Tofacitinib in Pediatric Ulcerative Colitis: A Retrospective Multicenter Experience.

BACKGROUND: Tofacitinib has recently been approved for treatment of moderate-to-severe ulcerative colitis (UC) in adults, yet pediatric data are limited. This international multicenter study describes the effectiveness and safety of tofacitinib in pediatric UC. METHODS: This is a retrospective review of children diagnosed with UC treated with tofacitinib from 16 pediatric centers internationally. The primary outcome was week 8 corticosteroid-free clinical remission (Pediatric Ulcerative Colitis Activity Index <10). Secondary outcomes were clinical response (≥20-point decrease in Pediatric Ulcerative Colitis Activity Index) at week 8, corticosteroid-free clinical remission at week 24, and colectomy rate and adverse safety events through to last follow-up. The primary outcome was calculated by the intention-to-treat principle. RESULTS: We included 101 children with a mean age at diagnosis of 12.8 ±â€…2.8 years and a median disease duration of 20 months (interquartile range [IQR], 10-39 months). All had treatment failure with at least 1 biologic agent, and 36 (36%) had treatment failure with 3 agents. Median follow-up was 24 weeks (IQR, 16-54 weeks). Sixteen (16%) children achieved corticosteroid-free clinical remission at week 8, and an additional 30 (30%) demonstrated clinical response. Twenty (23%) of 88 children achieved corticosteroid-free clinical remission at week 24. A total of 25 (25%) children underwent colectomy by median 86 days (IQR, 36-130 days). No serious drug-related adverse events were reported; there was 1 case of herpes zoster and 2 cases of minor blood test perturbations. CONCLUSIONS: In this largest real-life pediatric cohort to date, tofacitinib was effective in at least 16% of patients with highly refractory UC by week 8. Adverse events were minor and largely consistent with adult data.

Tofacitinib, widely reported in adult ulcerative colitis, has very limited pediatric data. This international collaboration is the largest pediatric study on the efficacy and safety of tofacitinib to date, providing important supportive data to clinicians and regulators.

Human milk oligosaccharide composition is affected by season and parity and associates with infant gut microbiota in a birth mode dependent manner in a Finnish birth cohort.

BACKGROUND: Human milk oligosaccharides (HMOs), their determinants, infant gut microbiota and health are under extensive research; however, seldom jointly addressed. Leveraging data from the HELMi birth cohort, we investigated them collectively, considering maternal and infant secretor status. METHODS: HMO composition in breastmilk collected 3 months postpartum (n = 350 mothers) was profiled using high-performance liquid chromatography. Infant gut microbiota taxonomic and functional development was studied at 3, 6, and 12 months (n = 823 stool samples) via shotgun metagenomic sequencing, focusing on HMO metabolism via glycoside hydrolase (GH) analysis. Maternal and infant secretor statuses were identified through phenotyping and genotyping, respectively. Child health, emphasizing allergies and antibiotics as proxies for infectious diseases, was recorded until 2 years. FINDINGS: Mother's parity, irritable bowel syndrome, gestational diabetes, and season of milk collection associated with HMO composition. Neither maternal nor infant secretor status associated with infant gut microbiota, except for a few taxa linked to individual HMOs. Analysis stratified for birth mode revealed distinct patterns between the infant gut microbiota and HMOs. Child health parameters were not associated to infant or maternal secretor status. INTERPRETATION: This comprehensive exploration unveils intricate links between secretor genotype, maternal factors, HMO composition, infant microbiota, and child health. Understanding these nuanced relationships is paramount for refining strategies to optimize early life nutrition and its enduring impact on long-term health. FUNDING: Sweet Crosstalk EU H2020 MSCA ITN, Academy of Finland, Mary and Georg C. Ehrnrooth Foundation, Päivikki and Sakari Sohlberg Foundation, and Tekes.

Changes in health-related quality of life during transition to adult healthcare: an international prospective cohort study.

OBJECTIVE: To study changes in health-related quality of life (HRQoL) in adolescents and young adults (AYAs) with chronic medical conditions across the transfer to adult healthcare and associations of HRQoL with transition readiness and experience of care. METHODS: Participants in this international (Finland, Australia) prospective cohort study were recruited in the year prior to transfer to adult health services and studied 12 months later. In addition to two HRQoL scales (Pediatric Quality of Life inventory (PedsQL), 16D), the Am I ON TRAC for Adult Care Questionnaire and Adolescent Friendly Hospital Survey measured transition readiness and experience of care and categorised by quartile. Data were compared before and after transfer to adult healthcare. RESULTS: In total, 512 AYAs completed the first survey (0-12 months before transfer of care) and 336 AYAs completed it 1 year later (retention rate 66%, mean ages 17.8 and 18.9 years, respectively). Mean total PedsQL scores (76.5 vs 78.3) showed no significant change, although the social and educational subdomains improved after transfer of care. The mean single-index 16D score remained the same, but in Finland, distress increased and the ability to interact with friends decreased after transfer. AYAs within the best quartiles of experience of care and transition readiness had better HRQoL than AYAs within the worst quartiles. CONCLUSIONS: Overall HRQoL of AYAs remained unchanged across the transfer to adult healthcare. Recognising and supporting AYAs with unsatisfactory experience of care and poor transition readiness could improve overall HRQoL during the transition process. TRIAL REGISTRATION NUMBER: NCT04631965.

Bowel function in a prospective cohort of 1052 healthy term infants up to 4 months of age.

The purpose of this study is to describe the defecation pattern of healthy infants up to 17 weeks of age. We included 1052 healthy term infants from the prospective HELMi cohort (NCT03996304). Parents filled in recurring online questionnaires on feeding, gastrointestinal function, and crying weekly for the first 17 weeks of life. Defecation frequency was highest at the age of 3 weeks (a median of 4 times/day, interquartile range (IQR) 2.9-5). At each time point, the median defecation frequency of breastfed infants was higher than that of infants receiving formula (e.g., at week 17 a median of 2 times/day, IQR 0.9-3.6, and a median of 1.1, IQR 0.6-1.4, respectively). The dominant color of the stool was most often yellow or light brown. Nearly black stools were reported in the first week of life in 3.4%. Nearly half (47.4%) of the infants had green stool color dominating for at least 1 week, with comparable frequency among breastfed (47.7%) and formula-fed (45.2%) infants. Green stools were associated with a higher defecation frequency (linear mixed-effect model p < 0.0001). Occasional blood in stool was reported in 9.3% and recurrent blood in 5.2% of the infants with no difference in stool consistency. Hard stools were rare (≤ 1%).     Conclusion: This study enlightens the spectrum of defecation patterns in healthy term infants during the first 17 weeks of life. A better understanding of bowel function helps healthcare professionals distinguish normal from abnormal when addressing defecation, the color of stools, and the type of feeding. What is Known: • Breastfed infants have more frequent and more yellow-colored stools than formula-fed infants. • Stools with green color are often suggested by the parents or even by medical professionals to indicate disease or discomfort in early life. What is New: • Nearly half of the healthy term infants had green stool dominating for at least one week during the first 17 weeks and occasional blood was reported in almost 10% of the infants during this period. • Data on normal variation in bowel function and stool may serve primary health care professionals when educating the families and caretakers of infants.

Dominant stricture in paediatric-onset primary sclerosing cholangitis is associated with impaired prognosis in a long-term follow-up.

BACKGROUND AND OBJECTIVES: The impact of dominant stricture (DS) on the outcomes of paediatric-onset primary sclerosing cholangitis (PSC) is unknown. This study was aimed at investigating the impact of DS on the clinical course and prognosis of patients with paediatric-onset PSC. METHODS: Patients with paediatric-onset PSC diagnosed between January 1993 and May 2017 were identified from hospital records or our PSC registry. Data including clinical, laboratory, cholangiography, and cytology at diagnosis and during follow-up (until July 2023) were reviewed. We graphed the Kaplan-Meier failure function and fitted crude and multivariable Cox model to calculate hazard ratios (HR) and 95% confidence intervals (CI) for selected variables. In these analyses, DS was treated as a time-varying variable. RESULTS: We identified 68 patients (42 males) with paediatric-onset PSC (median age at diagnosis 15 years). The median follow-up was 13 years and the median age at the last follow-up was 27 years. In total, 35 (51%) had concomitant autoimmune hepatitis. DS was diagnosed in 33 patients (48%): in eight at the time of PSC diagnosis (12%) and in 25 (37%) by the end of follow-up. In patients with DS, two developed cirrhosis, seven were transplanted and one patient was operated for a biliary mass with low-grade dysplasia. In patients without a DS, two developed cirrhosis, and four were transplanted; one female was excluded from survival analysis because she already had cirrhosis at the time of PSC diagnosis. Cirrhosis or biliary dysplasia or needing liver transplantation for these indications were more frequent after the development of DS (10/33, adjusted HR 4.26, 95%CI: 1.26-14.4). No cholangiocarcinomas or deaths occurred during the follow-up. CONCLUSIONS: DS was present at diagnosis or developed during follow-up in about half of the patients with paediatric-onset PSC and was associated with impaired outcome.

Effectiveness and Safety of Ustekinumab in Pediatric Ulcerative Colitis: A Multi-center Retrospective Study from the Pediatric IBD Porto Group of ESPGHAN.

BACKGROUND AND OBJECTIVES: Current data on ustekinumab therapy in children with ulcerative colitis (UC) or unclassified inflammatory bowel disease (IBDU) are limited. We aimed to evaluate the effectiveness and safety of ustekinumab in pediatric UC and IBDU. METHODS: This multicenter retrospective study included 16 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. Children with UC or IBDU treated with ustekinumab were enrolled. Demographic, clinical, laboratory, endoscopic, and imaging data as well as adverse events were recorded. Analyses were all based on the intention-to-treat principle. RESULTS: Fifty-eight children (39 UC and 19 IBDU, median age 14.5 [IQR 11.5-16.5] years) were included. All had failed biologic therapies, and 38 (66%) had failed two or more biologics. Corticosteroid-free clinical remission (CFR) was observed in 27 (47%), 33 (57%), and 37 (64%) children at 16, 26, and 52 weeks, respectively. Normalization of C-reactive protein and calprotectin < 150 µg/g were achieved in 60% and 52%, respectively, by 52 weeks. Endoscopic and radiologic remissions were reached in 8% and 23%, respectively. The main predictors of CFR were diagnosis of UC compared with IBDU (hazard ratio [HR] 2.2, 95% CI 1.03-4.85; p = 0.041) and no prior vedolizumab therapy (HR 2.1, 95% CI 1.11-4.27; p = 0.023). Ustekinumab serum levels were not associated with disease activity. Adverse events were recorded in six (10%) children, leading to discontinuation of the drug in three. CONCLUSION: Based on these findings, ustekinumab appears as an effective therapy for pediatric refractory UC and IBDU. The potential efficacy should be weighed against the risks of serious adverse events.

STEP-CD study: ustekinumab use in paediatric Crohn's disease-a multicentre retrospective study from paediatric IBD Porto group of ESPGHAN.

Ustekinumab is an effective therapy for adult Crohn's disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn's Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7-17.2) with a median follow-up of 7.4 months (IQR 5.6-11.8). Ninety-nine percent had received prior anti-TNF, 63% ≥ 2 anti-TNFα therapies and 22% vedolizumab. Baseline median wPCDAI was 39 (IQR 25-57.5) (71 (70%) patients with moderate-severe activity). Weeks 12 and 52 CS- and EEN-free remission were both 40.5%. Clinical response at week 6, iv induction route and older age at onset of ustekinumab treatment were predictive factors associated with clinical remission at week 12. Seven minor adverse events probably related to ustekinumab were reported. One patient died from an unrelated cause.  Conclusion: Our results suggest that ustekinumab is effective and safe in children with chronically active or refractory CD. What is Known: • Ustekinumab is an effective therapy for adult moderate to severe Crohn's disease (CD). • Off-label use of ustekinumab in children is increasing especially in anti-TNF refractory CD. What is New: • Is the largest cohort of real-world use of ustekinumab in paediatric CD to date. • Clinical response at week 6, iv induction and older age at onset of ustekinumab were predictive factors associated with clinical response at week 12.

The need for surgery in pediatric patients with inflammatory bowel disease treated with biologicals.

PURPOSE: Inflammatory bowel disease (IBD) in childhood often presents with a more extensive and more aggressive disease course than adult-onset disease. We aimed to evaluate if biological treatment started in childhood decreases the need for intestinal surgery over time. METHODS: This was a retrospective, single-center, cohort study. All pediatric patients with IBD initiated to biological therapy at the Children's Hospital, were included in the study and followed up to the first surgical procedure or re-operation in their adulthood or until 31.12.2021 when ≥ 18 of age. Data were collected from the pediatric registry of IBD patients with biologicals and medical charts. RESULTS: A total of 207 pediatric IBD patients were identified [150 with Crohn´s disease (CD), 31 with ulcerative colitis (UC), 26 with IBD unclassified (IBDU)] of which 32.9% (n = 68; CD 49, UC 13, IBDU 6) underwent intestinal surgery. At the end of a median follow-up of 9.0 years (range 2.0-25.9), patients reached a median age of 21.4 years (range 18-36). Patients who had intestinal surgery in childhood were more likely to have IBD-related surgery also in early adulthood. The duration of the disease at induction of the first biological treatment emerged as the only risk factor, with a longer duration in the surgical group than in patients with no surgery. CONCLUSION: Despite initiation of biological treatment, the risk of intestinal surgery remains high in pediatric IBD patients and often the need for surgery emerges after the transition to adult IBD clinics.

Psychological well-being of children and adolescents with inflammatory bowel disease.

OBJECTIVES: Prior studies on the psychological well-being in pediatric inflammatory bowel disease (PIBD) have reported controversial results. Our aim was to compare the psychological well-being and lifestyle factors in patients with PIBD and their controls and to assess the role of contributing disease characteristics. METHODS: This cross-sectional study included 60 PIBD patients aged 6-17 years (26 with Crohn's disease [CD], 34 with ulcerative colitis [UC] or unclassified colitis [IBD-U]) from two university hospitals in Finland, and their age- and sex-matched healthy controls. Psychological well-being was assessed with three measures: a questionnaire on overall psychological well-being (PSWB) and for adolescents also Beck Depression Inventory (BDI Ia) and Perceived Stress Scale (PSS). In addition to disease characteristics and pain, we assessed physical activity, sleep, screen time, and social well-being. RESULTS: Controls were more likely of stressing more (odds ratio [OR] = 3.67, 95% confidence interval [95% CI] 95% CI = 1.02-13.14), but other measures of psychological well-being did not differ statistically significantly between patients and controls. In CD, a clinically more active disease associated with inferior psychological well-being in adolescents (BDI [ρ = 0.63, p = 0.021], PSS [ρ = 0.70, p = 0.008], PSWB [ρ = 0.56, p = 0.049]). Longer time from diagnosis correlated with better psychological well-being on BDI (ρ = -0.39, p = 0.024) and PSS (ρ = -0.38, p = 0.034). Lifestyle was more sedentary in PIBD (less physical activity in children OR = 0.82, 95% CI = 0.68-0.99 and more screen time in adolescents OR = 1.18, 95% CI = 1.00-1.40). CONCLUSION: Although the clinical features of PIBD are potentially a burden for psychological well-being, many young patients cope well with their disease. Individual variation in well-being is remarkable, making supportive measures challenging.

Health-related quality of life and self-reported health status in adolescents with chronic health conditions before transfer of care to adult health care: an international cohort study.

BACKGROUND: Heath-related quality of life (HRQoL) is lower in adolescents with chronic health conditions compared to healthy peers. While there is evidence of some differences according to the underlying condition and gender, differences by measure and country are poorly understood. In this study we focus on the differences in HRQoL in adolescents with various chronic medical conditions in the year before transfer of care to adult health services. We also study the associations of two different HRQoL measurements to each other and to self-reported health. METHODS: We recruited 538 adolescents from New Children`s Hospital, Helsinki, Finland, and the Royal Children`s Hospital, Melbourne, Australia in 2017-2020. We used two validated HRQoL measurement instruments, Pediatric Quality of Life Inventory (PedsQL) and 16D, and a visual analog scale (VAS) for self-reported health status. RESULTS: In total, 512 adolescents (50.4% female, mean age 17.8 [SD 1.2] years), completed the survey measures. Higher HRQoL was reported in males than females in both countries (PedsQL 79.4 vs. 74.1; 16D 0.888 vs. 0.846), and in adolescents from Finland than Australia (80.6 vs. 72.2 and 0.905 vs. 0.825, p < 0.001 for all). Adolescents with diabetes, rheumatological, nephrological conditions and/or organ transplants had higher HRQoL than adolescents with neurological conditions or other disease syndromes (p < 0.001). PedsQL and 16D scores showed a strong correlation to each other (Spearman correlation coefficient r = 0.81). Using the 7-point VAS (1-7), 52% (248 of 479) considered their health status to be good (6-7) and 10% (48 of 479) rated it poor (1-2). Better self-reported health was associated with higher HRQoL. CONCLUSIONS: The HRQoL of transition aged adolescents varies between genders, diagnostic groups, and countries of residence. The association between self-reported health and HRQoL suggests that brief assessment using the VAS could identify adolescents who may benefit from in-depth HRQoL evaluation. TRIAL REGISTRATION: Trial registration name The Bridge and registration number NCT04631965 ( https://clinicaltrials.gov/ct2/show/NCT04631965 ).

Updates on the management of inflammatory bowel disease from periconception to pregnancy and lactation.

Inflammatory bowel disease (IBD) affects reproductive planning due to psychological effects and mechanical problems related to surgery. Children of people with IBD have an increased risk of about 10% if one parent has IBD and up to 33% if both parents have IBD. The fertility of people with IBD is similar to the general population, but fertility might be reduced in individuals with active IBD, ileal pouch-anal anastomosis, or perianal Crohn's disease. Flaring disease during pregnancy increases complications, such as preterm birth. Thus, disease management with appropriate medications can optimise outcomes. As most medications have minimal fetal risks, people with IBD should be informed about the risks of stopping medications and the importance of maintaining remission. A period of disease remission is advisable before pregnancy and could reduce the risks for both the pregnant person and the fetus. Flexible endoscopy, intestinal ultrasound, and gadolinium-free magnetic resonance enterography are safe during pregnancy. We provide state-of-the-art knowledge on the basis of the latest evidence to ensure successful pregnancy outcomes in controlled IBD.

Dual Biologic or Small Molecule Therapy in Refractory Pediatric Inflammatory Bowel Disease (DOUBLE-PIBD): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN.

BACKGROUND: Current data on dual biologic therapy in children are limited. This multicenter study aimed to evaluate the effectiveness and safety of dual therapy in pediatric patients with inflammatory bowel disease (IBD). METHODS: A retrospective study from 14 centers affiliated with the Pediatric IBD Interest and Porto Groups of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. Included were children with IBD who underwent combinations of biologic agents or biologic and small molecule therapy for at least 3 months. Demographic, clinical, laboratory, endoscopic, and imaging data were collected. Adverse events were recorded. RESULTS: Sixty-two children (35 Crohn's disease, 27 ulcerative colitis; median age 15.5 [interquartile range, 13.1-16.8] years) were included. They had all failed previous biologic therapies, and 47 (76%) failed at least 2 biologic agents. The dual therapy included an anti-tumor necrosis factor agent and vedolizumab in 30 children (48%), anti-tumor necrosis factor and ustekinumab in 21 (34%) children, vedolizumab and ustekinumab in 8 (13%) children, and tofacitinib with a biologic in 3 (5%) children. Clinical remission was observed in 21 (35%), 30 (50%), and 38 (63%) children at 3, 6, and 12 months, respectively. Normalization of C-reactive protein and decrease in fecal calprotectin to <250 µg/g were achieved in 75% and 64%, respectively, at 12 months of follow-up. Twenty-nine (47%) children sustained adverse events, 8 of which were regarded as serious and led to discontinuation of therapy in 6. CONCLUSIONS: Dual biologic therapy may be effective in children with refractory IBD. The potential efficacy should be weighed against the risk of serious adverse events.

This multicenter study describes 62 children with refractory inflammatory bowel disease who received dual biologic therapy. Clinical remission was observed in 21 (35%), 30 (50%), and 38 (63%) children at 3, 6, and 12 months, respectively. Several serious adverse events were reported.

Drug levels of VEDOLIZUMAB in patients with pediatric-onset inflammatory bowel disease in a real-life setting.

Vedolizumab (VDZ) is used off-label in pediatric inflammatory bowel disease (PIBD). There are less data on drug levels to achieve and maintain remission in children. We aimed to study vedolizumab (VDZ) trough levels in a pediatric population in a real-life setting. We traced 50 patients with PIBD receiving VDZ treatment at our hospital, reviewed their treatment protocol, trough levels, and antidrug antibodies, and compared those to fecal calprotectin (FC) levels and achievement of corticosteroid-free maintenance therapy (CF). VDZ trough level was available from 198 samples during a median follow- up of 12.6 months. Proceeding to maintenance therapy was associated with a decline in FC but not with VDZ trough levels that were comparable between patients with FC < 100 µg/g (remission), 100-1000 µg/g, or > 1000 µg/g at 3 months (mean levels of 36.8, 28.6, and 27 µg/mL, respectively p = 0.188). At 3 months, patients achieving CF (41%) and those on corticosteroids had comparable VDZ trough levels (33 vs. 27.5 µg/mL, respectively). At 6 months, the trough level was similar in groups with FC < 100 µg/g or FC > 1000 µg/g (31.5 and 27.6 µg/mL, p = 0.859). Treatment intensification did not improve the achieved CF at 12 months. None developed drug antibodies nor discontinued the therapy for an adverse event.   Conclusion: VDZ was a well-tolerated and safe biologic treatment. A positive response on gut inflammation after induction predicted proceeding to maintenance therapy whereas trough levels did not. A VDZ trough level associated with clinical remission or continuing with VDZ treatment could not be determined. What is Known: • In pediatric inflammatory bowel disease, vedolizumab is still in off-label use. • The results on the relationship between drug levels of vedolizumab and clinical remission in pediatric patients are contradictory. What is New: • This real-life setting in pediatric-onset inflammatory bowel disease showed no benefit of therapy enhancement during a median follow-up of one year. • Trough levels of vedolizumab were not associated with therapy outcomes.

Machine-learning analysis of cross-study samples according to the gut microbiome in 12 infant cohorts.

IMPORTANCE: There are challenges in merging microbiome data from diverse research groups due to the intricate and multifaceted nature of such data. To address this, we utilized a combination of machine-learning (ML) models to analyze 16S sequencing data from a substantial set of gut microbiome samples, sourced from 12 distinct infant cohorts that were gathered prospectively. Our initial focus was on the mode of delivery due to its prior association with changes in infant gut microbiomes. Through ML analysis, we demonstrated the effective merging and comparison of various gut microbiome data sets, facilitating the identification of robust microbiome biomarkers applicable across varied study populations.

De Novo Crohn's Disease in Children With Ulcerative Colitis Undergoing Ileal Pouch-Anal Anastomosis: A Multicenter, Retrospective Study From the Pediatric IBD Porto Group of the ESPGHAN.

BACKGROUND AND AIMS: We sought to define the prevalence and to characterize possible predictive factors of Crohn's disease (CD) occurring in children with ulcerative colitis (UC) after ileal pouch-anal anastomosis (IPAA). METHODS: This was a multicenter, retrospective study including 15 centers of the Porto IBD group of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition. Children with a confirmed diagnosis of UC undergoing colectomy with IPAA and a minimal follow up of 6 months were identified. The following data were collected: demographic data; endoscopic and histologic data; disease activity; laboratory exams; therapeutic history; indication for surgery, type, and timing; and IPAA functional outcomes and complications. In de novo CD cases, time of diagnosis, phenotype, location, and therapies were gathered. RESULTS: We identified 111 UC children undergoing IPAA from January 2008 to June 2018 (median age at colectomy: 13 years; age range: 1-18 years; female/male: 59/52). The median time from diagnosis to colectomy was 16 (range, 0-202) months. At the last follow-up, 40 (36%) of 111 children developed pouchitis. The criteria for de novo CD were met in 19(17.1%) of 111 children with a 25-month median (range, 3-61 months). At last follow-up, 12 (63.1%) of 19 were treated with biologics and in 5 (26.3%) of 19 children, the pouch was replaced with definitive ileostomy. In a multivariable logistic regression model, decreased preoperative body mass index z scores (odds ratio, 2.2; 95% confidence interval, 1.1-4.4; P = .01) resulted as the only variable associated with CD development. CONCLUSIONS: Children with UC undergoing IPAA carry a high risk of developing subsequent CD. De novo CD cases showed decreased preoperative body mass index z scores, identifying a poor nutritional status as a possible predictive factor.

This is the largest European study describing the prevalence of Crohn's disease (CD) development in children with ulcerative colitis undergoing subtotal colectomy with ileal pouch­anal anastomosis. Children affected by ulcerative colitis carry a higher risk when compared with adults to develop de novo CD after surgery. On the other hand, the multivariate analysis identified decreased values of preoperative body mass index z scores as a possible predictor of new-onset CD.

Infant liver biochemistry is different than current laboratory accepted norms.

The purpose is to study liver biochemistry in a well-defined cohort of term infants. The methods include healthy term infants (n = 619) provided blood samples at 3 and 6 months of age when participating to the DIABIMMUNE study. The infants were followed up at clinical study visits 3, 6, 12, 18, 24, and 36 months the participation rate being 88.6% at the end of follow-up, while none disclosed any signs of a liver disease. The serum levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin (BIL), and conjugated bilirubin (BIL-conj) were determined using Siemens Atellica CH 930 analyzers. The results are at 3 months of age, the upper 90% CI for ALT, AST, ALP, GGT, BIL, and BIL-conj were higher than the current upper reference limits in our accredited hospital laboratory. At 6 months, the upper 90% CIs for ALT had declined but was still higher than the cut-offs for a raised value. The upper 90% CI for AST remained as high as at 3 months, whereas ALP, BIL-conj, and GGT had decreased close to the current cut-offs. The type of feeding was associated with the levels of liver biochemistry. Exclusively or partially breastfed infants showed higher ALT, AST, BIL, and BIL-conj values at 3 months than formula-fed. Breastfed infants had higher AST, Bil, and Bil-conj values also at 6 months.  Conclusion: We encourage setting appropriate reference ranges for liver biochemistry for the first year of life and to note the type of feeding. What is Known: • Healthy infants may show higher values of liver biochemistry during their first year of life than in later life. • It has been speculated that type of feeding may play a role in liver biochemistry levels among infants. What is New: • In a cohort of healthy infants, several analytes of liver biochemistry were higher than the currently used upper reference limits at 3 and 6 months of age, and exclusively or partially breastfed infants showed higher values than formula-fed. • The findings address the importance of setting appropriate reference ranges for liver biochemistry for the first year of life.

An extended catalog of integrated prophages in the infant and adult fecal microbiome shows high prevalence of lysogeny.

Background and aims: The acquisition and gradual maturation of gut microbial communities during early childhood is central to an individual's healthy development. Bacteriophages have the potential to shape the gut bacterial communities. However, the complex ecological interactions between phages and their bacterial host are still poorly characterized. In this study, we investigated the abundance and diversity of integrated prophages in infant and adult gut bacteria by detecting integrated prophages in metagenome assembled genomes (MAGs) of commensal bacteria. Methods: Our study included 88 infants sampled at 3 weeks, 3 months, 6 months, and 12 months (n = 323 total samples), and their parents around delivery time (n = 138 total samples). Fecal DNA was extracted and characterized by using shotgun metagenomic sequencing, and a collection of prokaryotic MAGs was generated. The MAG collection was screened for the presence of integrated bacteriophage sequences, allowing their taxonomic and functional characterization. Results: A large collection of 6,186 MAGs from infant and adult gut microbiota was obtained and screened for integrated prophages, allowing the identification of 7,165 prophage sequences longer than 10 kb. Strikingly, more than 70% of the near-complete MAGs were identified as lysogens. The prevalence of prophages in MAGs varied across bacterial families, with a lower prevalence observed among Coriobacteriaceae, Eggerthellaceae, Veillonellaceae and Burkholderiaceae, while a very high prevalence of lysogen MAGs were observed in Oscillospiraceae, Enterococcaceae, and Enterobacteriaceae. Interestingly for several bacterial families such as Bifidobacteriaceae and Bacteroidaceae, the prevalence of prophages in MAGs was higher in early infant time point (3 weeks and 3 months) than in later sampling points (6 and 12 months) and in adults. The prophage sequences were clustered into 5,616 species-like vOTUs, 77% of which were novel. Finally, we explored the functional repertoire of the potential auxiliary metabolic genes carried by these prophages, encoding functions involved in carbohydrate metabolism and degradation, amino acid metabolism and carbon metabolism. Conclusion: Our study provides an enhanced understanding of the diversity and prevalence of lysogens in infant and adult gut microbiota and suggests a complex interplay between prophages and their bacterial hosts.

Outcome of Very Early Onset Inflammatory Bowel Disease Associated With Primary Sclerosing Cholangitis: A Multicenter Study From the Pediatric IBD Porto Group of ESPGHAN.

BACKGROUND: Whether primary sclerosing cholangitis related to inflammatory bowel disease (PSC-IBD) diagnosed before 6 years (ie, VEO-IBD) has a distinct phenotype and disease course is uninvestigated. We aimed to analyze the characteristics and natural history of VEO-PSC-IBD, compared with early and adolescent-onset PSC-IBD. METHODS: This is a multicenter, retrospective, case-control study from 15 centers affiliated with the Porto and Interest IBD group of ESPGHAN. Demographic, clinical, laboratory, endoscopic, and imaging data were collected at baseline and every 6 months. Inflammatory bowel disease-related (clinical remission, need for systemic steroids and biologics, and surgery) and PSC-related (biliary and portal hypertensive complications, need for treatment escalation and liver transplantation, cholangiocarcinoma, or death) outcomes were compared between the 2 groups. RESULTS: Sixty-nine children were included, with a median follow-up of 3.63 years (interquartile range, 1-11): 28 with VEO-PSC-IBD (23 UC [82%], 2 IBD-U [7%] and 3 [11%] CD), and 41 with PSC-IBD (37 UC [90%], 3 IBDU [7.5%] and 1 [2.5%] CD). Most patients with UC presented with pancolitis (92% in VEO-PSC-UC vs 85% in PSC-UC, P = .2). A higher number of patients with VEO-PSC-IBD were diagnosed with PSC/autoimmune hepatitis overlap syndrome than older children (24 [92%] vs 27 [67.5%] PSC-IBD, P = .03), whereas no other differences were found for PSC-related variables. Time to biliary strictures and infective cholangitis was lower in the VEO-PSC-IBD group (P = .01 and P = .04, respectively), while no difference was found for other outcomes. No cases of cholangiocarcinoma were reported. CONCLUSIONS: Primary sclerosing cholangitis related to inflammatory bowel disease has similar baseline characteristics whether diagnosed as VEO-IBD or thereafter. A milder disease course in terms of biliary complications characterizes VEO-PSC-IBD.

Very early onset primary sclerosing cholangitis associated with IBD (VEO-PSC-IBD) often presents with autoimmune features and shows a milder PSC disease course than later-onset disease. These findings highlight the significance of studying the distinctive genetic and pathophysiological factors specific to VEO disease.

Perinatal and Other Risk Factors for Common Infections in Infancy: A Prospective Cohort Study.

OBJECTIVE: Limited data from prospective cohort studies in high-income countries are available on the perinatal risk factors for common infections in children. Our hypothesis was that perinatal factors may be risk factors for infectious episodes during the first year of life. METHODS: In this prospective Health and Early Life Microbiota birth cohort study of full-term infants (n = 1052) born in 2016-2018, the number and duration of infection episodes were collected online at weekly to monthly intervals. In a multivariate regression model, the main exposures were perinatal factors such as mode of delivery and intrapartum antibiotics. Environmental factors were additional exposures. The outcomes were the number and duration of infectious episodes in the first year of life. RESULTS: The mean number of infection episodes was 4.2 (2.9 SD). The mean duration of infection symptoms was 44 days (40 SD). Upper respiratory infections accounted for 83% of the episodes (3674/4455). Perinatal factors were not associated with the number nor the duration of infection episodes, but cesarean section was associated with an increased occurrence of urinary tract infections in infancy [adjusted odds ratio (aOR): 3.6; 95% confidence interval (CI): 1.13-11.1]. Of the additional exposures male sex (aOR: 1.1; 95% CI: 1.0-1.2) and the presence of siblings (aOR: 1.3; 95% CI: 1.2-1.4) were associated with the number of infection episodes. CONCLUSIONS: This prospective cohort study showed that perinatal factors, mode of delivery and intrapartum antibiotics were not associated with the risk of common infections in infancy, but cesarean delivery was associated with a risk of urinary tract infections.

Psychiatric disorders in paediatric-onset immune-mediated inflammatory diseases: a nationwide Danish study.

OBJECTIVES: To investigate the frequency of psychiatric disorders before and after onset of paediatric-onset immune-mediated inflammatory diseases (pIMID). STUDY DESIGN: In a nationwide study from 1996 to 2018, we investigated psychiatric disorders in patients with paediatric-onset inflammatory bowel diseases, autoimmune liver diseases and rheumatic diseases, using Danish national healthcare and population registers. Each case was matched with up to 10 controls from the background population. The cumulative incidence for psychiatric disorders prior to pIMID onset in patients was compared with controls. Cox proportional regression was used to estimate adjusted HRs (aHR) with a 95% CI between cases and controls after the index date. RESULTS: We included 11 208 cases (57% female) and 98 387 controls. The median age at disease onset was 12.5 years (IQR 8-15) and follow-up time 9.8 years (IQR 5-15). We found an association between psychiatric disorders before index date and a diagnosis of subsequent pIMID (OR 1.3, 95% CI 1.2 to 1.4). Notably, after index date, cases also had an increased risk (aHR 1.6, 95% CI 1.5 to 1.7) of psychiatric disorders compared with controls. This risk was increased for all groups of psychiatric disorders. Female patients had an increased risk of suicide attempt after index date (aHR 1.4, 95% CI 1.1 to 1.8). CONCLUSION: Patients with pIMID are at increased risk for a broad spectrum of psychiatric disorders both before and after onset of pIMID. The results support the need for awareness of psychiatric morbidity in this young patient group and the need for coordinated healthcare for those with comorbid states.