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Celiac disease clinical presentation is constantly changing. We set to determine the prevalence of elevated transaminases in newly diagnosed celiac patients and to evaluate this sub-group of patients for associated clinical and laboratory findings and assess their natural course of disease following therapeutic diet initiation. We conducted a prospective-observational study of all newly diagnosed pediatric celiac patients, between August 2016 and April 2018, in a pediatric gastroenterology clinic. Clinical data, anthropometrics, and blood test results were recorded at diagnosis and at 3, 6, and 12 months, respectively, of follow-up. We compared patients with normal and elevated transaminases at diagnosis. ALT threshold was set at 24 U/l. Of 125 newly diagnosed celiac patients, 31 (24.8%) had elevated ALT at diagnosis; two (1.6%) with over 3 × ULN. Patients with elevated ALT at diagnosis were significantly younger (mean age 5.5 (SD 3.4) vs. 7.3 (SD 3.7) years, p

Background Non-alcoholic fatty liver disease (NAFLD) can range from simple steatosis to steatohepatitis with or without fibrosis. The predictors for liver fibrosis and the effect of nutritional intervention on hepatic fibrosis in pediatric population are not well established. We aimed to investigate the predictors for liver fibrosis and the effects of short-term nutritional intervention on steatosis and fibrosis among obese adolescents with NAFLD. Methods Cross-sectional study among obese adolescents. Sociodemographic and clinical data were collected. Liver fibrosis was estimated by Shearwave elastography. All participants were recommended to consume a low carbohydrate diet and were followed biweekly. Blood tests and elastography were performed upon admission and repeated after 3 months. Results Fifty-seven pediatric patients were recruited (35 males, mean age 13.5±2.9 years, mean body mass index [BMI] 38.8±9.7). Liver fibrosis was diagnosed in 34 (60%) subjects, which was moderate/severe (F≥2) in 24 (70%). A higher BMI Z score and moderate/severe steatosis correlated with moderate/severe fibrosis (P < 0.05). Seventeen patients completed 3 months of follow-up and displayed a decrease in BMI Z score (from BMI Z score 2.6±0.5 before intervention to 2.4±0.5 after intervention), with a significant decrease in liver fibrosis (P = 0.001). Conclusion Pediatric patients with high BMIs and severe liver steatosis are at risk for severe liver fibrosis. Nutritional intervention with minimal weight loss may improves hepatic fibrosis among the pediatric population. Trial registration TRN NCT04561804 (9/17/2020)

Background The effect of biologic therapy on the incidence of inflammatory bowel disease (IBD)-related hospitalizations is controversial. The high efficacy of biologic agents is weighted against potential therapy-related adverse events, however, there are no data on the effect of biologic therapy on the indications for hospitalization in IBD. We aimed to evaluate the impact of biologic therapy on the indications and rate of hospitalization in pediatric IBD. Methods This retrospective cohort study included all children ( Results Included were 218 hospitalizations of 100 children, of whom 65 (65%) had Crohn’s disease and 35 (35%) had ulcerative colitis. The indications for hospitalization were IBD exacerbations or complications in 194 (89%) and therapy-related adverse events in 24 (11%). The patients of 56 (25.7%) hospitalizations were receiving biologic therapy. In a multivariate analysis, no correlation between therapy and indication for hospitalization was found (p = 0.829). Among children under biologic therapy, a decrease in the rate of hospitalizations from 1.09 (0.11–3.33) to 0.27 (0–0.47) per year was observed for patients that were hospitalized during 2016–2019 (p = 0.043). Conclusion Biologic therapy did not influence the indication for hospitalization, but were associated with a decrease in the rate of hospitalization during 2016–2019 in pediatric IBD.

Very early-onset inflammatory bowel disease (IBD) and specifically infantile-onset IBD patients, are characterized by high rates of extensive colonic involvement and decreased response rate to standard therapeutic regimens, including infliximab (IFX). We present a case series of 4 patients with infantile-onset IBD achieving clinical and biologic remission, after treatment with therapeutic drug monitoring (TDM)-guided accelerated high-dose IFX therapy. All patients were treated with accelerated high-dose IFX induction of up to 22 mg/kg. In 3 of these patients, accelerated high-dose IFX was used following failure of intensified standard dose induction. All patients achieved remission following re-induction.We suggest that children with infantile-onset IBD may require a TDM-guided accelerated high-dose IFX induction and maintenance treatment in order to achieve and maintain remission. Personalized approach in these patients is essential in order to prevent underdosing and to avoid inappropriate interpretation of treatment failure.

The role of a positive family history in pediatric inflammatory bowel disease (IBD) in the era of biologic therapy has not been elucidated. We retrospectively reviewed the medical records of children with IBD and retrieved demographic and clinical characteristics, including the presence of a positive family history of IBD, IBD phenotype, disease course, and therapy. Overall, 325 children (age range at diagnosis 11-15 years) were included, of whom 82 (25.2%) had a positive family history. Children diagnosed during 2016-2020 had a higher frequency of positive family history compared to those diagnosed during 2010-2015 (31.8% versus 20.7%, respectively, p = 0.024). Children with a positive family history had a higher risk for a stricturing phenotype than those with a negative family history (11.3% versus 2.8%, respectively, p = 0.052). They more often received nutritional therapy (53.7% versus 36.6%, p = 0.007) and less often received corticosteroids (36.6% versus 52.7%, p = 0.012). More children with a negative family history needed intensification of biologic therapy (p = 0.041).Conclusion: The rate of a positive family history of IBD in the pediatric IBD population is increasing. A positive family history may have some impact upon IBD phenotype but none on IBD outcome. What is Known: •Familial clustering of inflammatory bowel disease (IBD) has been reported in 5%-15% of IBD patients. •The investigation of the impact of a positive family history upon IBD characteristics and severity revealed conflicting results. What is New: •In this cohort of 325 children with IBD, 25.2% had a positive family history. •The rate of a positive family history of IBD in the pediatric IBD population is increasing. •A positive family history may have some impact upon IBD phenotype but none on IBD outcome.

BackgroundAlterations in the microbiome have been postulated to drive inflammation in IBD. In this pilot randomized controlled trial, we evaluated the effectiveness of quadruple antibiotic cocktail in addition to intravenous-corticosteroids (IVCSs) in acute severe colitis (ASC).MethodsHospitalized children with ASC (pediatric ulcerative colitis activity index [PUCAI] ≥65) were randomized into 2 arms: the first received antibiotics in addition to IVCS (amoxicillin, vancomycin, metronidazole, doxycycline/ciprofloxacin [IVCS+AB]), whereas the other received only IVCS for 14 days. The primary outcome was disease activity (PUCAI) at day 5. Microbiome was analyzed using 16S rRNA gene and metagenome.ResultsTwenty-eight children were included: 16 in the AB + IVCS arm and 12 in the IVCS arm (mean age 13.9 ± 4.1 years and 23 [82%] with extensive colitis). The mean day-5 PUCAI was 25 ± 16.7 vs 40.4 ± 20.4, respectively (P = 0.037). Only 3 and 2 children, respectively, required colectomy during 1-year follow-up (P = 0.89). Microbiome data at time of admission were analyzed for 25 children, of whom 17 (68%) had a predominant bacterial species (>33% abundance); response was not associated with the specific species, whereas decreased microbiome diversity at admission was associated with day-5 response in the IVCS arm.ConclusionPatients with ASC have alterations in the microbiome characterized by loss of diversity and presence of predominant bacterial species. Quadruple therapy in addition to IVCS improved disease activity on day 5, but larger studies are needed to determine whether this is associated with improved long-term outcomes (clinicaltrials.gov NCT02033408).

Background The PAILOT trial was a randomized controlled trial aimed to evaluate proactive vs reactive therapeutic drug monitoring in children with Crohn’s disease (CD) treated with adalimumab. Our aim in this post hoc analysis of the PAILOT trial was to assess the efficacy and safety of adalimumab combination treatment in comparison with monotherapy at week 72 after adalimumab induction. Methods Participants were children 6–17 years old, biologic naïve, with moderate to severe CD, who responded to adalimumab induction at week 4. Patients receiving immunomodulators at baseline maintained a stable dose until week 24; patients could then discontinue immunomodulators. At each visit, patients were assessed for disease index, serum biomarkers, fecal calprotectin, adalimumab trough concentration, and anti-adalimumab antibodies. Results Out of the 78 patients (29% female; mean age, 14.3 ± 2.6 years), 34 patients (44%) received combination therapy. During the study period, there was no significant difference in the rates of sustained corticosteroid-free clinical remission (25/34, 73%, vs 28/44, 63%; P = 0.35) or sustained composite outcome of clinical remission, C-reactive protein ≤0.5 mg/dL, and calprotectin ≤150 µg/g (10/34, 29%, vs 14/44, 32%; P = 0.77) between the combination group and the monotherapy group, respectively. Clinical and biological outcomes did not differ between the proactive and reactive subgroups within the combination and monotherapy groups. Adalimumab trough concentrations and immunogenicity were not significantly different between groups. The rate of serious adverse events was not significantly different between groups but was numerically higher in the monotherapy group. Conclusions Combination therapy of adalimumab and an immunomodulator was not more effective than adalimumab monotherapy in children with CD (ClinicalTrials.gov No. NCT02256462).

Extraintestinal manifestations (EIM) are common complications of inflammatory bowel disease (IBD) associated with morbidity and reduced quality of life (QOL). The aim of this study was to identify and validate predictors for EIM in children with IBD. The medical records of children with IBD were retrospectively reviewed, and EIM present before diagnosis and those detected during follow-up, were recorded. One-hundred children were included, and their median age (interquartile range) was 13.9 (11.9–15.2) years. Forty-six (46%) children had EIM, including 10 (10%) whose EIM was present before diagnosis and 36 (36%) during follow-up. The most common EIMs were aphthous stomatitis (18%), arthralgia (14%), dermatologic manifestations (8%), and arthritis (6%). A body mass index in the lower or upper quartile (hazard ratio [HR] 9.30 and 23.71, respectively, p

Background and AimsThe role of hepcidin in inflammatory bowel disease [IBD] in children with anaemia is poorly understood. However, it has been shown that vitamin D suppresses hepcidin expression. We aimed to assess serum hepcidin levels and the effect of vitamin D treatment on those levels in newly diagnosed IBD paediatric patients.MethodsEighty-five children were prospectively recruited in the Dana-Dwek Children’s Hospital [40 newly diagnosed IBD, 45 healthy controls, 47% female, mean age 13.5 ± 3.4 years]. Blood samples for measurement of interleukin 6 [IL-6], C-reactive protein [CRP], hepcidin, iron parameters and 25-hydroxyvitamin D [25-(OH)-D] levels were obtained at baseline. Patients with mild-to-moderate signs and symptoms of IBD were treated with 4000 units of vitamin D daily for 2 weeks, after which the blood tests were repeated.ResultsBasal hepcidin, IL-6, CRP and platelet counts were significantly higher, and haemoglobin, serum iron and transferrin levels were significantly lower in the IBD children compared to controls [p < 0.001]. Eighteen patients completed 2 weeks of treatment with vitamin D. Following treatment, serum 25-(OH)-D concentrations increased by 40% [from 22.5 to 32.5 ng/mL], and serum hepcidin, CRP and ferritin levels decreased by 81%, 81% and 40% [from 33.9 to 6.7 ng/mL, from 23.9 to 4.7 mg/L, and from 27 to 16 ng/mL, respectively] [p ≤ 0.001].ConclusionSerum hepcidin levels were significantly higher in IBD paediatric patients compared to controls. Following vitamin D treatment, serum hepcidin concentration decreased significantly. These findings suggest a potential role for vitamin D in treating anaemia in IBD children.ClinicalTrials.gov numberNCT03145896

Objective: Combinations of antitumor necrosis factor alpha (TNFα) and immunomodulators may be indicated in high-risk inflammatory bowel disease patients. Our aims were to compare disease course between children that did and did not step down to anti-TNFα monotherapy and to define risk factors for complicated disease course after stepping down. Methods: A retrospective review of the medical records of consecutive children who were treated with combination therapy. Results: Of 64 children, 32 continued combination therapy while the others stepped down to monotherapy (median duration of 6 months [range 6–10]). Children that stepped down had a trend of lower anti-TNFα levels (median [interquartile range] of 2.4 [1–4.2] µg/mL) compared to those that did not step down (4.5 [2.2–6.23] µg/mL, p = 0.065). Children with Crohn’s disease that stepped down had a significantly higher risk for disease exacerbation, hospital admission, and operation (p < 0.025). Univariate analysis revealed that penetrating phenotype, upper gastrointestinal involvement, higher disease activity at diagnosis, and lower anti-TNFα levels under combination therapy were predictors for complicated course after stepping down. Conclusion: Stepping down to anti-TNFα monotherapy may be related to lower anti-TNFα levels and to a more complicated disease course thereafter. Predictors for a complicated course were identified.

OBJECTIVES Inflammatory bowel disease (IBD) has a high impact on nutritional status. Sarcopenia is related to higher risk of surgery and rescue therapy in adults with IBD; however, comparable data in pediatric populations are scarce. We evaluated muscle mass as a predictor of disease outcome in pediatric IBD. METHODS All pediatric IBD patients who underwent magnetic resonance enterography (MRE) during 2008 to 2019 were included. Muscle mass was assessed by measuring the area of the psoas muscle at the upper level of L3 on MRE. The psoas area divided by the body surface area (BSA) yielded the psoas index. Clinical and radiological data, including disease location, activity, course, and medications were documented. The control group included non-IBD children who underwent an MR imaging study. RESULTS We enrolled 101 IBD patients, 69 (68.3%) with Crohn disease (CD) and 32 (31.7%) with ulcerative colitis (UC) (mean age 15.03 ± 3.27 years). The psoas index was significantly lower in the IBD patients compared with the 87 controls (326 vs 528, respectively, P

OBJECTIVES Both the inflammatory burden of Crohn disease (CD) and corticosteroids have a negative effect on bone density. Exclusive enteral nutrition (EEN) avoids corticosteroids and promotes endoscopic healing. We aimed to explore the effect of nutritional therapy on bone health in pediatric CD. METHODS This was a planned sub-study of a clinical trial enrolling children with new-onset mild-moderate CD. Children were randomized to either 6 weeks EEN followed by 6 weeks 25% partial enteral nutrition (PEN) or 6 weeks of 50% PEN with a CD exclusion diet followed by 6 weeks of 25% PEN with exclusion diet. Bone formation and resorption were measured at baseline, week 12 and week 24 by serum C-Propeptide of Type I Procollagen (CICP) and type I Collagen N-Telopeptide (NTX), respectively. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) scan at baseline and week 24. RESULTS Median CICP improved from 130 ng/mL (106-189) at baseline to 223 (143-258) at week 12 and 193 (143-252) at week 24 (P = 0.016 for both, n = 29 children). Median NTX remained unchanged (P = 0.45 and P = 0.45). Thirty-six children had DXA scans performed at diagnosis; 81% and 33% had z scores of

OBJECTIVES The impact of pediatric-onset inflammatory bowel disease (IBD) on growth is debated. We aimed to investigate the effect of IBD on anthropometric measures at young adulthood. METHODS Children diagnosed with Crohn disease (CD) or ulcerative colitis (UC) (2005-2019) were identified in a national database along with matched non-IBD controls. RESULTS Overall, 2229 IBD cases (68% CD) were matched to 4338 controls. Only females with CD differed in final height from controls (z scores: -0.37 ± 1.09 vs -0.25 ± 1.06, respectively; P = 0.01), corresponding to a mean difference of 0.7 ± 0.2 cm (all females) and 1.2 ± 0.3 cm in females diagnosed

Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients p p n = 29) in YP vs. 58% (n = 45) in OP; p = 0.56).Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged What is Known? •Infliximab trough levels of paediatric IBD patients are influenced by several factors as dosing scheme, antibodies and inflammatory markers.•In 4.5–30% of the paediatric IBD patients, infliximab treatment was stopped within the first year. What is New? •The majority of young PIBD (

BackgroundNon-alcoholic fatty liver disease (NAFLD) can range from simple steatosis to steatohepatitis with or without fibrosis. The predictors for liver fibrosis, so as the effect of nutritional intervention on hepatic fibrosis in pediatric population are not well established. We aimed to investigate the predictors for liver fibrosis and the effects of short-term nutritional intervention on steatosis and fibrosis among obese adolescents with NAFLD.MethodsCross-sectional study among Obese adolescents. Sociodemographic and clinical data were collected. Liver fibrosis was estimated by Shearwave elastography. All participants were recommended to consume a low carbohydrate diet and were followed biweekly. Blood tests and elastography were performed upon admission and repeated after 3 months.ResultsFifty-seven pediatric patients were recruited (35 males, mean age 13.5 ± 2.9 years, mean body mass index [BMI] 38.8 ± 9.7). Liver fibrosis was diagnosed in 34 (60%) subjects, which was moderate/severe (F ≥ 2) in 24 (70%). A higher BMI Z score and moderate/severe steatosis correlated with moderate/severe fibrosis (P P = 0.001).ConclusionPediatric patients with high BMIs and severe liver steatosis are at risk for severe liver fibrosis. Nutritional intervention with minimal weight loss may improves hepatic fibrosis among pediatric population.

Background Primary care physicians (PCPs) play a pivotal role in the management of illnesses of the digestive tract. The study aim was to assess the adherence of PCPs to the guidelines on the management of Helicobacter pylori (H. pylori) infection and gastroesophageal reflux disease (GERD) in adults. Methods We conducted a cross-sectional study during March–July 2017 using the survey platform of Maccabi Healthcare Services in Israel. The study questionnaire assessed adherence to the Maastricht/Florence guidelines on H. pylori infection and the American College of Gastroenterology guidelines on the management of GERD. We sent the study questionnaires to a random sample of 610 PCPs via electronic mails. We contacted those who did not respond by telephone; eventually 180 physicians completed the survey. Results Ninety (50%) and 60 (36%) of the responders reported using professional guidelines for the diagnosis and management of H. pylori infection and GERD, respectively. Of the 180 participants, 153 (85%) reported referring patients with suspected peptic ulcer disease to H. pylori testing, 109 (61%) reported referring patients with unexplained iron deficiency anemia and 83 (46%) refer relatives of gastric cancer patients. In caring for young patients who have dyspepsia without alarm symptoms, 127 (74%) reported referral to a urea breath test for the diagnosis of H. pylori infection, and 136 (81%) referral to a specialist in gastroenterology if alarm symptoms present. Triple therapy with proton pump inhibitors/clarithromycin/amoxicillin or metronidazole was reported as first-line therapy by 141 (83%) participants. For GERD, 94–98% of the participants followed the appropriate recommendations. Conclusions We identified gaps between the practices of PCPs and the guidelines on H. pylori infection management, while guidelines on GERD management are well adopted. Simplification of the guidelines and exploring barriers towards their implementation by PCPs is warranted.

Background Functional abdominal pain (FAP) disorders are one of the most common gastrointestinal disorders in children. We aimed to define the association between obesity and functional abdominal pain (FAP) disorders and to assess differences between overweight/obese children and normal weight children with FAP disorders. Methods We conducted a retrospective study of children (2–18 years old) with a clinical diagnosis of FAP who were followed-up in our pediatric gastroenterology unit between 1/2016–10/2018. FAP disorders were defined according to the ROME IV criteria. Body mass index (BMI) percentiles were defined by CDC standards. Patients with BMIs ≥85th percentile were designated as being overweight/obese. A population control group was obtained from the 2015–2016 Israel national health survey. Results Data from 173 children with FAP disorders (median age 11.5 years, 114 females) were included. Seventy-one children (41%) were classified as having functional abdominal pain-NOS, 67 (38.7%) as having irritable bowel syndrome (IBS), and 35 (20.2%) has having functional dyspepsia. Fifty-three children (30.6%) were classified as being overweight/obese. Adolescents with FAP disorders had a significantly higher prevalence of overweight/obesity compared to controls (39.5% vs. 30%, respectively, p = 0.04). Children with FAP and overweight were older [12.4 (range 9.8–15.3) vs. 10.8 (7.4–14.1) years, p = 0.04] and had more hospitalizations due to FAP (20.8% vs. 7.6%, p = 0.01) compared to Children with FAP and normal weight. Conclusions Adolescents with FAP had higher prevalence of overweight/obesity compared to controls. Future studies are warranted to raise awareness of weight issues in FAP and determine the effect of weight loss on FAP.

OBJECTIVES Growth impairment is common in children with Crohn disease (CD). We aimed to assess the effect of adalimumab (ADL) treatment on linear growth in children with CD in a post-hoc analysis of the Pediatric Crohn's Disease AdalImumab Level-based Optimization Treatment randomized controlled trial. METHODS Children 6 to 17 years who responded to ADL induction were assessed consecutively for anthropometric parameters. Associations of these parameters with disease characteristics and disease activity were analyzed. RESULTS Overall, 66 patients completed 72 weeks of follow-up (25% girls, mean age of 15.6 ± 2.5 years). Median (interquartile range [IQR]) height z score improved from -0.6 (-1.6-0.15) at baseline to -0.33 (-1.3-0.5) at week 72 (P = 0.005) with lesser improvement in patients with perianal disease. Similar effect was noted in children with growth potential (boys younger than 16 years, girls younger than 14 years). Median (IQR) height velocity standard deviation was -0.32 (-1.5-0.8) at week 26, and +0.11 (-1.1-1.3) at week 72. Median weight z score increased from -0.54 (-1.2-0.15) to -0.1 (-0.9-0.6), P

Inflammatory bowel disease (IBD) has been associated with underweight and malnutrition, but obesity may also serve as a negative prognostic factor. This study aimed to present the longitudinal course of height, weight, and body mass index (BMI) of children from IBD diagnosis to 18 months of follow-up, and to describe the impact of BMI on the clinical course of the disease. One hundred and fifty-two children were identified, of whom 85 had Crohn's disease (CD) and 67 had ulcerative colitis (UC). During a median (interquartile range) follow-up of 2.95 (1.73-4.5) years, weight and BMI Z-scores increased in the first 18 months since diagnosis in both the CD (P 0.001) and UC (P 0.028) groups. BMI in lower and upper quartiles at diagnosis was associated with higher risk of hospitalization (hazard ratio [HR] = 2.72, P = 0.021). In a multivariate analysis, BMI in the lower quartile at diagnosis and at 6, 12, and 18 months was associated with higher risk of disease exacerbation (HR = 2.36, 1.90, 1.98, and 2.43, respectively, P 0.021), as was BMI in the upper quartile (HR = 2.59, 2.91, and 2.29, respectively, P 0.013).Conclusion: BMI in the lower and upper quartiles at diagnosis and during follow-up was associated with a more severe disease course in children with IBD. What is Known: • Inflammatory bowel disease (IBD) has been associated with underweight and malnutrition. • The impacts of weight and body mass index (BMI) on the presentation and course of IBD have been mainly investigated in the adult population. What is New: • In the era of the obesity epidemic, this study identifies both low and high BMIs at diagnosis and at follow-up as a marker for poor outcome in pediatric IBD. • The results support using BMI as a predictor of IBD course and prognosis.

Background Gastrointestinal endoscopy may be associated with pain and anxiety. Predictors for high pain scores after endoscopies in children are not known. The aim of our study was to identify risk factors for prolonged recovery and higher pain scores after gastrointestinal endoscopy in children. Methods All the children that were electively admitted for gastrointestinal endoscopies were included. We retrospectively collected demographic, clinical and endoscopic data as well as information on the recovery process. A numerical rating scale and the Faces, Legs, Activity, Cry, and Consolability Scale were used for pain scoring. Results During the study period (01/2016–10/2016), 284 children (median age 10.7 years, interquartile range 6.7–14.8) were recruited. In a univariate analysis, older age, higher pre-procedure pain scores, longer procedure durations, higher number of biopsies and longer recovery duration were associated with higher post-procedure pain scores. In a multivariate analysis higher pain scores before the procedure (OR 12.42, 95% CI 3.67–42, P P P = 0.001). Conclusion Older age and higher pain score before the procedure were identified as predictors for higher pain score after pediatric gastrointestinal endoscopies. Children with these risk factors should be identified before the procedure in order to personalize their post-procedure management.

Background & Aims: Dietary therapies based on exclusion of usual dietary elements induce remission in children with Crohn's disease (CD), whereas re-exposure induces rebound inflammation. We investigated whether a short trial of dietary therapy, to identify patients with and without a rapid response or remission on the diet (DiRe), can be used to predict success or failure of long-term dietary therapy. Methods: We collected data from the multicenter randomized trial of the CD exclusion diet (CDED). We analyzed data from 73 children with mild to moderate CD (mean age, 14.2 ± 2.7 y) randomly assigned to groups given either exclusive enteral nutrition (EEN, n = 34) or the CDED with 50% (partial) enteral nutrition (n = 39). Patients were examined at baseline and at weeks 3 and 6 of the diet. Remission was defined as CD activity index scores below 10 and response was defined as a decrease in score of 12.5 points or clinical remission. Inflammation was assessed by measurement of C-reactive protein. Results: At week 3 of the diet, 82% of patients in the CDED group and 85% of patients in the EEN group had a DiRe. Median serum levels of C-reactive protein had decreased from 24 mg/L at baseline to 5.0 mg/L at week 3 (P

Approximately 10% of children with celiac disease (CD) have ultra-short celiac disease (USCD), where histological abnormalities are limited to the duodenal bulb. The aim of our retrospective study was to identify clinical and serological characteristics at baseline and at follow-up of children with USCD. All children that were diagnosed with CD in our unit during 7/2010–12/2017, in whom biopsies were taken from duodenal bulb and second part, were included. We compared disease characteristics and course between children with USCD and children with involvement in the second part of the duodenum. Out of 3740 children who underwent upper gastrointestinal endoscopies, 648 were diagnosed with CD. Seventy-one (11%) of those children had limited involvement in the duodenal bulb. The USCD group included more females (P = 0.021), were older (P = 0.005), had a lower prevalence of diarrhea (P = 0.003), anemia (P = 0.007), anti-tissue transglutaminase (TTG) antibodies count (P

Hepcidin is a master regulator of iron metabolism. Recently, it has been shown that vitamin D suppresses hepcidin expression. Our hypothesis was that hepcidin levels inversely correlate with vitamin D levels in anemic children during acute infection. A prospective study was performed on 90 patients (45 females, 45 males, mean age 7.3 ± 5 years) who were admitted to the pediatric ward. Sixty-two patients had infectious disease (32 with coexisting anemia, 30 without anemia), and 28 patients were hospitalized for noninfectious causes. Blood samples for IL-6, hepcidin, iron status parameters, and 25-hydroxyvitamin D (25-OHD) were obtained within 72 h after admission. Serum concentrations of IL-6 and hepcidin were significantly higher and 25-OHD, iron, and transferrin were significantly lower in anemic children with infectious disease compared with controls. Children with a serum 25-OHD level 20 ng/ml (OR: 6.1, CI: 1.15–32.76). Correlation analyses found positive associations between hepcidin levels and ferritin (R2 = 0.47, P

Background Lactose malabsorption affects 70% of the world population. The hydrogen breath test (HBT) is used clinically to test for this condition. The aim of our study was to describe the relationship between symptoms experienced before and during the HBT and test results. Methods We included children who underwent the HBT in the pediatric gastroenterology unit at Dana-Dwek Children's Hospital during a 6-month period. Previous symptoms and those experienced before and after the HBT were assessed using a questionnaire and a validated pain scale. Results Ninety-five children were included in the study, and 66.3% had a positive HBT. Diarrhea and flatulence during the test were significantly more frequent in the group with a positive HBT compared to those with a negative test (31.7% vs. 9.4%, P = 0.016 and 69.8% vs. 40.6%, P = 0.006, respectively). The frequency of abdominal pain and bloating was similar. Conclusions Diarrhea and flatulence during the HBT are the most specific symptoms of lactose intolerance. Abdominal pain should not be automatically attributed to lactose intolerance even in the presence of lactose malabsorption. Coupling the HBT with a real-time questionnaire facilitates interpretation of results and subsequent recommendations.

Background Previous studies have shown a lower level of parasympathetic activity in patients with inflammatory bowel disease (IBD) compared to healthy subjects. Heart rate variability (HRV) oscillations are used to detect autonomic instability and was found to be lower in adults with IBD compared to controls. Nevertheless, the data on the relation between the autonomic function and IBD outcome are scarce. The aim of the study was to evaluate HRV as a predictor to paediatric IBD outcome. Methods Children ( Results Overall, 34 IBD children with an average age of 15.32±2.18 years were included: 21 (61.8%) children with Crohn’s disease and 13 (38.2%) with ulcerative colitis. Children in clinical remission had a significantly higher RMSSD compared to patients with active disease (67.72±27.81 and 45.76±22.04, respectively, p=0.022). In addition, patients with normal serum C-reactive protein ( Conclusion HRV may not only reflect IBD activity, but also serve as a predictor to disease exacerbation in paediatric IBD.

Background Previous studies have suggested that adult patients with inflammatory bowel disease (IBD) that have a positive family history of IBD may be at risk for a more aggressive clinical course, compared with sporadic cases. The role of a positive family history in paediatric IBD, however, has not been elucidated. Methods We retrospectively reviewed the medical records of children with IBD and retrieved demographic and clinical characteristics, including IBD phenotype, course and therapy. We have documented the presence of a positive family history of IBD, and compared the clinical data of children with a positive family history to that of children with a negative family history. Results Overall, 325 children with a median (IQR) age of 13.9 (11–15) years at diagnosis were included: 194 (59.7%) with Crohn’s disease (CD) and 131 (40.3%) with ulcerative colitis. A positive family history of IBD was observed in 82 children (25.2%). Of them, 36 (43.9%) had a first-degree family member with IBD, and 23 (28%) had more than one family member with IBD. Children with a positive family history had a higher risk for stricturing phenotype (11.3% versus 2.8%, P=0.05) and were treated more often by nutritional therapy (53.7% versus 36.6%, P=0.007) and less by corticosteroids (36.6% versus 52.7%, P=0.012). Children with a negative family history had a higher need to intensification of biologic therapy [Hazard ratio (HR)=1.792, 95% confidence interval (CI) 1.005–3.195, P=0.041 and HR=2.597, 95% CI 1.224–5.525, P=0.008 for CD) (Figure 1). No difference in the risk for IBD exacerbation, hospitalization and operation was found between the groups. Conclusion A positive family history of IBD may have a mild impact on the phenotype and course of paediatric IBD.

Helicobacter pylori, one of the most common bacterial pathogens in humans, is generally acquired during childhood. The inverse correlation between H. pylori colonization and obesity that was found in adults has not been investigated in depth in children. Our aim was to assess the correlation between overweight and obesity and H. pylori colonization in a pediatric population.H. pylori colonization in 70 symptomatic children was determined after antral biopsies during esophagogastroduodenoscopy. Data on anthropometric measurements, sociodemographic characteristics, and medical history were recorded.The participants' mean age was 12.41 ± 3.16 years, 58% were females, and 24% were obese or overweight (BMI85th percentile). The H. pylori colonization rate was 31%. There were no significant differences between the H. pylori-infected and H. pylori-noninfected groups in terms of age, gender, or clinical and sociodemographic characteristics. Nevertheless, the prevalence of overweight and obesity was significantly lower in children with H. pylori colonization compared to children with normal histology (31% in the noninfected group compared to 11% in the infected group, p = 0.04). The mean fat percentage was 24.3 ± 8.8 and 19.4 ± 6.9, respectively (p = 0.02).The findings of this prospective study are in agreement with previous studies and demonstrate an inverse relationship between H. pylori colonization and overweight or obesity among symptomatic children. A larger prospective, multiethnic investigation is warranted to more definitively determine the extent of this association.

Background: Vedolizumab, an anti-integrin antibody, has proven to be effective in adults with inflammatory bowel disease [IBD], but the data in paediatrics are limited. We describe the short-term effectiveness and safety of vedolizumab in a European multi-centre paediatric IBD cohort. Method: Retrospective review of children [aged 2–18 years] treated with vedolizumab from 19 centres affiliated with the Paediatric IBD Porto group of ESPGHAN. Primary outcome was Week 14 corticosteroid-free remission [CFR]. Results: In all, 64 children were included (32 [50%] male, mean age 14.5 ± 2.8 years, with a median follow-up 24 weeks [interquartile range 14–38; range 6–116]); 41 [64%] cases of ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U] and 23 [36%] Crohn’s disease [CD]. All were previously treated with anti-tumour necrosis factor [TNF] [28% primary failure, 53% secondary failure]. Week 14 CFR was 37% in UC, and 14% in CD [P = 0.06]. CFR by last follow-up was 39% in UC and 24% in CD [p = 0.24]. Ten [17%] children required surgery, six of whom had colectomy for UC. Concomitant immunomodulatory drugs did not affect remission rate [42% vs 35%; p = 0.35 at Week 22]. There were three minor drug-related adverse events. Only 3 of 16 children who underwent endoscopic evaluation had mucosal healing after treatment (19%). Conclusions: Vedolizumab was safe and effective in this cohort of paediatric refractory IBD. These data support previous findings of slow induction rate of vedolizumab in CD and a trend to be less effective compared with patients with UC.

Background The PAILOT trial was a randomised controlled trial aimed to evaluate proactive vs. reactive therapeutic drug monitoring in children with Crohn’s disease (CD) treated with adalimumab. Our aim, in this post-hoc analysis of the PAILOT trial, was to assess the efficacy and safety of adalimumab combination treatment in comparison to monotherapy at week 72 after adalimumab induction. Methods Participants were children 6–17 years old, biologic naïve, with moderate-to-severe CD, who responded to adalimumab induction at week 4. Patients receiving immunomodulators at baseline, maintained a stable dose until week 24; patients could then discontinue immunomodulators. At each visit patients were assessed for disease index, serum biomarkers, faecal calprotectin, adalimumab trough concentration and anti-adalimumab antibodies. Results Out of the 78 patients (29% female; mean age, 14.3 ± 2.6 years), 34 patients (44%) received combination therapy. During the study period there was no significant difference in the rates of sustained corticosteroid free clinical remission (25/34, 73% vs. 28/44, 63%; p = 0.35), and sustained composite outcome of clinical remission, CRP≤0.5 mg/dl and calprotectin≤150 µgr/gr (10/34, 29% vs. 14/44, 32%; p = 0.77) between the combination group and the monotherapy group, respectively. Clinical and biological outcomes did not differ between the proactive and reactive sub-groups within the combination and monotherapy groups. Adalimumab trough concentrations and immunogenicity were not significantly different between groups. The rate of serious adverse events was not significantly different between groups but numerically higher in the monotherapy group. Conclusion Combination therapy of adalimumab and an immunomodulator was not more effective than adalimumab monotherapy in children with CD.

Background Growth impairment is common in children with Crohn’s disease. We aimed to assess the effect of adalimumab treatment on linear growth in children with Crohn’s disease in a post-hoc analysis of the PAILOT randomised controlled trial. Methods Children 6–17 years old with moderate-to-severe Crohn’s disease, naïve to biologic treatment, who responded to adalimumab induction, were assessed at week 4, 8 andevery8 weeks thereafter until week 72 for anthropometric parameters (height, weight and body mass index, BMI, Z-scores). We also analysed the associations of these parameters with clinical disease activity, inflammatory biomarkers, faecal calprotectin and adalimumab trough concentration. Results Overall, 66 patients had available anthropometric parameters between week 4 to 72(29% females, mean age 14.3 ± 2.6 years). The median improvement of height z–score /month was +0.014, 95% CI 0.004–0.024, p = 0.006 with an overall improvement during the study period from -0.62 (IQR −1.6–0.15) to −0.33 (IQR -1.3–0.5). The median increase of weight z- score/month was +0.025, 95% CI 0.015–0.034, p = 0.025 [overall increase from -0.54 (IQR −1.2–0.15) to −0.1, (IQR -0.9–0.6)], whereas the median increase in BMI z –score/month was +0.02, 95% CI 0.008–0.031, p = 0.001 [overall increase from −0.4 (IQR −1.0–0.5) to 0.0 (IQR −0.8–0.9)]. There was a significant correlation between paediatric Crohn’s disease activity index and erythrocyte sedimentation rate at week 4 and height z-score changes (p = 0.043 and p = 0.048), respectively, and a marginal correlation with C-reactive protein (p = 0.06). There was a significant correlation between sustained clinical and biologic remission (weeks 4–72) and changes in height z-score during follow-up (p = 0.001). Faecal calprotectin, adalimumab trough concentrations and combination therapy with an immunomodulator were not associated with height z-score changes. Conclusion Adalimumab treatment significantly improved linear growth, and normalised weight and BMI in children with moderate-to-severe Crohn’s disease.

Background Inflammatory bowel disease (IBD) is a chronic immune-mediated disease with high impact on nutritional status. Sarcopenia was related to higher risk of intestinal resection and rescue therapy in adult IBD patients; however, data in paediatric population is missing. The aim of this study was to evaluate muscle mass as a predictor of disease outcome in paediatric IBD. Methods All paediatric IBD patients that underwent a magnetic resonance enterography (MRE) study for disease assessment at the Tel Aviv Sourasky Medical Center in 2008–2019 were retrospectively included. Muscle mass was assessed by measuring the area of the psoas muscle at the upper level of L3 on MRE by a freehand region of interest (ROI). Psoas index was defined as the average psoas area divided by body surface area, and then was divided into quartiles. Disease location and radiological signs of IBD were documented. Clinical data including disease activity and course, medications, exacerbations and laboratory results were documented. Results We included 101 patients, 69 (68.3%) Crohn’s disease patients and 32 (31.7%) ulcerative colitis patients. The mean age was 13.05 ± 3.48 years at diagnosis and 15.03 ± 3.27 years at MRE. The psoas index was significantly lower in patients with presence of fatty proliferation (p = 0.021), comb sign (p = 0.001) and extensive disease in MRE (p = 0.012) and in radiologic evidence of disease complications such as abscess or fistula (p = 0.027). In a univariate analysis, patients with psoas index in the lower quartile had significantly higher risk of need for biologic therapy during follow-up (HR = 35.1, p < 0.001; Figure 1) and higher risk of disease exacerbation (HR = 25.1, p < 0.001; Figure 2) compared with patients with psoas index in the upper quartile. In a multivariate analysis adjusted for age, gender, disease type, haemoglobin, C-reactive protein, albumin, disease activity and interval from diagnosis to MRE, patients with psoas index in the lower quartile had significantly higher risk of need for biologic therapy (HR = 12.1, p = 0.046) and of disease exacerbation (HR = 9, p = 0.047) compared with patients with psoas index in the upper quartile. Conclusion Sarcopenia correlates with the radiological severity of IBD and was found to be an independent predictor for severe clinical disease course. Muscle mass in MRE studies may be used as a possible marker for disease outcome in paediatric IBD.

Background Adherence of primary-care pediatricians to guidelines in pediatric gastroenterology is essential to achieve optimal clinical outcomes. The study aim was to examine adherence of primary-care pediatricians to the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition guidelines on the management of Helicobacter pylori (H. pylori) infection and celiac disease. Methods We conducted a cross-sectional study during March–July 2017 using the survey platform of Maccabi Healthcare Services, the second largest state-mandated health organization in Israel. We sent the study questionnaire to a random sample of 300 pediatricians via electronic mails and to increase the response rate, we performed a telephone interview. Overall, 108 (36%) pediatricians provided completed questionnaires. Results Using professional guidelines for the management of H. pylori infection and celiac disease was reported by 34 and 37% of pediatricians, respectively. Referral to H. pylori testing was reported by 78 and 52% of pediatricians in children with suspected duodenal ulcer and unexplained iron deficiency anemia, respectively, with the stool antigen enzyme immunoassay being mostly (51%) used as the first choice diagnostic test. Most pediatricians reported prescription of triple therapy; proton pump inhibitors/clarithromycin/amoxicillin (59%) or metronidazole (21%). For celiac disease, overall adherence to all guidelines was high both for initial evaluation and for confirmation of diagnosis. Conclusions Adherence to the guidelines on management of H. pylori infection was low, while adherence to the guidelines on celiac disease management was high among primary-care pediatricians. Educational interventions are needed to improve H. pylori infection management among primary-care pediatricians.

Inflammatory bowel disease (IBD) exacerbations may lead to prolonged and complicated hospitalizations. The characteristics of exacerbation-related hospitalizations and predictors for poor outcome of pediatric patients hospitalized due to IBD have not been thoroughly described. All children who were hospitalized due to IBD exacerbation in a tertiary referral center between 2004 and 2017 were enrolled. Data on demographic and disease characteristics before and during hospitalization were retrospectively reviewed, as was the course of hospitalization, including laboratory findings, diagnostic work-up, and management. Poor outcomes were defined as prolonged hospitalization (≥ 7 days) and/or the need for surgery during hospitalization. There were 181 hospitalizations of 78 IBD children with a median (IQR) age of 14.8 (11.8-16.2) years. They included 53 (67.9%) with Crohn's disease and 25 (32.1%) with ulcerative colitis. In a multivariate analysis, severe disease activity at hospitalization (odds ratio [OR] = 3.33, P = 0.013), lower weight percentile (OR = 0.98, P = 0.009), treatment with antibiotics (OR = 5.03, P = 0.001), blood transfusion (OR = 8.03, P = 0.003), undergoing endoscopy (OR = 2.73, P = 0.027), and imaging studies during hospitalization (OR = 3.61, P = 0.001) predicted prolonged hospitalization. Surgical intervention was performed in 16 patients (8.8%), due to penetrating (OR = 7.73, P = 0.019) and stricturing disease (OR = 12.38, P < 0.001).Conclusion: We identified predictors for poor outcomes of children hospitalized due to IBD. Among the variables that can be measured at the beginning of the admission, severe disease activity was the most significant predictor recognition of these predictors that may contribute to modification of patient management.What is Known:• Inflammatory bowel disease (IBD) patients may require hospitalization due to disease exacerbation or treatment-related complications.• Hospitalizations of IBD patients constitute a heavy emotional burden on patients and families.What is New:• Lower weight percentile, severe disease activity, and a lower albumin level were predictors for prolonged hospitalization in children with IBD.• Recognition of these predictors may contribute to modification of patient management.

The course and evolution of pediatric acute pancreatitis (AP) is poorly understood. Prognostication models in children perform poorly and lack consensus. We aimed to identify predictors of AP severity, and the risk for AP recurrence.We retrospectively studied all patients hospitalized with AP at a single tertiary center, between January 1995 and June 2016. Patient demographics and admission laboratory data were assessed for severity and recurrence prediction.A total of 68 patients accounting for a total of 117 (15 moderate-severe) AP episodes were reviewed. Patients with moderate-severe disease were significantly younger (median [interquartile range (IQR)] of 8.3 [4.0-14.4] vs 13.8 [8.1-16.0] years, P = 0.02). Young age at presentation was associated with odds ratio of 3.8 (confidence interval [CI] 1.2-12.1) for children younger than 12 years and 5.8 (CI 1.6-21.4) for children younger than 6 years for developing moderate-severe disease.Further subanalysis of the 59 patients with first-time AP episodes, demonstrated younger age (median [IQR] of 5.3 [2.9-10.4] vs 12.0 [6.3-15.8] years, P = 0.03) and elevated white blood cell count (median [IQR] of 22.8 [11.8-31.3] vs 11.0 [8.1-14.6] 10/L, P 0.01) of patients with moderate-severe disease, conferring a risk for moderate-severe disease with odds ratio of 7.5 (CI 1.5-38.2) for children younger than 6 years and 5.3 (CI 1.1-25.4) for patients with white blood cell count15 × 10/L, respectively. Fourteen (23.7%) of 59 patients with first-time episodes had recurrent AP. Analysis of the data at the primary episode failed to identify predictors to indicate future recurrence.In our cohort, only young age (12 years) predicted AP severity. No parameters were identified to predict future development of AP recurrence.

Converging evidence indicates that orexins (ORXs), the regulatory neuropeptides, are implicated in anxiety- and depression-related behaviors via the modulation of neuroendocrine, serotonergic, and noradrenergic systems. This study evaluated the role of the orexinergic system in stress-associated physiological responses in a controlled prospective animal model. The pattern and time course of activation of hypothalamic ORX neurons in response to predator-scent stress (PSS) were examined using c-Fos as a marker for neuronal activity. The relationship between the behavioral response pattern 7 days post-exposure and expressions of ORXs was evaluated. We also investigated the effects of intracerebroventricular microinfusion of ORX-A or almorexant (ORX-A/B receptor antagonist) on behavioral responses 7 days following PSS exposure. Hypothalamic levels of ORX-A, neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF) were assessed. Compared with rats whose behaviors were extremely disrupted (post-traumatic stress disorder [PTSD]-phenotype), those whose behaviors were minimally selectively disrupted displayed significantly upregulated ORX-A and ORX-B levels in the hypothalamic nuclei. Intracerebroventricular microinfusion of ORX-A before PSS reduced the prevalence of the PTSD phenotype compared with that of artificial cerebrospinal fluid or almorexant, and rats treated with almorexant displayed a higher prevalence of the PTSD phenotype than did untreated rats. Activated ORX neurons led to upregulated expressions of BDNF and NPY, which might provide an additional regulatory mechanism for the modulation of adaptive stress responses. The study indicates that the activated ORX system might promote adaptive responses to PSS probably via stimulation of BDNF and NPY secretion, and early intervention with ORX-A reduces the prevalence of the PTSD phenotype and increases the prevalence of adaptive phenotypes. The findings provide some insights into the mechanisms underlying the involvement of the ORX system in stress-related disorders.

Cytomegalovirus (CMV) colitis is a relatively common end-organ infectious complication in immunocompromised hosts which negatively affects clinical outcomes. This paper presents the contemporary approaches to the diagnosis and management of CMV colitis and discusses some of the controversies of this condition, focusing on methods of diagnosis. While certain risk factors for CMV colitis are well recognized, the clinical as well as endoscopic features of this condition are nonspecific. Rapid diagnosis and management are usually needed, especially in critically ill patients, which necessitate invasive diagnostic procedures. Hematoxylin and eosin staining of colonic mucosal tissue may show the typical viral inclusions associated with CMV colitis that are highly specific for this condition. However, the staining has low sensitivity compared to immunohistochemistry, which is considered the gold standard for diagnosis of CMV colitis. Tissue polymerase chain reaction (PCR) is highly sensitive for diagnosis, but is controversial for many reasons, detailed in this paper. A high index of suspicion is needed, and once diagnosis is made, treatment should be highly considered to improve the outcome of these severely ill patients. Noninvasive diagnostic tests will be available in the future and will hopefully improve the diagnosis and care of patients with CMV colitis.

Sleep disruption modifies the immune system and can trigger flares of inflammatory bowel diseases (IBD). Changes in expression of clock genes have been reported in patients with IBD. We investigated whether a change in the circadian clock is an early event in development of IBD.We performed a prospective study of patients younger than 21 years old who underwent diagnostic endoscopies at the pediatric and adult gastroenterology units at the Tel Aviv Sourasky Medical Center from August 2016 through August 2017. Questionnaires were completed by 32 patients with IBD (8-21 years old) and 18 healthy individuals (controls) that provided data on demographics, sleep, disease activity scores. We also obtained data on endoscopic scores, anthropometric parameters, blood level of C-reactive protein (CRP), and fecal level of calprotectin. Peripheral blood and intestinal mucosa samples were analyzed for expression levels of clock gene (CLOCK, BMAL1, CRY1, CRY2, PER1, and PER2).Levels of CRP and fecal calprotectin were significantly higher in patients with IBD compared with controls (P.05). Expression levels of clock genes (CLOCK, CRY1, CRY2, PER1, and PER2) were significantly lower in inflamed intestinal mucosa from patients compared with intestinal mucosa from controls (P.05). Expression levels of all clock genes except for PER2, were also significantly lower in non-inflamed intestinal mucosal tissues from patients compared with controls (P.05). Expression levels of clock genes (CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2) were lower in white blood cells from patients with IBD compared with controls. This reduction was greater in white blood cells from patients with ulcerative colitis than in patients with Crohn's disease.Young, newly diagnosed, untreated patients with IBD have reduced expression of clock genes in inflamed and non-inflamed intestinal mucosal samples, and also in blood cells, compared with healthy individuals. Alterations in expression of clock genes might be an early event in IBD pathogenesis. ClinicalTrials.gov Identifier: NCT03662646.

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.

AIM Nutritional deficiencies associated with coeliac disease include iron, folic acid and fat-soluble vitamins. This study compared the prevalence and degree of vitamin A deficiency among newly diagnosed coeliac disease patients to controls in a developed country. METHODS This prospective cohort study included all children evaluated by gastroscopy at Dana-Dwek Children's Hospital, Israel, between September 2014 and February 2017. Vitamin A, haemoglobin, C-reactive protein (CRP), ferritin, tissue transglutaminase, immunoglobulin A and vitamin D levels were measured. RESULTS Of the 113 children (69% females), 47 were diagnosed with coeliac disease whereas the others were the controls (mean age of 8.2 ± 3.8 years and 12.4 ± 3.5 years, respectively). There was no group difference in vitamin A, vitamin D or CRP levels. Among coeliac children, two had true vitamin A deficiency compared with three controls, while 18 coeliac children had subclinical vitamin A deficiency compared with 25 controls (p > 0.05). CONCLUSION Paediatric coeliac disease was not associated with increased prevalence of vitamin A deficiency. Children evaluated for gastrointestinal complaints in a developed country were found to have an unexpectedly high prevalence of subclinical vitamin A deficiency. Further prevalence and causality assessments of vitamin A deficiency in developed countries are needed.

Patients with inflammatory bowel disease (IBD) are predisposed to infections. Cytomegalovirus (CMV) colitis in adult IBD patients, particularly ulcerative colitis (UC), is related to severe or steroid-refractory disease. The aim of this review is to summarize the data on the prevalence and role of CMV colitis in children with IBD. Data on CMV colitis in children continue to be very limited due to its rarity. As in adults, children with coexisting UC and CMV tend to have more severe colitis, are resistant to corticosteroids, and are at high risk for colectomies on short- and long-term follow-up. In children, as in adults, the significance of CMV colitis, in terms of whether CMV is a pathogen that aggravates acute severe colitis or simply reflects disease severity, is still unknown.

In the original article, author Carsten Posovszky's surname was incorrectly spelt. This has now been corrected.

Gastroesophageal reflux (GER) is commonly observed in children, particularly during the first year of life. Pharmacological therapy is mostly reserved for symptomatic infants diagnosed with GER disease (GERD), usually as defined in a recent consensus statement. The purpose of the present article was to review the reported adverse effects of pharmacological agents used in the treatment of paediatric GERD. We conducted this review using the electronic journal database Pubmed and Cochrane database systematic reviews using the latest 10-year period (1 January 2003 to 31 December 2012). Our search strategy included the following keywords: omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, rantidine, cimetidine, famotidine, nizatidine, domperidone, metoclopramide, betanechol, erythromycin, baclofen, alginate. We used Pubmed's own filter of: 'child: birth-18 years'. All full articles were reviewed and we only included randomized controlled trials retrieved from our search. We addressed a summary of our search on a drug-by-drug basis with regard to its mechanism of action and clinical applications, and reviewed all of the adverse effects reported and the safety profile of each drug. Adverse effects have been reported in at least 23% of patients treated with histamine H2 receptor antagonists (H2 RAs) and 34% of those treated with proton pump inhibitors (PPIs), and mostly include headaches, diarrhoea, nausea (H2 RAs and PPIs) and constipation (PPIs). Acid suppression may place immune-deficient infants and children, or those with indwelling catheters, at risk for the development of lower respiratory tract infections and nosocomial sepsis. Prokinetic agents have many adverse effects, without major benefits to support their routine use.

Background Enlarged tonsils and adenoids are the major etiology of obstructive sleep apnea (OSA) in children. Lymphatic hyperplasia is common to both OSA and celiac disease. We aimed to investigate the effect of a gluten-free diet on OSA symptoms in children with celiac disease. Methods Children with celiac disease aged 2–18 years were prospectively recruited before the initiation of a gluten-free diet. Children with negative celiac serology who underwent gastrointestinal endoscopies for other indications served as controls. All participants completed a validated OSA-related symptoms questionnaire and the pediatric sleep questionnaire (PSQ) at baseline and 6 months later. Results Thirty-four children with celiac disease (mean age 6.6 ± 3.5 years) and 24 controls (mean age 7.3 ± 4.6 years, P = 0.5) were recruited. There were no significant differences in gender, body mass index or season at recruitment between the two groups. The rate of positive PSQ scores was higher (more OSA-related symptoms) in the control group compared to the celiac group, both at recruitment and at the 6-month follow-up (33.3% vs. 11.8%, P = 0.046, and 16.7% vs. 0, P = 0.014, respectively). PSQ scores improved significantly in both groups at the 6-month follow-up (P

Data on the clinical presentation of constitutional mismatch repair deficiency syndrome (CMMRD) is accumulating. However, as the extraintestinal manifestations are often fatal and occur at early age, data on the systematic evaluation of the gastrointestinal tract is scarce. Here we describe 11 subjects with verified biallelic carriage and who underwent colonoscopy, upper endoscopy and small bowel evaluation. Five subjects were symptomatic and in six subjects the findings were screen detected. Two subjects had colorectal cancer and few adenomatous polyps (19, 20 years), three subjects had polyposis-like phenotype (13, 14, 16 years), four subjects had few adenomatous polyps (8, 12-14 years) and two subjects had no polyps (both at age 6). Of the three subjects in the polyposis-like group, two subjects had already developed high-grade dysplasia or cancer and one subject had atypical juvenile polyps suggesting juvenile polyposis. Three out of the five subjects that underwent repeated exams had significant findings during short interval. The gastrointestinal manifestations of CMMRD are highly dependent upon age of examination and highly variable. The polyps may also resemble juvenile polyposis. Intensive surveillance according to current guidelines is mandatory.

Polyposis syndromes in children are distinct entities clinically and pathologically. These syndromes have multiple genetic characteristics, with development of polyps at various sites of the gastrointestinal (GI) tract, and are associated with an increased risk of colon cancer. They are relatively rare, and have mostly been characterized in the adult population, whereas little epidemiologic data have been reported in children.The aim of this study was to summarize the pediatric experience collected over a period of 11 years on polyposis syndromes in three major Israeli tertiary centers.Medical records of children below 18 years old and their families, diagnosed with polyposis syndromes between 1999 and 2010, were reviewed. The data included disease presentation, genetic profile, surveillance, and treatment.Fifty patients with polyposis syndromes were identified. The most frequent syndrome was familial adenomatous polyposis (FAP) in 33 children (66%), of whom 25 children (75.7%) had a known mutation. The mean age at presentation was 10.6±3.9 years (range 4-17 years). Most children were examined because of a family history of a polyposis syndrome (42 children, 84%). Among symptomatic children (32 children), the most frequent complaint was rectal bleeding (42%), followed by abdominal pain (22%), intussusception (10%), and diarrhea (4%). The youngest symptomatic patient was 4 years old at presentation, with rectal bleeding.All patients underwent multiple colonoscopies and upper GI endoscopies according to specific guidelines. Thirteen children underwent colonic surgery (39%); nine children had FAP. Adenocarcinoma of the colon was diagnosed in a 12.5-year-old child.In this cohort study, FAP was the most common type of polyposis syndrome diagnosed in this pediatric population. Colon cancer was present at the onset of symptoms in a 12.5-year-old patient with FAP. We therefore recommend strict adherence to the hereditary GI cancer guidelines to prevent morbidity and mortality in FAP and other inherited polyposis syndromes.

Background & Aims Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). Methods We performed a nonblinded, randomized controlled trial of 78 children with CD (6–18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 μg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). Results The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 μg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). Conclusions In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.