Outcome in pediatric celiac disease is independent of the diagnostic approach in patients with high antibody levels.

OBJECTIVES: European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines enable the diagnosis of celiac disease (CD) without biopsies in patients with immunoglobulin A (IgA)-antibodies against tissue transglutaminase (TGA-IgA) ≥ 10× the upper limit of normal (ULN) and positivity of endomysial antibodies in a second blood sample. Limited data exist comparing the biopsy versus the nonbiopsy diagnostic approach regarding long-term outcomes in CD patients. Our study aimed to investigate the influence of the diagnostic approach on adherence to gluten-free diet (GFD), serological remission (defined as normalization of TGA-IgA during follow-up (FU)) and clinical remission in CD patients with TGA-IgA ≥ 10× ULN. METHODS: Retrospective multicenter study. Patients with CD and TGA-IgA ≥ 10× ULN at diagnosis were included in the study. Patients with confirmed diagnosis by biopsy were compared to patients diagnosed by nonbiopsy approach using univariate analysis, Kaplan-Meier survival curve, and logistic regression models. RESULTS: A total of 282 CD patients (192 [68.1%] in the biopsy group; 90 [31.9%] in the nonbiopsy group) were analyzed. The median time to normalization of TGA-IgA was 16.5 months [interquartile range, IQR: 13, 28] in the biopsy and 15 months [IQR: 12, 26] in the nonbiopsy group; p = 0.14). Rates of normalized TGA-IgA at first to third-year FU were comparable between both groups. Adherence to GFD did not seem to be influenced by the diagnostic approach. CONCLUSIONS: The nonbiopsy approach is not inferior to the biopsy approach in terms of adherence to GFD and serological remission in patients with CD.

Drug-Related Adverse Events Necessitating Treatment Discontinuation in Pediatric Inflammatory Bowel Disease Patients.

OBJECTIVES: Inflammatory bowel disease (IBD) requires long-term drug therapy in most patients, posing a risk for adverse drug events with the need for discontinuation. In this study, we investigated adverse events (AE) necessitating drug discontinuation in pediatric and adolescent IBD patients. METHODS: We used data prospectively collected from IBD patients below the age of 18 enrolled in the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS), namely demographic variables, medical characteristics, drug treatments, and related AE. We analyzed the frequency, type, and risk factors for AE necessitating drug discontinuation. RESULTS: A total of 509 pediatric IBD patients fulfilled the inclusion criteria of which 262 (51.5%) were diagnosed with Crohn disease (CD), 206 (40.5%) with ulcerative colitis (UC), and 41 (8%) with IBD-unclassified (IBD-U). In total, 132 (25.9%) presented with at least 1 drug-related AE that required drug cessation. Immunomodulators [methotrexate 29/120 (24.2%), azathioprine 57/372 (15.3%)] followed by tumor necrosis factor (TNF)-alpha antagonists [adalimumab 8/72 (11.1%), infliximab 22/227 (9.7%)] accounted for the highest proportions of AE necessitating treatment discontinuation. Treatment schemes with at least 3 concomitant drugs significantly amplified the risk for development of drug-related AE [odds ratio = 2.50, 95% confidence interval (1.50-4.17)] in all pediatric IBD patients. CONCLUSIONS: Drug-related AE necessitating discontinuation are common in pediatric and adolescent IBD patients. Caution needs to be taken in the case of concomitant drug use.

Comparative study of preterm infants fed new and existing human milk fortifiers showed favourable markers of gastrointestinal status.

AIM: This study examined the influence of different human milk fortifiers on biomarkers of gastrointestinal immaturity and inflammation in preterm infants. METHODS: We report secondary outcomes from a controlled, double-blind, randomised, parallel group study conducted from 2011 to 2014 in neonatal intensive care units at 11 metropolitan hospitals in France, Belgium, Germany, Switzerland and Italy. Preterm infants born at up to 32 weeks or weighing up to 1500 g were randomised to a new powdered human milk fortifier (n = 77) or a control fortifier (n = 76) for a minimum of 21 days. We analysed faecal markers of gut inflammation, namely alpha-1 antitrypsin and calprotectin, and maturity, namely elastase-1. RESULTS: Faecal alpha-1 antitrypsin was slightly lower in the new than control fortifier group after 21 days of full enteral feeding, with a geometric mean and standard deviation of 1.52 ± 1.32 vs 1.82 ± 1.44 mg/g stools (P = .01). There was no significant difference in faecal calprotectin (median [Q1-Q3] of 296 [136-565] µg/g stools in both groups combined at study day 21). Faecal elastase-1 was lower in the new fortifier than control fortifier group (202.5 ± 1.6 vs 257.7 ± 1.5 µg/g stools, P = .016). CONCLUSION: Mean values for each parameter were within the ranges in healthy term infants, indicating favourable markers of gastrointestinal status in both groups. In addition, for faecal calprotectin, the relatively high concentration observed in preterm infants fed fortified human milk suggests that the threshold level for detecting necrotising enterocolitis should be revised.

Management of Juvenile Polyposis Syndrome in Children and Adolescents: A Position Paper From the ESPGHAN Polyposis Working Group.

The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Polyposis Working Group developed recommendations to assist clinicians and health care providers with appropriate management of patients with juvenile polyposis. This is the first juvenile polyposis Position Paper published by ESPGHAN with invited experts. Many of the published studies were descriptive and/or retrospective in nature, consequently after incorporating a modified version of the GRADE system many of the recommendations are based on expert opinion. This ESPGHAN Position Paper provides a guide for diagnosis, assessment, and management of juvenile polyposis syndrome in children and adolescents, and will be helpful in the appropriate management and timing of procedures in children and adolescents. The formation of international collaboration and consortia is proposed to monitor patients prospectively to advance our understanding of juvenile polyposis conditions.

The Use of 5-Aminosalicylic Acid in Children and Adolescents With Inflammatory Bowel Disease.

BACKGROUND: In ulcerative colitis (UC) 5-aminosalicylic acid (5-ASA) is recommended as primary therapy for mild to moderate disease. Topical 5-ASA has been proven especially effective. In Crohn's disease (CD) the evidence for a beneficial role of 5-ASA is weak. We investigated the use of topical and systemic 5-ASA therapy in children and adolescents with inflammatory bowel disease. MATERIALS AND METHODS: Data of patients younger than 18 years, registered between April 2008 and December 2015 in the Swiss Inflammatory Bowel Disease Cohort, were analyzed. RESULTS: Three hundred twenty pediatric inflammatory bowel disease patients were included; 189 with CD and 131 with UC. Over one third of UC patients [51 (39%)] received topical 5-ASA therapy and 43 (33%) received combination therapy during their disease course. UC patients with left-sided colitis or proctitis were more likely to receive topical or combination therapy as compared with patients with pancolitis (P<0.001 and <0.001, respectively). An increase in the use of topical 5-ASA therapy in UC patients was noted over time from 5% to 38%. Forty-seven percent of CD patients were treated with oral 5-ASA during their disease course. The usage was stable over time at approximately 15% to 20%. CONCLUSIONS: In recent years a very positive trend showing an increase in topical 5-ASA therapy in children and adolescents with UC has been observed. However topical therapy is still used with relative low frequency, especially in patients with a more extensive disease. Conversely, despite weak evidence supporting 5-ASA use in CD patients it has been frequently prescribed. Physicians should continue to encourage their UC patients to use topical therapy.

Nutrient intake of Swiss toddlers.

PURPOSE: During the first years of life, food preferences are shaped that might last throughout a person's entire life affecting his/her health in the long term. However, knowledge on early feeding habits is still limited for toddlers. Therefore, the goal of the present study was to: (1) assess toddlers' nutrient intake; (2) compare the findings to past studies as well as to national feeding recommendations and (3) identify major food sources for energy and macronutrients. METHODS: A food survey using a 4-day diary was conducted. The dietary software nut.s® was used to analyse the data. RESULTS: A cohort of 188 healthy toddlers (aged 1-3 years) was analysed. The energy intake of most toddlers was below the recommended daily intake (RDI) but in accordance with earlier studies. Protein intake was three- to fourfold higher than the RDI and reached the proposed upper limit of 15% of total energy intake. Fat intake was in accordance with the RDI, but the balance of saturated and unsaturated fatty acids should be improved. Carbohydrate intake met the RDI. For the micronutrients, iron and vitamin D intakes showed critical values. CONCLUSION: As in other European countries, the diet of Swiss toddlers in general seems adequate but does not meet all nutritional requirements. In particular, the quality of the fats and vitamin D supplementation should be improved. For proteins and iron, additional research is needed to gain more confidence in the recommendations.

Growth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized Trial.

OBJECTIVES: The aim of this study was to assess growth and nutritional biomarkers of preterm infants fed human milk (HM) supplemented with a new powdered HM fortifier (nHMF) or a control HM fortifier (cHMF). The nHMF provides similar energy content, 16% more protein (partially hydrolyzed whey), and higher micronutrient levels than the cHMF, along with medium-chain triglycerides and docosahexaenoic acid. METHODS: In this controlled, multicenter, double-blind study, a sample of preterm infants ≤32 weeks or ≤1500 g were randomized to receive nHMF (n = 77) or cHMF (n = 76) for a minimum of 21 days. Weight gain was evaluated for noninferiority (margin = -1 g/day) and superiority (margin = 0 g/day). Nutritional status and gut inflammation were assessed by blood, urine, and fecal biochemistries. Adverse events were monitored. RESULTS: Adjusted mean weight gain (analysis of covariance) was 2.3 g/day greater in nHMF versus cHMF; the lower limit of the 95% CI (0.4 g/day) exceeded both noninferiority (P < 0.001) and superiority margins (P = 0.01). Weight gain rate (unadjusted) was 18.3 (nHMF) and 16.8 g ·â€Škg ·â€Šday (cHMF) between study days 1 and 21 (D1-D21). Length and head circumference (HC) gains between D1 and D21 were not different. Adjusted weight-for-age z score at D21 and HC-for-age z score at week 40 corrected age were greater in nHMF versus cHMF (P = 0.013, P = 0.003 respectively). nHMF had higher serum blood urea nitrogen, pre-albumin, alkaline phosphatase, and calcium (all within normal ranges; all P ≤ 0.019) at D21 versus cHMF. Both HMFs were well tolerated with similar incidence of gastrointestinal adverse events. CONCLUSIONS: nHMF providing more protein and fat compared to a control fortifier is safe, well-tolerated, and improves the weight gain of preterm infants.

Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease: Prevalence, Presentation, and Anti-TNF Treatment.

BACKGROUND: There is a paucity of data on extraintestinal manifestations (EIM) and their treatment in pediatric patients with inflammatory bowel disease (IBD). METHODS: Since 2008, the Pediatric Swiss IBD Cohort Study has collected data on the pediatric IBD population in Switzerland. Data on 329 patients were analyzed retrospectively. RESULTS: A total of 55 patients (16.7%) experienced 1-4 EIM (39 Crohn disease, 12 ulcerative colitis, and 4 IBD-unclassified patients). At IBD onset, presence of EIM was more frequent than in the adult population (8.5% vs 5.0%, P = 0.014). EIM were more frequent in Crohn disease when compared to ulcerative colitis/IBD-unclassified (22.5% vs 10.3%, P = 0.003). The most prevalent EIM were peripheral arthritis (26/329, 7.9%) and aphthous stomatitis (24/329, 7.3%). Approximately 27.6% of all EIM appeared before IBD diagnosis. Median time between IBD diagnosis and occurrence of first EIM was 1 month (-37.5-149.0). Thirty-one of the 55 patients (56.4%) were treated with 1 or more anti-tumor necrosis factor (TNF) agents. IBD patients with EIM were more likely to be treated with anti-TNF compared to those without (56.4% vs 35.0%, P = 0.003). Response rates to anti-TNF depended on underlying EIM and were best for peripheral arthritis (61.5%) and uveitis (66.7%). CONCLUSIONS: In a cohort of pediatric patients with IBD, EIM were frequently encountered. In up to 30%, EIM appeared before IBD diagnosis. Knowledge of these findings may translate into an increased awareness of underlying IBD, thereby decreasing diagnostic delay. Anti-TNF for the treatment of certain EIM is effective, although a substantial proportion of new EIM may present despite ongoing anti-TNF therapy.

Changes in health-related quality of life over a 1-year follow-up period in children with inflammatory bowel disease.

PURPOSE: Little is known about disease-specific health-related quality-of-life (HRQoL) changes over time in paediatric patients with inflammatory bowel disease (IBD), and about their associations with baseline medical characteristics. METHODS: In this study, 153 paediatric patients with IBD from the multicentre prospective Swiss IBD cohort study were included at baseline. Of these, 90 patients were analysed at a 1-year follow-up. Medical data were extracted from hospital records, while HRQoL data were measured using the standardized, self-report disease-specific IMPACT-III questionnaire. RESULTS: The IBD diagnosis of the included children was made an average of 2.0 years before their baseline assessment. Over the 1-year follow-up period, a significant increase in overall HRQoL and in the HRQoL domain 'physical functioning' was evident. On multivariate analysis, overall HRQoL changes over time were predicted by baseline HRQoL, baseline disease activity, and disease activity changes over time. HRQoL improvements were significantly associated with decreases in physician-assessed disease activity. Children reporting a low baseline HRQoL and children with inactive or mildly-active disease experienced greater improvements. CONCLUSIONS: Children with more severe baseline disease activity had the greatest risk for HRQoL deterioration over the 1-year follow-up period. However, among possible factors that might influence HRQoL changes over time, the child's medical characteristics explained only a small proportion of their variability in our sample. We, therefore, recommend that researchers and clinicians focus on factors that are not incorporated within the multidimensional HRQoL concept if they seek to gain better insights into factors that influence HRQoL changes over time in children with IBD.

Impact of Overweight and Obesity on Disease Outcome in the Pediatric Swiss Inflammatory Bowel Disease Cohort.

Given the paucity of data, we aimed to assess the impact of obesity on disease activity, complications, and quality of life (QoL) in pediatric inflammatory bowel disease (IBD) patients. Methods: Prospective analysis of pediatric IBD patients. Patients were categorized into 4 groups according to the World Health Organization (WHO) child growth standards: obese, overweight, normal weight, and underweight. Results: Three hundred twenty-seven pediatric patients were included (146 with Crohn's disease [CD], 181 with ulcerative colitis of whom 13 [4%] were underweight, 272 [83.2%] had normal weight, 22 [6.7%] were overweight, and 20 [6.1%] were obese). Compared with normal weight patients, obese ulcerative colitis had a significantly higher clinical but not biological disease activity nor severity. Compared with normal weight patients, overweight/obese CD patients did not have higher clinical or biological disease activity nor severity. Perianal abscesses and surgery for this purpose were more frequently observed in overweight/obese CD patients compared with normal weight controls. Overweight/obese IBD patients were similarly hospitalized in the last 12 months compared with normal weight controls. Conclusions: Prevalence of overweight/obesity was 12.8% in pediatric IBD patients. Obesity was not associated with a decrease in disease remission rates nor an increase in the risk of complicated disease progression in IBD pediatric patients, except for the occurrence of perianal abscesses and related surgery in CD patients.

Impact of Diagnostic Delay on Disease Course in Pediatric- versus Adult-Onset Patients with Ulcerative Colitis: Data from the Swiss IBD Cohort.

Introduction: Given the lack of data, we aimed to assess the impact of the length of diagnostic delay on the natural history of ulcerative colitis (UC) in pediatric (diagnosed <18 years) and adult patients (diagnosed ≥18 years). Methods: Data from the Swiss Inflammatory Bowel Disease Cohort Study were analyzed. Diagnostic delay was defined as the interval between the first appearance of UC-related symptoms until diagnosis. Logistic regression modeling evaluated the appearance of the following complications in the long term according to the length of diagnostic delay: colonic dysplasia, colorectal cancer, UC-related hospitalization, colectomy, and extraintestinal manifestations (EIMs). Results: A total of 184 pediatric and 846 adult patients were included. The median diagnostic delay was 4 [IQR 2-7.5] months for the pediatric-onset group and 3 [IQR 2-10] months for the adult-onset group (p = 0.873). In both, pediatric- and adult-onset groups, the length of diagnostic delay at UC diagnosis was not associated with colectomy, UC-related hospitalization, colon dysplasia, and colorectal cancer. EIMs were significantly more prevalent at UC diagnosis in the adult-onset group with long diagnostic delay than in the adult-onset group with short diagnostic delay (p = 0.022). In the long term, the length of diagnostic delay was associated in the adult-onset group with colorectal dysplasia (p = 0.023), EIMs (p < 0.001), and more specifically arthritis/arthralgias (p < 0.001) and ankylosing spondylitis/sacroiliitis (p < 0.001). In the pediatric-onset UC group, the length of diagnostic delay in the long term was associated with arthritis/arthralgias (p = 0.017); however, it was not predictive for colectomy and UC-related hospitalization. Conclusions: As colorectal cancer and EIMs are associated with considerable morbidity and costs, every effort should be made to reduce diagnostic delay in UC patients.

Molecular and Histological Profiling Reveals an Innate-Shaped Immune Microenvironment in Solitary Juvenile Polyps.

INTRODUCTION: Solitary juvenile polyps (JP) are characterized by a benign disease course with low recurrence rate but present with signs of intestinal inflammation. To better understand the underlying pathogenesis, we performed histological and molecular evaluation targeting distinct immune mechanisms. METHODS: Pediatric patients with JP (n = 12), with treatment-naïve inflammatory bowel disease (IBD; [n = 41]) as inflammatory control, and non-IBD controls (n = 14) were investigated. For a comparative analysis of infiltrating immune cells, a next-generation tissue microarray of biopsies was assembled, immunostained, and scored. Targeted transcriptional profiling was performed using a customized immunology panel. RESULTS: In JP, a predominant accumulation of neutrophils and eosinophils was observed. RNA expression profiles revealed increased levels of CXCL8, CXCL5, and CCL11 transcripts in JP, indicating an enhanced recruitment of neutrophils and eosinophils. Moreover, messenger RNA levels of the proinflammatory cytokine IL1b and the inflammation-amplifying receptor TREM1 were higher in JP, whereas we could not find signs of a functionally polarized Tcell response in JP when compared with IBD. DISCUSSION: Patients with JP and patients with treatment-naïve IBD have distinct cell infiltrates during active disease. The ample presence of eosinophils in JP supports neutrophil accumulation, which is responsible for the elevated release of calprotectin. Intriguingly, however, we were not able to identify a functionally polarized T-cell response in JP, which indicates that during the acute onset of inflammation in JP, a potent adaptive immune memory is not established. This may explain the low reoccurrence rate of JP.

Newborns with Bloody Stools-At the Crossroad between Efficient Management of Necrotizing Enterocolitis and Antibiotic Stewardship.

The onset of bloody stools in neonates often results in antibiotic treatment for suspected necrotizing enterocolitis (NEC). Food protein-induced allergic proctocolitis (FPIAP) is an often-neglected differential diagnosis. We performed a retrospective analysis of antibiotic exposure at our tertiary center from 2011 to 2020 that included three time periods of differing antimicrobial stewardship goals. We compared these data with the conventional treatment guidelines (modified Bell's criteria). In our cohort of 102 neonates with bloody stools, the length of antibiotic exposure was significantly reduced from a median of 4 to 2 days. The proportion of treated neonates decreased from 100% to 55% without an increase in negative outcomes. There were 434 antibiotic days. Following a management strategy according to modified Bell's criteria would have led to at least 780 antibiotic days. The delayed initiation of antibiotic treatment was observed in 7 of 102 cases (6.9%). No proven NEC case was missed. Mortality was 3.9%. In conclusion, with FPIAP as a differential diagnosis of NEC, an observational management strategy in neonates with bloody stools that present in a good clinical condition seems to be justified. This may lead to a significant reduction of antibiotic exposure. Further prospective, randomized trials are needed to prove the safety of this observational approach.

Clinical presentation of celiac disease and the diagnostic accuracy of serologic markers in children.

There has been growing recognition of a changing clinical presentation of celiac disease (CD), with the manifestation of milder symptoms. Serologic testing is widely used to screen patients with suspected CD and populations at risk. The aim of this retrospective analysis was to evaluate the clinical presentation of CD in childhood, assess the diagnostic value of serologic tests, and investigate the impact of IgA deficiency on diagnostic accuracy. We evaluated 206 consecutive children with suspected CD on the basis of clinical symptoms and positive serology results. Ninety-four (46%) had biopsy-proven CD. The median age at diagnosis of CD was 6.8 years; 15% of the children were <2 years of age. There was a higher incidence of CD in girls (p = 0.003). Iron deficiency and intestinal complaints were more frequent in children with CD than those without CD (61% vs. 33%, p = 0.0001 and 71% vs. 55%, p = 0.02, respectively), while failure to thrive was less common (35% vs. 53%, p = 0.02). The sensitivity of IgA tissue transglutaminase (IgA-tTG) was 0.98 when including all children and 1.00 after excluding children with selective IgA deficiency. The specificity of IgA-tTG was 0.73 using the recommended cut-off value of 20 IU, and this improved to 0.94 when using a higher cut-off value of 100 IU. All children with CD and relative IgA deficiency (IgA levels that are measurable but below the age reference [n = 8]) had elevated IgA-tTG. In conclusion, CD is frequently diagnosed in school-age children with relatively mild symptoms. The absence of intestinal symptoms does not preclude the diagnosis of CD; many children with CD do not report intestinal symptoms. While the sensitivity of IgA-tTG is excellent, its specificity is insufficient for the diagnostic confirmation of a disease requiring life-long dietary restrictions. Children with negative IgA-tTG and decreased but measurable IgA values are unlikely to have CD.

Systematic Analysis of the Impact of Diagnostic Delay on Bowel Damage in Paediatric Versus Adult Onset Crohn's Disease.

BACKGROUND AND AIMS: Length of diagnostic delay is associated with bowel strictures and intestinal surgery in adult patients with Crohn's disease [CD]. Here we assessed whether diagnostic delay similarly impacts on the natural history of paediatric CD patients. METHODS: Data from the Swiss IBD Cohort Study were analysed. Frequency of CD-related complications [bowel stenosis, perianal fistula, internal fistula, any fistula, resection surgery, fistula/abscess surgery, any complication] at diagnosis and in the long term [up to 30 years after CD diagnosis] was compared between paediatric patients [diagnosed <18 years] and adult patients [diagnosed ≥18 years] using multivariate Cox proportional hazard regression modelling. RESULTS: From 2006 to 2016, 387 paediatric and 1163 adult CD patients were included. Median [interquartile range: IQR] diagnostic delay was 3 [1-9] for the paediatric and 6 [1-24] months for the adult group, respectively. Adult onset CD patients presented at diagnosis more frequently with bowel stenosis [p <0.001] and bowel surgery [p <0.001] compared with paediatric CD patients. In the long term, length of diagnostic delay was significantly associated with bowel stenosis [p = 0.001], internal fistula [p = 0.038], and any complication [p = 0.024] in the adult onset CD population. No significant association between length of diagnostic delay and CD-related outcomes in the long term was observed in the paediatric population. CONCLUSIONS: Adult CD patients have longer diagnostic delay compared with paediatric CD patients and present at diagnosis more often with bowel stenosis and surgery. Length of diagnostic delay was found to be predictive for CD-related complications only in the adult but not in the paediatric CD population.

Change of treatment modalities over the last 10 years in pediatric patients with inflammatory bowel disease in Switzerland.

BACKGROUND AND AIM: During the past decade, several new drugs were approved for the treatment of pediatric inflammatory bowel disease (IBD). We aimed to evaluate if and how pharmacologic treatment options for pediatric IBD in Switzerland have changed over time. PATIENTS AND METHODS: Data from the pediatric Swiss IBD Cohort Study, a national prospective cohort study initiated in 2006, were analyzed. Patients were divided into two groups: patients with IBD diagnosis until 2009 (168 patients) and patients with IBD diagnosis in 2010 and after (210 patients). Both groups were analyzed regarding the past and the current therapies as well as need for surgery. RESULTS: Overall, 378 pediatric patients with IBD were analyzed, of which 51.9% had Crohn's disease (CD) and 48.1% had ulcerative colitis/indeterminate colitis. Median age at diagnosis was 12 years. The majority (65.4%) of the patients with ulcerative colitis experienced pancolitis, whereas 45.4% of patients with CD presented with ileocolonic disease at diagnosis. A decreased use of corticosteroids in pediatric patients with CD can be found after 2010 (P=0.041). Use of 5-aminosalicylic acid for patients with CD was dramatically reduced after the year 2010 (33.5 vs. 67.7% after 6 years of disease). A significant shift toward earlier use of biologicals could be shown after 2010 (P<0.001). However, there was no significant decrease of surgery rate after 5 years of disease. CONCLUSION: In the past decade, a significant earlier use of anti-tumor necrosis factor-α agents in pediatric patients with IBD was observed with steroid-sparing effect in patients with CD. However, this change was not associated with reduction of surgery.

PR3-ANCA and panel diagnostics in pediatric inflammatory bowel disease to distinguish ulcerative colitis from Crohn's disease.

BACKGROUND: Accurate classification of patients with inflammatory bowel disease into the subtypes ulcerative colitis (UC) and Crohn's disease (CD) is still a challenge, but important for therapy and prognosis. OBJECTIVES: To evaluate the diagnostic utility of anti-neutrophil cytoplasmic antibodies specific for proteinase-3 (PR3-ANCA) for ulcerative colitis (UC) and the value of an antibody panel incorporating PR3-ANCA to differentiate between Crohn's disease (CD) and UC. STUDY DESIGN: In this cohort study, 122 pediatric and adolescent individuals were retrospectively included (61 IBD patients of two clinical centers, 61 non-IBD controls). All subjects had a comprehensive antibody profile done from stored sera taken close to time of diagnosis. By employing quasi-exhaustive logistic regression the best discriminative model for UC and CD,subjects was determined in a training cohort and confirmed in a validation cohort. RESULTS: PR3-ANCA was specifically associated with UC (odds ratio (OR), 17.6; 95% confidence interval (CI); 3.6, 87); P < .001). A four antibody-panel including PR3-ANCA had an AUC of 90.81% (95%CI; 81.93, 99.69) to distinguish between UC and CD in the training cohort. In a smaller external validation cohort, the AUC was 84.13% (95%CI; 64.21, 100) for accurate diagnosis of CD and UC. CONCLUSION: PR3-ANCA is highly specific for UC. The differentiating capability of a panel, which contains PR3-ANCA and weighs broadly available antibodies, is superior and utilization of the panel can support accurate classification in the work-up of pediatric and adolescent patients with IBD patients.

Age at disease onset of inflammatory bowel disease is associated with later extraintestinal manifestations and complications.

INTRODUCTION: A small but increasing number of patients with inflammatory bowel disease are diagnosed during childhood or adolescence, and disease distribution and severity at onset vary according to the age at diagnosis. Clinical factors present at the time of diagnosis can be predictive of the disease course. AIM: The aim of this study was to characterize disease behavior and the cumulative complications and extraintestinal manifestations 10 years after the diagnosis and to assess their association with age at diagnosis. PATIENTS AND METHODS: Data of patients participating with the Swiss IBD cohort study registry, a disease duration of 10 years and a complete data set were analyzed. The outcome was defined as the cumulative change of disease behavior, the occurrence of extra-intestinal manifestations or complications, and the necessity for medical or surgical interventions. RESULTS: A total of 481 patients with Crohn's disease (CD) and 386 patients with ulcerative colitis (UC), grouped according to disease onset before 10, 17, 40, or after 40 years of age, were analyzed. Despite differences in sex, initial disease location, and smoking habits, at 10 years after the diagnosis, no difference was found regarding disease behavior in CD or regarding progression of disease extension in UC. Similarly, no age-of-onset-dependent cumulative need for medical or surgical therapies was found. However, higher rates of anemia and lower rates of arthralgia and osteopenia were found in both pediatric-onset CD and UC, and a tendency toward higher rates of stomatitis in pediatric-onset CD, and of primary sclerosing cholangitis and ankylosing spondylitis in pediatric-onset UC. CONCLUSION: After 10 years of disease evolution, age at disease onset is not anymore associated with disease behavior but only with a small difference in the occurrence of specific extraintestinal manifestations and complications.

Growth of Infants Fed Formula with Evolving Nutrition Composition: A Single-Arm Non-Inferiority Study.

The nutritional composition of human milk evolves over the course of lactation, to match the changing needs of infants. This single-arm, non-inferiority study evaluated growth against the WHO standards in the first year of life, in infants consecutively fed four age-based formulas with compositions tailored to infants' nutritional needs during the 1st, 2nd, 3rd-6th, and 7th-12th months of age. Healthy full-term formula-fed infants (n = 32) were enrolled at ≤14 days of age and exclusively fed study formulas from enrollment, to the age of four months. Powdered study formulas were provided in single-serving capsules that were reconstituted using a dedicated automated preparation system, to ensure precise, hygienic preparation. The primary outcome was the weight-for-age z-score (WAZ) at the age of four months (vs. non-inferiority margin of -0.5 SD). Mean (95% CI) z-scores for the WAZ (0.12 (-0.15, 0.39)), as well as for the length-for-age (0.05 (-0.19, 0.30)), weight-for-length (0.16 (-0.16, 0.48)), BMI-for-age (0.11 (-0.20, 0.43)), and head circumferencefor-age (0.41 (0.16, 0.65)) at the age of four months, were non-inferior. Throughout the study, anthropometric z-scores tracked closely against the WHO standards (within ±1 SD). In sum, a fourstage, age-based infant formula system with nutritional compositions tailored to infants' evolving needs, supports healthy growth consistent with WHO standards, for the first year of life.

Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations.

BACKGROUND: Autosomal recessive mutations in deoxyguanosine kinase (DGUOK) have been identified in the hepatocerebral form of mitochondrial DNA (mtDNA) depletion syndrome. OBJECTIVES: To describe the clinical spectrum of DGUOK-related mtDNA depletion syndrome in 6 children and to summarize the literature. RESULTS: We identified pathogenic mutations in DGUOK in 6 children with the hepatocerebral form of mtDNA depletion syndrome. We describe the clinical, neuroradiologic, histologic, and genetic features in these children. All children showed severe hepatopathy, while involvement of other organs (skeletal muscle and brain) was variable. We identified 5 novel mutations (1 of them in 2 children) and 2 previously described mutations. Three different mutations affected the initial methionine, suggesting a mutational hot spot. One of our patients underwent liver transplantation; pathologic findings revealed (in addition to diffuse hepatopathy) a hepatocellular carcinoma, implying a possible link between mtDNA depletion syndrome and tumorigenesis. CONCLUSION: We studied 12 children with infantile hepatoencephalopathies and mtDNA depletion syndrome and found pathogenic DGUOK mutations in 6, suggesting that this gene defect is a frequent but not an exclusive cause of the hepatic form of mtDNA depletion syndrome.