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Objectives: The aims of our study were to evaluate health-related quality of life (HRQoL) in children affected by inflammatory bowel disease (IBD) during the first wave of Coronavirus disease 2019 (COVID-19) pandemic and after 12 months. Methods: This was a single-center, prospective, observational study conducted between April 2020 and April 2021. Children from 10 to 18 years with a confirmed diagnosis of IBD were enrolled during the first COVID-19-related national quarantine. The following information was collected at the baseline and after 12 months: IBD subtype, location and phenotype, disease activity, current and previous therapies. Patients were asked to complete the PROMIS Anxiety and IMPACT III questionnaires. Results: One hundred and eighteen patients were enrolled, of whom 54 (46%) were affected by Crohn disease (CD) and 64 (54%) with ulcerative colitis (UC; median age: 15.5 years, range 10.3-18; M/F: 68/50). Median HRQoL was significantly decreased after 12 months compared with the beginning of COVID-19-related quarantine (T1: 76.7 vs T2: 72.8; P < 0.001). At 12 months, a higher number of children were reported to be in active disease when compared with the enrollment [T2: 22/108 (20.4%) vs T1: 12/118 (10%); P = 0.02]. Multivariate analysis showed a significant influence on HRQoL of quarantine period (P < 0.001), female sex (P = 0.016), biologic therapy (P = 0.011), and active disease (P < 0.001). Conclusions: A deterioration of HRQoL after 12 months from COVID-19-related quarantine was observed. Additionally, the higher number of children with active disease at 12 months compared with enrollment may suggest detrimental consequences of the reduced disease control, contributing to decreased HRQoL.

Background Scarce data have investigated the association between pediatric inflammatory bowel disease (IBD) and eosinophilic esophagitis (EoE). We, therefore, aimed to describe the epidemiology and the possible peculiar phenotype and natural history of such an association. Methods Case-control study is based on the Italian Society for Pediatric Gastroenterology (SIGENP) national registry. All children with a combined diagnosis of IBD and EoE were included. The overall prevalence and incidence in 2 periods, 2009 to 2015, and 2016 to 2021, were calculated. Cases were matched with IBD only and EoE only patients in a 1:3:3 ratio. Phenotype and outcomes (courses of steroids, risk of complications, surgery, treatment escalation, and hospitalization) were compared between groups. Results Eleven patients (age 11.2 ± 2.8 years, Males 91%) with EoE-IBD out of 3090 patients with IBD were identified, resulting in an overall prevalence of 0.35% and an incidence of 0.18% for 2009 to 2015 and 0.45% for 2016 to 2021. Treatment escalation rates for IBD were significantly higher in patients with IBD compared with EoE-IBD at 12- and 24-month follow-up (0% vs 30%, P = .04; and 9% vs 45.5%, P = .03, respectively). Furthermore, patients with IBD were at a significantly higher risk of hospitalization than both EoE-IBD and EoE patients (log rank P Conclusions The incidence and prevalence of EoE in children with IBD are low, although the incidence seems to be rising in recent years. Having EoE appears to be associated with a milder IBD disease course, whereas having IBD does not seem to affect the natural history of EoE. More data are needed to better define the phenotype of such association.

Background Exclusive enteral nutrition (EEN) is the first choice to induce remission and promote mucosal healing in pediatric Crohn’s disease (CD). However, full adherence to EEN treatment may be problematic for children with CD. Methods The goal of the current multicenter retrospective study was to define predictive factors of nonadherence to treatment and nonremission at the end of induction treatment. Those data together were analyzed with the ultimate goal of trying to define an individualized induction treatment for children with CD. Results Three hundred seventy-six children with CD from 14 IBD pediatric referral centers were enrolled in the study. The rate of EEN adherence was 89%. Colonic involvement and fecal calprotectin >600 μg/g at diagnosis were found to be associated with a reduced EEN adherence. Exclusive enteral nutrition administered for 8 weeks was effective for inducing clinical remission in 67% of the total cohort. Factors determining lower remission rates were age >15 years and Pediatric Crohn’s Disease Activity Index >50. Conclusion Although EEN is extremely effective in promoting disease remission, several patients’ related factors may adversely impact EEN adherence and response. Personalized treatments should be proposed that weigh benefits and risks based on the patient’s disease location, phenotype, and disease activity and aim to promote a rapid control of inflammation to reduce long-term bowel damage.

Background: Functional gastrointestinal disorders (FGIDs) are common during the pediatric age. FGIDs are not related to biochemical or structural abnormalities. However, since they have a high prevalence, several studies have evaluated an overlap between FGIDs and organic diseases. Individuals with celiac disease (CD) have been shown to be at an increased risk for functional abdominal pain, even if they adhere well to a gluten-free diet (GFD). Little information is available for the pediatric age group. The aims of our study were to evaluate the prevalence of FGIDS in CD children 1 year after diagnosis and to compare the prevalence of FGIDs in CD children on a GFD with processed foods compared with those on a GFD with natural products. Aim: To assess the prevalence of FGIDs in children with CD after 1 year of follow-up and to compare the prevalence of FGIDs in children with CD on a GFD with processed foods and in children on a GFD with natural products. Methods: We recruited pediatric patients aged 1-18 years with a new CD diagnosis. Participants were randomized to two groups: Group A on a GFD with processed foods (diet 1); and group B on a GFD with natural products (diet 2). Clinical monitoring, diet assessment and the questionnaire on pediatric gastrointestinal symptoms-Rome IV version were performed at diagnosis (T0) and after 12 mo of follow-up (T1). Dietary intake was assessed using a 3-d food diary record. Data from the diaries were evaluated using WinFood nutrient analysis software. We assessed the prevalence of FGIDs at T1 and the correlation with the type of GFD. Results: We registered 104 CD children, with 55 patients in group A (53.0%) and 49 patients in group B (47.0%). Initially, 30 of the 55 (54.5%) CD children were symptomatic in group A, while 25 of 49 (51.0%) were symptomatic in group B. At T1, in spite of a low or negative serology for CD, FGIDs prevalence was 10/55 (18.0%) in group A and 8/49 (16.3%) in group B, with no statistically significant difference between the two groups (P = 0.780). At T1 the macro- and micronutrient intake was similar across the two groups with no significant differences in nutrient analysis. However, in both groups at T1 we found that a lower prevalence of FGIDs (P = 0.055) was associated with an inferior caloric (odds ratio = 0.99, 95% confidence interval: 0.99-1.00) and fat (odds ratio = 0.33, 95% confidence interval: 0.65-0.95) intake. Conclusion: Our results showed that CD children on a GFD have gastrointestinal symptoms with an elevated prevalence of FGIDs. Our study suggests that developing FGIDs may be linked to caloric intake and percentage of food fat, but it does not change between a GFD with processed foods or a GFD with natural products. However, long-term monitoring is required to evaluate a correlation between FGIDs and various types of GFDs.

The RNA-binding protein Pcbp2 is widely expressed in the innate and adaptive immune systems and is essential for mouse development. To determine whether Pcbp2 is required for CD4+ T cell development and function, we derived mice with conditional Pcbp2 deletion in CD4+ T cells and assessed their overall phenotype and proliferative responses to activating stimuli. We found that Pcbp2 is essential for T conventional cell (Tconv) proliferation, working through regulation of co-stimulatory signaling. Pcbp2 deficiency in the CD4+ lineage did not impact Treg abundance in vivo or function in vitro. In addition, our data demonstrate a clear association between Pcbp2 control of Runx1 exon 6 splicing in CD4+ T cells and a specific role for Pcbp2 in the maintenance of peripheral CD4+ lymphocyte population size. Last, we show that Pcbp2 function is required for optimal in vivo Tconv cell activation in a T cell adoptive transfer colitis model system.

Background The reduction of bone mineral density and osteoporosis have high impacts on the health of patients with inflammatory bowel diseases (IBD). We have previously shown that a dysregulated iron metabolism occurs in IBD and leads to a decrease in circulating iron concentration and excessive intracellular sequestration of iron. Studies suggest that iron overload significantly affects the bone, accelerating osteoclast (OC) differentiation and activation, promoting bone resorption. Moreover, we demonstrated that iron overload causes OC overactivity. The cannabinoid receptor type 2 (CB2) and the transient receptor potential vanilloid type-1 (TRPV1) are potential therapeutic targets for bone diseases. The aim of this study was to evaluate the roles of CB2 and TRPV1 receptors and of iron in the development of osteoporosis in pediatric IBD. Methods We differentiated OCs from peripheral blood mononuclear cells of patients with IBD and healthy donors and evaluated CB2 and TRPV1 receptor expression; OC activity, and iron metabolism by Western blot, TRAP assays, bone resorption assays, and iron assays. Moreover, we analyzed the effects of the pharmacological modulation of CB2 and TRPV1 receptors on OC activity and on the iron metabolism. Results We confirmed the well-known roles of CB2 and TRPV1 receptors in bone metabolism and suggested that their stimulation can reduce the OC overactivity induced by iron, providing new insights into the pathogenesis of pediatric IBD-related bone resorption. Conclusions Stimulation of CB2 and TRPV1 could reduce IBD-related osteoporosis due to their direct effects on OC activity and to modulating the iron metabolism.

Background Besides major clinical/biochemical features, neutropenia and inflammatory bowel disease (IBD) constitute common complications of Glycogen storage disease type Ib (GSD Ib). However, their management is still challenging. Although previous reports have shown benefit of empagliflozin administration on neutropenia, no follow-up data on bowel (macro/microscopic) morphology are available. We herein present for the first time longitudinal assessment of bowel morphology in a GSD Ib child suffering from Crohn disease-like enterocolitis treated with empagliflozin. Case presentation A 14-year-old boy with GSD Ib and severe IBD was (off-label) treated with empagliflozin (20 mg/day) after informed oral and written consent was obtained from the patient’s parents. No adverse events were noted. Clinical symptoms and stool frequency improved within the first week of treatment. Pediatric Crohn disease activity index (PCDAI) normalised within the first month of treatment. Abdomen magnetic resonance imaging (MRI) performed 3 months after treatment initiation showed dramatic decrease in disease activity and length. Similar findings were reported on histology at 5.5 months. At 7.5 months hemoglobin levels normalised and fecal calprotectin almost normalised. Improved neutrophil count, metabolic control and quality of life were also noted. G-CSF dose was decreased by 33% and the patient was partly weaned from tube feeding. Conclusions This is the first report presenting extensive gastrointestinal morphology follow-up in a GSD Ib patient receiving empagliflozin. The present case suggests that empagliflozin can be safe and effective in inducing IBD remission in GSD Ib patients and can even postpone surgery. Future studies are required to confirm its effect over time and assess its benefit in various disease stages. The development of an international collaborating networks for systematic data collection is worthy.

Purpose of review Despite its recognized efficacy and tolerability profile, during the last decade a rise of adverse events following ibuprofen administration in children has been reported, including a possible role in worsening the clinical course of infections. Our aim was to critically evaluate the safety of ibuprofen during the course of pediatric infectious disease in order to promote its appropriate use in children. Recent findings Ibuprofen is associated with severe necrotizing soft tissue infections (NSTI) during chickenpox course. Pre-hospital use of ibuprofen seems to increase the risk of complicated pneumonia in children. Conflicting data have been published in septic children, while ibuprofen in the setting of Cystic Fibrosis (CF) exacerbations is safe and efficacious. No data is yet available for ibuprofen use during COVID-19 course. Summary Ibuprofen should not be recommended for chickenpox management. Due to possible higher risks of complicated pneumonia, we suggest caution on its use in children with respiratory symptoms. While it remains unclear whether ibuprofen may have harmful effects during systemic bacterial infection, its administration is recommended in CF course. Despite the lack of data, it is seems cautious to prefer the use of paracetamol during COVID-19 acute respiratory distress syndrome in children.

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2, spreading in Italy during the first months of 2020, abruptly changed the way of practicing medicine in this country. As a consequence of the lockdown, the diagnostic and therapeutic management of paediatric chronic conditions, such as inflammatory bowel disease (IBD) has been affected. During the peak of COVID-19 pandemic, elective visits, endoscopies and infusions have been postponed, with potential clinical and psychological impact on disease course and a high likelihood of increasing waiting lists. While slowly moving back towards normality, clinicians need to recognize the best ways to care for patients with IBD, carefully avoiding risk factors for new potential epidemic outbreaks. In this uncertain scenario until the development and spread of COVID-19 vaccine, it is necessary to continue to operate with caution. Hereby we provide useful indications for a safer and gradual restarting of routine clinical activities after COVID-19 peak in Italy.

Background: The new concept of disease remission for pediatric inflammatory bowel diseases (IBD) implies the achievement of mucosal healing. Aims: We aimed to evaluate endoscopic and histologic healing in children with Ulcerative Colitis (UC) and Crohn's disease (CD) in clinical remission after 52 weeks of Azathioprine. Methods: From December 2012 to July 2015 we prospectively enrolled IBD children starting Azathioprine. Enrolled patients in clinical remission underwent colonoscopy after 52 weeks. Macroscopic assessment was described with Mayo score and the simplified endoscopic score for UC and CD, respectively. For microscopic assessment, an average histology score was used. Data on inflammatory markers and fecal calprotectin were also collected. Results: Fourty-seven patients were included in the analysis. Endoscopic healing was detected in 20/26 (76.9%) UC children and 10/21 (47.6%) CD patients. Median Mayo score and simplified endoscopic score were significantly decreased at week 52 (p < 0.001; p = 0.005). Median average histology score was not significantly different at week 52 in both diseases. Fecal calprotectin was directly correlated with simplified endoscopic score (T0: r = 0.4, p = 0.05; T52: r = 0.5, p = 0.01), but not with Mayo score. No correlation was found between endoscopic and histologic scores. Conclusions: IBD children under Azathioprine reach endoscopic healing, but not histological remission.

The primary role of environment on inflammatory bowel disease (IBD) onset has been recently stressed. We aimed to investigate the effect of environmental factors in an IBD pediatric cohort.A total of 467 subjects (264 IBD and 203 controls) were enrolled. All patients underwent a questionnaire including 5 different groups of environmental risk factors: family history of IBD and autoimmune diseases, perinatal period, home amenities and domestic hygiene, childhood diseases and vaccinations, and diet.In a multivariate model, mother's degree (odds ratio [OR]: 5.5; 2.5-11.6), duration of breast feeding3rd month (OR: 4.3; 1.6-10.5), father's employment (OR: 3.7; 1.2-8.7), gluten introduction6th month (OR: 2.8; 1.5-5), number of siblings2 (OR: 2.8; 1.5-5.3), and family history of autoimmune diseases (OR: 2.7; 1.4-5.3) were significant risk factors for Crohn disease. Low adherence to Mediterranean diet (OR: 2.3; 1.2-4.5), gluten introduction6th month (OR: 2.8; 1.6-4.9), and number of siblings2 (OR: 2; 1.1-3.6) were significant risk factors for ulcerative colitis. Owning pets (OR: 0.3; 0.1-0.7) and bed sharing (OR: 0.2; 0.1-0.6) were protective factors for Crohn disease, whereas owning pets (OR: 0.4; 0.2-0.8) and family parasitosis (OR: 0.07; 0.01-0.4) were protective factors for ulcerative colitis.Our study confirms that environmental factors are closely linked to IBD onset and may partly explain IBD rise in developed countries.

BackgroundVaccine-preventable diseases and opportunistic infections in pediatric inflammatory bowel disease (IBD) are increasingly recognized issues. The aims of this study were to evaluate vaccinations, immunization status, and consequent therapeutic management in children with IBD and to analyze the differences among patients diagnosed before (Group 1) and after June 2012 (Group 2).MethodsThis was a multicenter, retrospective cohort investigation. Between July 2016 and July 2017, 430 children with IBD were enrolled in 13 centers. Diagnosis, therapeutic history, vaccinations, and immunization status screening at diagnosis and at immunosuppressant (IM)/biologic initiation and reasons for incomplete immunization were retrieved.ResultsVaccination rates at diagnosis were unsatisfactory for measles, mumps, and rubella (89.3%), Haemophilus influenzae (81.9%), meningococcus C (23.5%), chickenpox (18.4%), pneumococcus (18.6%), papillomavirus (5.9%), and rotavirus (1.9%). Complete immunization was recorded in 38/430 (8.8%) children, but specific vaccines were recommended in 79/430 patients (18.6%), without differences between the 2 groups. At IM start, 22% of children were tested for Epstein-Barr virus (EBV) status, with 96.2% of EBV-naïve patients starting azathioprine, without differences between Groups 1 and 2. Screening for latent tuberculosis (TB) before start of biologics was performed in 175/190 (92.1%), with up to 9 different screening strategies and numerous inconsistencies.ConclusionsWe demonstrated a poor immunization status at diagnosis in children with IBD, which was not followed by proper vaccination catch-up. EBV status before IM initiation and latent TB before biologics were not adequately assessed. Thus, the overall impact of the current guidelines seems unsatisfactory.

We sought to correlate hepcidin levels in inflammatory bowel disease [IBD] children with disease activity, inflammatory markers, and iron load test [ILT] and to compare IBD patients with coeliac and healthy patients.Between December 2012 and June 2013, 145 subjects [50 IBD patients, 45 coeliac patients and 50 healthy controls] were included in the study. All patients underwent the following examinations: blood count, iron status, erythropoiesis parameters, serum hepcidin, C-reactive protein [CRP], and erythrocyte sedimentation rate [ESR]. In order to evaluate the efficacy of iron absorption, ILT was performed in IBD patients. Disease activity indexes and IBD duration, localisation, and therapy were also evaluated, and a faecal sample for calprotectin collected.Serum hepcidin was significantly higher in IBD patients with active disease compared with both coeliac and healthy patients [p = 0.005, p = 0.003 respectively]. In a multivariate logistic regression model, having a Paediatric Crohn's Disease Activity Index [PCDAI] / Paediatric Ulcerative Colitis Activity Index [PUCAI] ≥ 30 resulted in the only variable independently associated with a positive serum hepcidin (odds ratio [OR] = 6.87; 95% confidence interval [CI] 1.4-33, p = 0.01]]. Patients with iron malabsorption [IM] showed higher values of ESR, CRP, and hepcidin [p = 0.02, p = 0.001, and p = 0.06, respectively]. Eight out of 12 [66.7%] children with IM showed an active disease compared with 6/31 [19.3%] children with normal ILT [p = 0.01]. Hepcidin levels correlated negatively with ILT [r = -0.451, p = 0.002], and positively with ferritin and CRP [r = 0.442, p = 0.0001; r = 0.243, p = 0.009, respectively]Our study demonstrates that serum hepcidin is increased in IBD children with active disease and it is responsible for IM.

Formation of the mammalian hematopoietic system is under a complex set of developmental controls. Here, we report that mouse embryos lacking the KH domain poly(C) binding protein, Pcbp2, are selectively deficient in the definitive erythroid lineage. Compared to wild-type controls, transcript splicing analysis of the Pcbp2-/- embryonic liver reveals accentuated exclusion of an exon (exon 6) that encodes a highly conserved transcriptional control segment of the hematopoietic master regulator, Runx1. Embryos rendered homozygous for a Runx1 locus lacking this cassette exon (Runx1ΔE6) effectively phenocopy the loss of the definitive erythroid lineage in Pcbp2-/- embryos. These data support a model in which enhancement of Runx1 cassette exon 6 inclusion by Pcbp2 serves a critical role in development of hematopoietic progenitors and constitutes a critical step in the developmental pathway of the definitive erythropoietic lineage.

OBJECTIVES Existing studies usually do not measure the free vitamin D in pediatric patients with inflammatory bowel disease (IBD) and not consider the effect of inflammation on vitamin D levels. The aim of our study was to evaluate the concentrations of vitamin D-binding protein (VDBP), total and free 25-hydroxyvitamin-D (25(OH)D), and to correlate these values with the disease activity markers. METHODS Newly diagnosed children with IBD and a group of healthy controls (HCs) were enrolled. VDBP and total and free 25(OH)D levels were measured by enzyme-linked immunosorbent assay and compared using the Student t test. In each patient with IBD, the activity scores of disease and the main inflammation markers were correlated to total and free 25(OH)D levels. C-reactive protein was also measured in the control group, and it was related to VDBP by a linear regression test for all the groups. RESULTS Fifty-one consecutive children were enrolled: IBD = 33, HC = 18. Levels of total 25(OH)D were higher in HC than in patients with IBD (P = 0.01). The free/total 25(OH)D ratio was, however, higher in patients with IBD compared to HC (P

OBJECTIVES The aims of this retrospective study were to describe ulcerative colitis (UC) phenotype at diagnosis and follow-up and to identify possible predictors of severe disease course. METHODS This was a retrospective, single-center study. We reviewed the charts of patients with UC diagnosed between 2 and 18 years at our referral center from January 2007 to January 2016. Laboratory and clinical features at diagnosis, such as disease extent, atypical phenotypes, extraintestinal manifestations, and therapies, and pattern changes during the follow-up, including relapse rate, disease extension, and the cumulative risk for colectomy were collected. RESULTS One hundred eleven patients were enrolled. Atypical phenotypes were identified at diagnosis in 55 out of 111 patients (49.5%). Extraintestinal manifestations were detected in 16 out of 111 (14.4%) at the diagnosis. During the follow-up 60 out of 111 (54%) patients needed to start azathioprine, 9 out of 111 (8.1%) patients started biologic therapy and 10 out of 111 (patients underwent surgery, resulting in a cumulative risk of 8% at 5 years and 16% at 10 years. Steroid refractoriness (hazard ratio: 13.9) and starting of biologic therapy (hazard ratio: 25.3) represented the best predictors for surgery. The cumulative probability of first relapse was 47% at 6 months and 63% at 1 year. Disease extension was reported in 21 out of 70 patients (30%). CONCLUSION Pediatric UC is associated with a severe phenotype and a high percentage of atypical features. Surgery rate seems to be decreased from early reports.

OBJECTIVES: Gastroesophageal reflux (GER) is a frequently occurring condition in infants capable of causing distressing symptoms. The aim of our study is to evaluate the efficacy of Mg alginate plus simethicone (Gastrotuss Baby, DMG Italia SRL, Pomezia, Italy), compared with rice-starch-thickened formula or with reassurance alone, in the treatment of GER in infants. METHODS: The present randomized controlled trial was conducted in full-term infants affected by symptoms suggestive of GER, evaluated through a validated questionnaire (Infant Gastroesophageal Reflux Questionnaire Revised). The patients were randomized into 3 groups according to treatment (group A: Mg alginate plus simethicone; group B: thickened formula; group C: reassurance with lifestyle changes). Evaluation of symptom scores was performed after 1 month (T1) and 2 months (T2). RESULTS: A total of 64 (85.3%) of 75 enrolled infants (median age 5 months; range 1-10) concluded the study. After 1 month of treatment (T1), infants treated with Mg alginate plus simethicone showed a statistically significant improvement in symptoms compared with the thickened formula and reassurance (P

Hiatal hernia (HH) affects from 10% to 50% of adult population. The correlation between HH, gastroesophageal reflux disease, dyspeptic symptoms, and esophagitis has long been known in adults. The primary objective of our prospective observational study was to estimate the prevalence of HH in children undergoing esophagogastroduodenoscopy (EGD), irrespective of their symptoms. METHODS: We prospectively enrolled 111 consecutive children (48 boys and 63 girls; mean age 94.9 ± 52.3 months) referred for EGD. In all of the patients a asymptomatic score assessment based on the Rome III criteria was used to measure frequency, severity, and duration of gastrointestinal symptoms. HH presence was endoscopically defined; esophagitis presence was evaluated either endoscopically and histologically. Children were divided in 2 age-range groups: 48 months (group 2). RESULTS: Twenty-three patients of 111 (20.7%) had evidence of a sliding HH at EGD. In children from group 2, we found a statistically significant association of HH with heartburn (P = 0.03, 95% confidence interval 1-9.3, r = 0.1) and regurgitation (P = 0.003, 95% confidence interval 1.7-20.4, r = 0.3). Regarding esophagitis presence, no association was found at any age either with defined esophagitis or with dilated intercellular spaces. CONCLUSIONS: Prevalence of HH in our study population was 20.7%. According to our data, HH correlates with the presence of heartburn and regurgitation in children, but not in toddlers. No association was found with esophagitis at any age.

BACKGROUND: Early-onset inflammatory bowel disease (IBD) is generally aggressive, with a high probability of complications and need of surgery. Despite the introduction of highly effective biological drugs, treatment with azathioprine continues to be important even for early-onset IBD; however, in these patients azathioprine response seems to be reduced. This study evaluated azathioprine doses, metabolite concentrations, and their associations with patients' age in children with IBD treated at 6 tertiary pediatric referral centers. METHODS: Azathioprine doses, metabolites, and clinical effects were assessed after at least 3 months of therapy in 17 early-onset (age < 6 yr, cases) and 51 nonearly-onset (aged > 12 and

Background Infant colic (IC) is a prevalent physiological event of infants, which can disrupt the child's home environment. We aimed to investigate the effectiveness of a mixture of Matricariae chamomilla L., Melissa officinalis L. and tyndallized Lactobacillus acidophilus (HA122) compared with Lactobacillus reuteri DSM 17938 and with simethicone for the treatment of IC. Methods A multicenter randomized comparative study was conducted in infants with colic, according to Rome III criteria, who were randomly assigned to receive M. chamomilla L., M. officinalis L. and tyndallized L. acidophilus (HA122) (Colimil® Plus®; Milte Italia Spa, Milan, Italy) (Group A), L. reuteri DSM 17938 (Group B) and simethicone (Group C). Treatment was given to subjects for 28 days. Key Results One-hundred and seventy-six patients completed the study. Mean daily crying time at day 28 was significantly lower in group A (−44, 95% CI: −58 to −30, P

Background We aimed at describing the efficacy of azathioprine (AZA) in pediatric ulcerative colitis, comparing the outcomes of early (0-6 months) versus late (6-24 months) initiation of therapy. Methods Children with ulcerative colitis treated with AZA within 24 months of diagnosis were included. Corticosteroid (CS)-free remission and mucosal healing (MH), assessed by endoscopy or fecal calprotectin, at 12 months were the primary outcomes. Patients were also compared for CS-free remission and MH, need for treatment escalation or surgery, number of hospitalizations, and adverse events during a 24-month follow-up. Results A total of 121 children entered the study (median age 10.5 ± 4.0 years, 59% girls). Seventy-six (63%) started AZA between 0 and 6 months (early group) and 45 (37%) started between 6 and 24 months (late group). Seventy-five percent and 53% of patients in the early and late group, respectively, received CS at the diagnosis (P = 0.01). CS-free remission at 1 year was achieved by 30 (50%) of the early and 23 (57%) of the late patients (P = 0.54). MH occurred in 37 (37%) patients at 1 year, with no difference between the 2 groups (33% early, 42% late; P = 0.56). No difference was found for the other outcomes. Conclusions Introduction of AZA within 6 months of diagnosis seems not more effective than later treatment to achieve CS-free remission in pediatric ulcerative colitis. MH does not depend on the timing of AZA initiation; however, because of the incomplete comparability of the 2 groups at the diagnosis and the use of fecal calprotectin as a surrogate marker of MH, our results should be further confirmed by prospective studies.

AIM: To investigate gastrointestinal complications associated with non-steroidal anti-inflammatory drug (NSAIDs) use in children. METHODS: A retrospective, multicenter study was conducted between January 2005 and January 2013, with the participation of 8 Italian pediatric gastroenterology centers. We collected all the cases of patients who refer to emergency room for suspected gastrointestinal bleeding following NSAIDs consumption, and underwent endoscopic evaluation. Previous medical history, associated risk factors, symptoms and signs at presentation, diagnostic procedures, severity of bleeding and management of gastrointestinal bleeding were collected. In addition, data regarding type of drug used, indication, dose, duration of treatment and prescriber (physician or self-medication) were examined. RESULTS: Fifty-one patients, including 34 males, were enrolled (median age: 7.8 years). Ibuprofen was the most used NSAID [35/51 patients (68.6%)]. Pain was the most frequent indication for NSAIDs use [29/51 patients (56.9%)]. Seven patients had positive family history of Helicobacter pylori (H. pylori) infection or peptic ulcer, and 12 had associated comorbidities. Twenty-four (47%) out of 51 patients used medication inappropriately. Hematemesis was the most frequent symptom (33.3%). Upper gastrointestinal endoscopy revealed gastric lesions in 32/51 (62%) patients, duodenal lesions in 17 (33%) and esophageal lesions in 8 (15%). In 10/51 (19.6%) patients, a diagnosis of H. pylori gastritis was made. Forty-eight (94%) patients underwent medical therapy, with spontaneous bleeding resolution, while in 3/51 (6%) patients, an endoscopic hemostasis was needed. CONCLUSION: The data collected in this study confirms that adverse events with the involvement of the gastrointestinal tract secondary to NSAID use are also common in children.

ACKGROUND AND AIM: Two different subtypes of functional dyspepsia (FD) are recognized in adults: epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). The aim of the study was to assess the presence of FD subtypes in childhood at diagnosis and to observe changes at follow-up. METHODS: A total of 100 patients with a diagnosis of FD based on pediatric Rome III criteria were consecutively enrolled. FD subtypes were successively classified through adult Rome III classification. Children were revaluated after 6 months of follow-up (T1). RESULTS: At T0, 17 (17%) of 100 patients were classified as EPS, whereas 47 (47%) of 100 patients fulfilled criteria for PDS. In 36 (36%) of 100 children an overlap between the 2 subtypes was identified. Nausea was significantly higher in PDS and overlap groups when compared with EPS (χ = 21.7, P = 0.0001; χ = 20.7, P = 0.0001). Headache was significantly increased in PDS and overlap groups compared with patients with EPS (χ = 9.8, P = 0.001; χ = 13.1, P = 0.0001, respectively). At T1 among children belonging to PDS group at enrolment, 9 of 47 (19.1%) changed to EPS group, and 9 of 47 (19.1%) changed to the overlap group. Five (29.4%) of 17 patients and 2 (11.8%) of 17 children diagnosed as having EPS at T0 switched to PDS and overlap group, respectively. Of the 36 patients with overlap at enrollment, 11 (30.6%) satisfied criteria for PDS, and 7 (19.4%) switched to EPS group. CONCLUSIONS: Two distinct FD subtypes are identifiable in pediatric population. A high percentage of overlap and a variation of subtype over time were found, suggesting a common pathophysiologic mechanism.

Infant colic is a prevalent physiological event of healthy children under 3 months of age, which can disrupt the child's home environment. Despite its benign natural history, sometimes it requires a therapeutic approach. There is limited evidence supporting the use of complementary and alternative treatments. The aim of this study was to investigate the effectiveness of a mixture of standardized extract of matricariae Chamomilla L., Melissa Officinalis L. and tyndallized Lactobacillus Acidophilus (H122) compared with Lactobacillus Reuteri (DSM 17938) and with simethicone for the treatment of infantile colic.

Background: Few case reports describe the clinical features of pancreatic involvement in inflammatory bowel disease. Aim: To investigate prevalence and disease course of inflammatory bowel disease children with pancreatitis and with exclusive hyperamylasemia and hyperlipasemia. Methods: We used a web-registry to retrospectively identify paediatric inflammatory bowel disease patients with hyperamylasemia and hyperlipasemia. Participants were re-evaluated at 6 months and 1 year. Results: From a total of 649 paediatric patients, we found 27 with hyperamylasemia and hyperlipasemia (4.1%). Eleven patients (1.6%) fulfilled diagnostic criteria for acute pancreatitis. Female gender was significantly associated with acute pancreatitis (p = 0.04). Twenty-five children (92.5%) had colonic disease. At 6 months 1/11 children with acute pancreatitis (9%) showed acute recurrent pancreatitis, while 1 patient (9%) had persistent hyperamylasemia and hyperlipasemia. At 12 months, 1 patient showed chronic pancreatitis (9.1%). Of the 16 children with exclusive hyperamylasemia and hyperlipasemia, 4 developed acute pancreatitis (25%), while 1 patient (6.2%) still presented exclusive hyperamylasemia and hyperlipasemia at 6 months. At 12 months, 11/16 patients (68.7%) reached a remission of pancreatic involvement, whereas 5 remaining patients (32.3%) had persistent hyperamylasemia and hyperlipasemia. Conclusions: In inflammatory bowel disease children, acute pancreatitis is more common in colonic disease and in female gender. Pancreatic function should be monitored, considering that pancreatic damage may evolve. (C) 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Background: Clostridium difficile infection is associated with pediatric inflammatory bowel disease (IBD) in several ways. We sought to investigate C. difficile infection in pediatric patients with IBD in comparison with a group of children with celiac disease and to evaluate IBD disease course of C. difficile infected patients. Methods: In this prospective, comparative, multicenter study, 211 pediatric patients with IBD were enrolled from October 2010 to October 2011 and tested for the presence of C. difficile toxins A and B in their stools at 0, 6, and 12 months. During the same study period, stool specimens for C. difficile toxins analysis were collected from 112 children with celiac disease as controls. Results: Clostridium difficile occurrence was significantly higher in patients with IBD compared with patients with celiac disease (7.5% versus 0.8%; P = 0.008). Clostridium difficile was associated with active disease in 71.4% of patients with IBD (P = 0.01). Colonic involvement was found in 85.7% of patients with C. difficile. Antibiotics, proton pump inhibitors, hospitalization, and IBD therapies were not associated with increased C. difficile detection. At 12 months, a higher number of C. difficile-positive patients at the enrollment started immunosuppressant/biological therapy compared with patients without C. difficile (P = 0.01). At 6 and 12 months, patients with C. difficile were more frequently in active disease than patients without C. difficile (P = 0.04; P = 0.08, respectively). Hospitalizations were higher at 6 months in C. difficile group (P = 0.05). Conclusions: In conclusion, this study demonstrates that pediatric IBD is associated with increased C. difficile detection. Patients with C. difficile tend to have active colonic disease and a more severe disease course. Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.

Background:Clostridium difficile infection is associated with pediatric inflammatory bowel disease (IBD) in several ways. We sought to investigate C. difficile infection in pediatric patients with IBD in comparison with a group of children with celiac disease and to evaluate IBD disease course of C. difficile infected patients.Methods:In this prospective, comparative, multicenter study, 211 pediatric patients with IBD were enrolled from October 2010 to October 2011 and tested for the presence of C. difficile toxins A and B in their stools at 0, 6, and 12 months. During the same study period, stool specimens for C. difficile toxins analysis were collected from 112 children with celiac disease as controls.Results:Clostridium difficile occurrence was significantly higher in patients with IBD compared with patients with celiac disease (7.5% versus 0.8%; P = 0.008). Clostridium difficile was associated with active disease in 71.4% of patients with IBD (P = 0.01). Colonic involvement was found in 85.7% of patients with C. difficile. Antibiotics, proton pump inhibitors, hospitalization, and IBD therapies were not associated with increased C. difficile detection. At 12 months, a higher number of C. difficile-positive patients at the enrollment started immunosuppressant/biological therapy compared with patients without C. difficile (P = 0.01). At 6 and 12 months, patients with C. difficile were more frequently in active disease than patients without C. difficile (P = 0.04; P = 0.08, respectively). Hospitalizations were higher at 6 months in C. difficile group (P = 0.05).Conclusions:In conclusion, this study demonstrates that pediatric IBD is associated with increased C. difficile detection. Patients with C. difficile tend to have active colonic disease and a more severe disease course.

Objectives Diagnostic and therapeutic benefits of double-balloon enteroscopy (DBE) have been documented in adults, with few data available on pediatric patients. We evaluated the diagnostic and therapeutic utility of DBE in children. Methods A prospective assessment of 113 DBE procedures in 58 consecutive children younger than 18 years (36 boys, 22 girls; median age 12.7 years, range 1-18 years) was performed for a variety of suspected small bowel (SB) disorders from January 2008 to August 2012 in a tertiary referral center for pediatric patients. All of the children had undergone upper gastrointestinal endoscopy and ileocolonoscopy. A total of 19 patients had undergone radiological investigations for SB (n = 11 magnetic resonance imaging; n = 5 barium enterography; n = 3 computed tomography) and 54 patients had undergone wireless capsule endoscopy (WCE). Results The overall median (range) examination time was 92.5 (45-275) minutes. The median (range) estimated insertion length of SB distal to pylorus was 230 (80-450) cm and proximal to ileocecal valve was 80 (5-275) cm. The common indications for DBE were polyposis syndromes (n = 21) and obscure gastrointestinal bleeding (n = 16). The findings included polyps (n = 19), mucosal ulcers and erosions (n = 8), submucosal elevations with white nodules (n = 4), and angioma/angiodysplasia (n = 2). The overall diagnostic yield for SB lesions using DBE was 70.7% (41/58) and for WCE was 77.7% (42/54). Endotherapeutic intervention was successfully used in 46.5% (n = 27/58). The endoscopic, medical, and surgical contributions to change in management by DBE were 72.4% (n = 42/58). Three complications (5.2%) were noted with uneventful recovery. Conclusions The diagnostic yield of DBE was comparable to WCE, but with the addition of therapeutic possibility and histological yield. We believe this technique could be a valuable addition to existing endoscopic techniques, complementary to WCE, and may be considered as an alternative diagnostic and therapeutic option in the SB in children.

AIM: To investigated the molecular cause of very early-onset ulcerative colitis (UC) in an 18-mo-old affected child. METHODS: We analysed the interleukin-10 (IL10) receptor genes at the DNA and RNA level in the proband and his relatives. Beta catenin and tumor necrosis factor-?? (TNF??) receptors were analysed in the proteins extracted from peripheral blood cells of the proband, his relatives and familial adenomatous polyposis (FAP) and PTEN hamartoma tumor syndrome (PHTS) patients. Samples were also collected from the proband's inflamed colorectal mucosa and compared to healthy and tumour mucosa collected from a FAP patient and patients affected by sporadic colorectal cancer (CRC). Finally, we examined mesalazine and azathioprine effects on primary fibroblasts stabilised from UC and FAP patients. RESULTS: Our patient was a compound heterozygote for the IL10RB E47K polymorphism, inherited from his father, and for a novel point mutation within the IL10RA promoter (the -413G->T), inherited from his mother. Beta catenin and tumour necrosis factor ?? receptors-I (TNFRI) protein were both over-expressed in peripheral blood cells of the proband's relatives more than the proband. However, TNFRII was over-expressed only in the proband. Finally, both TNF??-receptors were shown to be under-expressed in the inflamed colon mucosa and colorectal cancer tissue compared to healthy colon mucosa. Consistent with this observation, mesalazine and azathioprine induced, in primary fibroblasts, IL10RB and TNFRII over-expression and TNFRI and TNF?? under-expression. We suggest that ??-catenin and TNFRI protein expression in peripheral blood cells could represent molecular markers of sub-clinical disease in apparently healthy relatives of patients with early-onset UC. CONCLUSION: A synergistic effect of several variant alleles of the IL10 receptor genes, inherited in a Mendelian manner, is involved in UC onset in this young child.

Aim Aims of this study were to evaluate the efficacy of a cow's milk protein (CMP) elimination diet on induction and maintenance of remission and to define association with atopy in children with ulcerative colitis (UC). Methods Twenty-nine consecutive patients (mean age: 11.2 years; range: 4.6–17 years; F/M: 15/14) with newly diagnosed UC were randomized either to receive a CMP elimination diet (n = 14) or to continue a free diet (n = 15) associated with concomitant steroid induction and mesalazine maintenance treatment. Children were prospectively evaluated at four time points: within 1 month, 6 months and 1 year after diagnosis or at the time of relapse. Results Twenty-five of the 29 enrolled patients responded to the UC induction therapy with a complete remission (86.2%), 13 belonging to CMP elimination diet group and 12 to free diet group (p = 0.59). Overall, our data showed that 7 of 13 (53.8%) patients treated with CMP elimination diet and 8 of 15 (53.3%) patients on free diet and UC therapy relapsed within 1 year of follow-up (p = 1). Conclusions In conclusion, data of this paediatric, randomized trial suggest that CMP elimination has no role in the management of UC in non-sensitized children.

OBJECTIVES: To evaluate the correlation between stool characteristics (consistency and frequency) and gut transit time in children and to determine whether the Bristol Stool Form Scale is a reliable method of assessing intestinal transit rate in children. STUDY DESIGN: From March 2011 to March 2012, 44 children (25 boys and 19 girls, mean age 7.8 years) with a diagnosis of functional constipation and 36 healthy, nonconstipated children (17 boys and 19 girls, mean age 7.6 years) were enrolled. All participants maintained a 1-week stool diary, recording the time and date of every bowel movement and stool form, and then completed a validated questionnaire on functional constipation according to Rome III criteria. Whole gut transit time (WGTT) was then assessed using the radiopaque markers test. RESULTS: There was a significant correlation between stool form and WGTT in both constipated and nonconstipated children (correlation coefficient -0.84, P

Gastrointestinal (GI) motility problems represent an important cause of morbidity and sometimes mortality in patients affected by developmental disorders. This article describes motility disorders in Down syndrome, cerebral palsy, familial dysautonomia, and Williams syndrome. These problems do not often receive appropriate attention, either because priority is given to other medical aspects of the disorder, or because of the inability of affected children to communicate their symptoms. A better approach to the diagnosis and treatment of GI disorders is required to improve quality of life and minimize morbidity and mortality among patients with developmental disorders.

Objectives To evaluate the beneficial effects of Lactobacillus reuteri (DSM 17938) in infants with functional chronic constipation. Study design A double-blind, placebo-controlled, randomized study was conducted from January 2008 to December 2008 in 44 consecutive infants at least 6 months old (mean age ± SD, 8.2 ± 2.4 SD; male/female, 24/20) admitted to the Gastrointestinal Endoscopy and Motility Unit of the Department of Pediatrics, University "Federico II" of Naples, with a diagnosis of functional chronic constipation. The 44 infants with chronic constipation were randomly assigned to 2 groups: group A (n = 22) received supplementation with the probiotic L reuteri (DSM 17938) and group B (n = 22) received an identical placebo. Primary outcome measures were frequency of bowel movements per week, stool consistency, and presence of inconsolable crying episodes, recorded in a daily diary by parents. Results Infants receiving L reuteri (DSM 17938) had a significantly higher frequency of bowel movements than infants receiving a placebo at week 2 ( P = .042), week 4 ( P = .008), and week 8 ( P = .027) of supplementation. In the L reuteri group, the stool consistency was reported as hard in 19 infants (86.4%) at baseline, in 11 infants (50%) at week 2, and in 4 infants (18.2%) at weeks 4 and 8. However, there was no significant difference between L reuteri and placebo groups in the stool consistency at all weeks ( P = .63, week 2; P = .38, week 4; P = .48, week 8). Similarly, there was no statistically difference in the 2 groups in the presence of inconsolable crying episodes. No adverse effects were reported. Conclusions The administration of L reuteri (DSM 17938) in infants with chronic constipation had a positive effect on bowel frequency, even when there was no improvement in stool consistency and episodes of inconsolable crying episodes. Because of their safety profile, probiotics may be an attractive option in the treatment of functional constipation.

To the Editor: The pathogenesis of Crohn's disease (CD) is not known: the currently accepted hypothesis is that genetic susceptibility and environmental factors cooperate to trigger the chronic inflammation typical of the disease. Recent evidence implicating the gut microbiome in CD development has generated interest in its characterization (1). Previous studies have shown that bacterial diversity is reduced in CD patients, that bacterial populations in CD patients differ in relation to phenotype, and that the microbial composition differs significantly between inflamed and non-inflamed mucosal areas (2).

Swallowed button batteries (BB) which remain lodged in the oesophagus are at risk of serious complications, particularly in young children. The authors report a 3-year-old child, who rapidly developed an oesophageal perforation, following the ingestion of a 20-mm lithium BB which was initially mistaken for a coin. A thoracotomy and T-tube management of the perforation led to a positive outcome. BBs (20 mm) in children should be removed quickly and close observation is required as the damage initiated by the battery can lead to a significant injury within a few hours.

Systemic mastocytosis (SM) is a rare myeloproliferative neoplasm characterized by proliferation and hyperactivation of clonal mast cells. Clinical manifestations are heterogeneous and encompass cutaneous lesions, gastrointestinal alterations, osteoporosis, anaphylaxis and involvement of bone marrow and other organs due to neoplastic mast cells (MC) infiltration. As consequence, diagnosis may be difficult and patients (pts) are often evaluated by different specialists before the disease is recognized. To date, only few studies (Lim 2009, Escribano 2009, Cohen 2014) described relatively large series of pts with SM. We performed a multicentre retrospective study to evaluate clinical and biological features and therapeutic management in a large series of pts from 10 Italian centres experienced in management of SM and organized in multidisciplinary groups of specialists. We collected 455 pts diagnosed with SM according to WHO criteria. Additionally 26 pts with mastocytosis in the skin (MIS) evaluated with BM examination did not fulfil criteria for SM, leading to diagnosis of Cutaneous Mastocytosis (CM); however 2/26 pts with CM had both cKITD816V mutation and CD2/CD25 expression on MC in BM, additional 3 showed either cKITD816V or CD2/CD25. Moreover, we found 22 pts without MIS but with features of monoclonal mast cell activation syndrome. Of the 455 pts with WHO-SM (male 56%), 252 (55%) had MIS: median age at MIS diagnosis (dg) was 37 years (y) (range 0-79), while at SM dg it was 46.5 (range 18-82). Time from onset of MIS to dg of SM was 9 y (range 0-43). In 18/252 pts (7%) MIS occurred before age of 18 y (median 9, range 0-17) and persisted over childhood. Median age at dg of SM without MIS (203/455 pts, 45%) was older: 54 y, range 19-79 (p Disclosures Martinelli: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy.