enable centers to monitor and improve the quality of their data. PRINCIPAL FINDINGS: There was a pattern of improvement across measures of data quality. The proportion of visits with complete critical data increased from 72 percent to 82 percent. The percent of registered patients improved from 59 percent to 83 percent. Of three additional measures of data consistency and timeliness, one improved performance from 42 percent to 63 percent. Performance declined on one measure due to changes in network documentation practices and maturation. There was variation among care centers in data quality. CONCLUSIONS: A quality improvement based approach to data quality monitoring and improvement is feasible and effective.

Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study.

BACKGROUND: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING: US National Institutes of Health.

Low Insulin-like Growth Factor-1 Influences Fatigue and Quality of Life in Children With Inflammatory Bowel Disease.

OBJECTIVE: Fatigue is common among patients with inflammatory bowel disease (IBD). Proinflammatory cytokines are elevated in chronic inflammation and can induce "sickness behaviors," such as fatigue. Chronic inflammatory states also lead to growth hormone resistance, demonstrated by low levels of insulin-like growth factor (IGF-1) and elevated growth hormone. This study evaluated the relationship between IGF-1, proinflammatory cytokine levels, and fatigue in patients with IBD. METHODS: In this prospective study children with IBD, ages 10 to 16 years, were recruited from a subspecialty ambulatory clinic. Participants and their parents completed age-appropriate generic and disease-specific health-related quality of life (HRQOL) instruments. Serum samples obtained at the same encounter were analyzed for Th17 cytokine and IGF-1 levels. HRQOL scores were compared to a healthy sample and HRQOL scores and cytokine levels were compared by IGF-1 z score quartiles. RESULTS: A total of 67 patients with IBD were recruited, median age of 13.7 years (interquartile range, 11.7-15.3). Forty-eight (72%) had inactive disease based on Physician Global Assessment. Patients with IBD reported lower generic HRQOL (P = 0.0006) and more fatigue (P = 0.0004) than a healthy sample. Patients with IGF-1 z scores in the lowest quartile had significantly lower disease-specific HRQOL (P = 0.01) and more fatigue (P = 0.02) than the remainder of the cohort. Serum interleukin (IL)-10, IL-17A, IL-6, and interferon-γ were significantly higher in patients with IBD with IGF-1 z scores in the lowest quartile (P < 0.05). CONCLUSIONS: Children with subclinical IBD experience more fatigue and lower generic HRQOL than healthy children. Lower IGF-1 z scores are associated with more fatigue, and this relationship may be mediated through proinflammatory cytokines.

Factors associated with early outcomes following standardised therapy in children with ulcerative colitis (PROTECT): a multicentre inception cohort study.

BACKGROUND: Previous retrospective studies of paediatric ulcerative colitis have had limited ability to describe disease progression and identify predictors of treatment response. In this study, we aimed to identify characteristics associated with outcomes following standardised therapy after initial diagnosis. METHODS: The PROTECT multicentre inception cohort study was based at 29 centres in the USA and Canada and included paediatric patients aged 4-17 years who were newly diagnosed with ulcerative colitis. Guided by the Pediatric Ulcerative Colitis Activity Index (PUCAI), patients received initial standardised treatment with mesalazine (PUCAI 10-30) oral corticosteroids (PUCAI 35-60), or intravenous corticosteroids (PUCAI ≥65). The key outcomes for this analysis were week 12 corticosteroid-free remission, defined as PUCAI less than 10 and taking only mesalazine, and treatment escalation during the 12 study weeks to anti-tumour necrosis factor α (TNFα) agents, immunomodulators, or colectomy among those initially treated with intravenous corticosteroids. We identified independent predictors of outcome through multivariable logistic regression using a per-protocol approach. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Patients were recruited between July 10, 2012, and April 21, 2015. 428 children initiated mesalazine (n=136), oral corticosteroids (n=144), or intravenous corticosteroids (n=148). Initial mean PUCAI was 31·1 (SD 13·3) in children initiating with mesalazine, 50·4 (13·8) in those initiating oral corticosteroids, and 66·9 (13·7) in those initiating intravenous corticosteroids (p<0·0001 for between-group comparison). Week 12 outcome data were available for 132 patients who initiated with mesalazine, 141 with oral corticosteroids, and 143 with intravenous corticosteroids. Corticosteroid-free remission with the patient receiving mesalazine treatment only at 12 weeks was achieved by 64 (48%) patients in the mesalazine group, 47 (33%) in the oral corticosteroid group, and 30 (21%) in the intravenous corticosteroid group (p<0·0001). Treatment escalation was required by nine (7%) patients in the mesalazine group, 21 (15%) in the oral corticosteroid group, and 52 (36%) in the intravenous corticosteroid group (p<0·0001). Eight patients, all of whom were initially treated with intravenous corticosteroids, underwent colectomy. Predictors of week 12 corticosteroid-free remission were baseline PUCAI less than 35 (odds ratio 2·44, 95% CI 1·41-4·22; p=0·0015), higher baseline albumin by 1 g/dL increments among children younger than 12 years (4·05, 1·90-8·64; p=0·00030), and week 4 remission (6·26, 3·79-10·35; p<0·0001). Predictors of treatment escalation by week 12 in patients initially treated with intravenous corticosteroids included baseline total Mayo score of 11 or higher (2·59, 0·93-7·21; p=0·068 [retained in model due to clinical relevance]), rectal biopsy eosinophil count less than or equal to 32 cells per high power field (4·55, 1·62-12·78; p=0·0040), rectal biopsy surface villiform changes (3·05, 1·09-8·56; p=0·034), and not achieving week 4 remission (30·28, 6·36-144·20; p<0·0001). INTERPRETATION: Our findings provide guidelines to assess the response of children newly diagnosed with ulcerative colitis to standardised initial therapy and identify predictors of treatment response and failure. These data suggest that additional therapeutic interventions might be warranted to improve early outcomes, especially in patients presenting with severe disease and requiring intravenous corticosteroids. FUNDING: National Institutes of Health.

North American Pediatric Gastroenterology Fellowship Needs Assessment in Inflammatory Bowel Disease: Trainee and Program Director Perspectives.

BACKGROUND: Pediatric inflammatory bowel disease (IBD) care is complex and rapidly evolving. The Crohn's and Colitis Foundation of America and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition cosponsored a needs assessment survey of pediatric gastroenterology trainees and program directors (PDs) to inform on educational programming. METHODS: A Web-based, self-completed survey was provided to North American trainees and PDs during the 2013-2014 academic year. Standard descriptive statistics summarized demographics and responses. RESULTS: One hundred sixty-six of 326 (51%) trainees (62% female) and 37 of 74 (50%) PDs responded. Median trainees per program = 5 and median total faculty = 10 (3 IBD experts); 15% of programs did not have a self-identified "IBD expert" faculty member. Sixty-nine percent of trainees were confident/somewhat confident in their IBD inpatient training, whereas 54% were confident/somewhat confident in their outpatient training. Trainees identified activities that would most improve their education, including didactics (55%), interaction with national experts (50%), trainee-centered IBD Web resources (42%), and increased patient exposure (42%). Trainees were most confident in managing inpatient active Crohn's disease/ulcerative colitis, phenotype classification, managing biological therapies, and using clinical disease activity indices. They were least confident in managing J-pouch complications, performing pouchoscopy, managing extraintestinal manifestations, and ostomy-related complications. Eighty-five percent would like an IBD-focused training elective. Most directors (86%) would allow trainees to do electives at other institutions. CONCLUSIONS: This IBD needs assessment survey of pediatric gastroenterology trainees and PDs demonstrated a strong resource commitment to IBD training and clinical care. Areas for educational enrichment emerged, including pouch and ostomy complications.

Prevalence of subclinical vitamin K deficiency in cholestatic liver disease.

BACKGROUND AND OBJECTIVE: Prothrombin time (PT), a surrogate marker of vitamin K deficiency, may underestimate the prevalence of vitamin K deficiency in cholestatic liver disease. This study investigated the frequency of vitamin K deficiency in children and adults with cholestatic liver disease by determining plasma protein induced in vitamin K absence II (PIVKA-II), and assessed the relation between plasma PIVKA-II levels and markers of cholestasis, measured PT, international normalized ratio (INR), serum undercarboxylated osteocalcin (ucOC), serum vitamins A and E, and serum 25-hydroxyvitamin D levels. PATIENTS AND METHODS: Blood was collected from patients with cholestatic liver disease for liver biochemistries, PT, INR, bile acids, 25-hydroxyvitamin D, vitamin A, vitamin E, ucOC, and PIVKA-II. RESULTS: Thirty-one patients were enrolled (age range 0.5-54 years, median age 5.7 years, 17 females). Nine patients (29%) had increased INRs, whereas 21 (68%) had elevated plasma PIVKA-II levels. All patients with increased INRs had increased plasma PIVKA-II. Fifteen of 21 patients with increased plasma PIVKA-II were receiving supplemental vitamin K therapy (range 7.8-700 mug/kg/day). Plasma PIVKA-II levels were positively correlated with serum conjugated bilirubin, bile acids, aspartate aminotransferase, alanine aminotransferase, PT, INR, and serum ucOC (P