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.

Travel Time to Treating Center is Associated With Diagnostic Delay in Pediatric Inflammatory Bowel Disease.

BACKGROUND & AIMS: Delayed diagnosis of inflammatory bowel disease (IBD) leads to prolonged symptoms and worse long-term outcomes. We sought to evaluate whether race, ethnicity, disease type, and social factors are associated with delayed diagnosis of pediatric IBD. METHODS: We performed a cross-sectional study of newly diagnosed pediatric patients with IBD at 22 United States sites from 2019 to 2022. Parents/guardians reported race, ethnicity, time between symptom onset and diagnosis, and other social determinants of health. Through bivariate and multivariable analyses using generalized estimating equations, we evaluated associations between these factors and diagnosis time defined as ≤60 days, 61 to 180 days, 181 to 365 days, and >365 days. RESULTS: We enrolled 869 participants (mean age at diagnosis, 13.1 years; 52% male; 57% Crohn's disease [CD]; 34% ulcerative colitis [UC]; 8% Hispanic; 30% non-White). Overall, the mean time to diagnosis was 265.9 days. After adjustment, factors associated with longer diagnosis time included CD vs UC (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.9-3.5), 2 or more other health conditions (OR, 1.7; 95% CI, 1.1-2.7), and longer travel time to clinic (>1 hour [OR, 1.7; 95% CI, 1.2-2.4], >2 hours (OR, 1.8; 95% CI, 1.2-2.9] each vs <30 minutes). There was no association with race, ethnicity, birth country, gender, parent education, household income, insurance type, health literacy, and health system distrust. CONCLUSIONS: Consistent with prior literature, diagnostic delay is longer for CD than UC. Reassuringly, time to diagnosis is equitable across racioethnic groups. New models of diagnostic care are needed for communities affected by longer travel times.

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.

HLA DQA1*05 and risk of anti-TNF treatment failure and anti-drug antibody development in children with Crohn's Disease: HLA DQA1*05 and Pediatric Crohn's Disease.

OBJECTIVES: HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. METHODS: We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs. combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. RESULTS: A trend towards increased treatment failure among HLA DQA1*05 positive participants was not significant (HR 1.58, 95% CI 0.95-2.62; p=0.08). After stratification by HLA DQA1*05 and by methotrexate vs. placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05 positive patients on placebo (HR 0.31, 95% CI 0.13-0.70; p=0.005).A trend toward increased ADA development among HLA DQA1*05 positive participants was not significant (odds ratio [OR] 1.96, 95% CI 0.90-4.31, p=0.09). After further stratification, HLA DQA1*05 negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05 positive patients on placebo (OR 0.12, 95% CI 0.03-0.55; p=0.008). CONCLUSIONS: In a randomized trial of children with CD initiating anti-TNF, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

Posttransplant inflammatory bowel disease after successful solid organ transplantation: Not out of the woods yet.

OBJECTIVES: Gastrointestinal symptoms can occur following pediatric solid organ transplantation (SOT), and a subset of children will develop chronic inflammatory bowel disease (IBD) posttransplant. The goal of this study was to characterize patients who developed IBD following SOT, their treatment modalities, and clinical course. METHODS: A retrospective review was performed of electronic medical records of patients 0-18 years of age who underwent heart, kidney, liver, or intestinal transplantation at our center from January 2009 to April 2019. Patients who developed IBD were included in the final analysis. Demographics, symptoms, and clinical information were recorded. Endoscopic and histologic data and initial and current medications were noted for each patient. Outcomes of interest included phenotype at the time of IBD diagnosis, surgical interventions for IBD, and clinical trajectory at last median follow-up. RESULTS: Eight patients with IBD after heart (n = 3, 37.5%), kidney (n = 2, 25.0%), liver (n = 1, 12.5%), intestinal (n = 1, 12.5%), or multivisceral (heart and kidney, n = 1, 12.5%) transplants were included. Before IBD diagnosis, most patients developed diarrhea (n = 5, 62.5%) and abdominal pain (n = 5, 62.5%). Abnormal endoscopic findings were most common in the colon. Patients were started on medications including 5-aminosalicylates, steroids, and azathioprine. Two patients required biologic therapy and were receiving vedolizumab at last follow-up. Some patients required adjustment of immune suppression. CONCLUSIONS: Posttransplant IBD can occur following SOT. Patients exhibit inflammatory, nonstricturing disease though one patient experienced fistulizing disease. Complications are uncommon and many patients enter remission with 5-aminosalicylates alone, though some require adjustment in primary immune suppression.

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.

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.

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.

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.

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.

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.

Following Through: The Impact of Culinary Medicine on Mediterranean Diet Uptake in Inflammatory Bowel Disease.

BACKGROUND: The Mediterranean diet (MD) is recommended for all patients with inflammatory bowel disease (IBD) unless there is a specific contraindication. Culinary medicine has emerged as a method for improving dietary education. Patients and caregivers are often invested in making dietary changes to improve disease control. Here, we examine the dietary preferences of a group of young people with IBD and apply culinary medicine techniques with an in-person MD-focused cooking class. METHODS: A survey evaluating dietary attitudes was sent to an IBD email listserv at our tertiary care center (n = 779). A validated questionnaire, the Mediterranean Diet Quality Index for Children and Adolescents was used to assess MD adherence. IBD dietitians customized 2 in-person MD-focused cooking classes, one for children 6 to 12 years of age (arm 1) and one for adolescents 13 to 17 years of age (arm 2). Baseline, 1-month follow-up, and 3-month follow-up surveys were completed. RESULTS: There were 112 survey responses. Participants were 67.0% male with diagnosis of Crohn's disease (50.0%), ulcerative colitis (42.0%), or IBD unclassified (8.0%). Most were managed on advanced therapies (82.0%). Most reported making decisions about diet (82.0%) in order to help with IBD, had met with a dietitian (69.0%), and were interested in learning more about the MD (55.3%). MD scores were primarily in the average (49.5%) and poor (41.1%) diet categories. Only those eating together as a family 3 or more times per week or those who had met with a dietitian scored in the optimal diet category. The median MD score at baseline was 4.5, increasing to 6.0 at 1 month and 7.0 at 3 months postintervention. Almost all (90%) would recommend cooking classes to others. Common barriers to MD uptake included lack of knowledge about which foods to prepare, concern about taste, and time to prepare food. CONCLUSIONS: This study showcases high patient and caregiver interest in dietary management of IBD and demonstrates efficacy of education via application of culinary medicine. Classes were well received by families and MD adherence scores increased postintervention. As patients with IBD and their families are often motivated to incorporate dietary therapy into their care, this work highlights the role of culinary medicine and value of future study.

As the Mediterranean diet is now recommended for all patients with inflammatory bowel disease, we have shown high interest in dietary therapy and applied culinary medicine techniques as a valuable tool for increasing diet uptake in an effort to improve outcomes.

Durable Immune Response and Long-term Efficacy of COVID-19 Vaccination in Children With Inflammatory Bowel Disease.

BACKGROUND: Children with inflammatory bowel disease (IBD) may have diminished serologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and increased risk for subsequent severe coronavirus disease 2019 (COVID-19) infection. We sought to describe outcomes among those who developed SARS-CoV-2 infection following vaccination, characterize SARS-CoV-2 antibodies 1 year post-vaccination, and identify factors associated with durable serologic response. METHODS: We recruited children with IBD who received ≥2 doses of SARS-CoV-2 vaccine and prospectively collected data on (1) demographics, IBD characteristics, and therapy and (2) SARS-CoV-2 vaccination, testing, and infection symptoms. Serum was obtained for measurement of anti-receptor-binding domain IgG antibodies following a 2-part immunization at 12 and 52 weeks. RESULTS: We enrolled 298 participants (mean age 11.9 ±â€…3.82, 50% female, 67% Crohn's disease). Symptomatic COVID-19 infection after vaccination occurred in half of the participants, although only 2 (1%) required hospitalization. Anti-tumor necrosis factor alpha (TNF-α) was associated with higher likelihood of symptomatic COVID-19 infection, with an adjusted hazard ratio of 2.7 (95% CI, 1.5-5.0; P = .001). Nearly all participants (99%) had detectable antibody at Week 52. Children aged 1-5 years had lower 52-week antibody level compared to older children (P = .04), as did those on anti-TNF-α therapy (P = .007) and those who received only 2 vaccine doses prior to Week 52 (P < .001). CONCLUSIONS: SARS-CoV-2 vaccination provides lasting serologic response and protection against severe COVID-19 for most children with IBD, despite the use of lower vaccine doses in younger children and wide-ranging classes of immunosuppressive therapies.

We demonstrate high rates of durable antibody response and low rates of coronavirus disease 2019-related hospitalization 1 year following severe acute respiratory syndrome coronavirus 2 vaccination in children with inflammatory bowel disease. Anti-tumor necrosis factor alpha therapy, young age, and fewer vaccine doses were associated with lower 52-week antibody level.

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

BACKGROUND: Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). METHODS: We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. RESULTS: Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 µg/mL [P = .49]; adalimumab: 11.1 vs 10.5 µg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 µg/mL [P < .01]; adalimumab: 9.1 vs 12.3 µg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). CONCLUSIONS: LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

For children with Crohn's disease treated with biologic medications, with and without low-dose methotrexate, the role of drug levels on treatment failure in a recent prospective trial is unclear. These data suggest patients on infliximab with therapeutic drug levels are more likely to continue any therapy, and the effect on patients treated with adalimumab requires more investigation.

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.

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.