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Background: Paediatric Inflammatory Crohn's MRE Index (PICMI) is a multi-point index of intestinal inflammation (mucosal and transmural) for children with CD. The present study aims to assess whether PICMI at diagnosis may predict the course of CD and to test the inter-reader agreement., Methods: CD children with a ≥ 1-year follow-up were retrospectively enrolled. Three radiologists calculated PICMI at diagnosis and association between PICMI and Paediatric Crohn's Disease Activity Index (PCDAI) and CD Endoscopic Index of Severity (CDEIS) was tested., Results: 68 children (median age 13 years IQR: 11-14) with CD with PICMI at diagnosis: remission 6 (8.8 %), mild 29 (42.6 %), moderate 24 (35.3 %), severe 9 (13.2 %), were enrolled. PICMI score significantly correlated with PCDAI at diagnosis (p: 0.036). Steroid-free remission at 1, 3 and 5 years was comparable between PICMI groups (p: 0.606). Higher PICMI at diagnosis was associated with higher biologic introduction at 1 year: incidence rate ratio IRR: 2.17 (1.09-4.42); p = 0.019, 3-year IRR: 2.12 (1.15-3.96); p = 0.011, and 5 years: 2.21 (1.20-4.08); p = 0.007., Conclusions: PICMI score is a reliable and almost reproducible index to score activity in children with CD. Children with higher PICMI scores of disease activity at diagnosis required more biologic treatment to achieve comparable rates of steroid-free remission if compared with lower PICMI scores., Competing Interests: Conflict of interest AR, CV, AG, PAB, DI, NS, MC, GZ, PM, LDA, LN: none related to the paper., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: Data on upadacitinib therapy in children with ulcerative colitis (UC) or unclassified inflammatory bowel disease (IBD-U) are scarce. We aimed to evaluate the effectiveness and safety of upadacitinib as an induction therapy in pediatric UC or IBD-U., Methods: In this multicenter retrospective study, children treated with upadacitinib for induction of remission of active UC or IBD-U from 30 centers worldwide were enrolled. Demographic, clinical and laboratory data as well as adverse events (AEs) were recorded at week 8 post induction., Results: One hundred children were included (90 UC and 10 IBD-U, median age 15.6 [interquartile range 13.3-17.1] years). Ninety-eight were previously treated with biologic therapies, and 76 were treated with ≥2 biologics. At the end of the 8-week induction period, clinical response, clinical remission, and corticosteroid-free clinical remission (CFR) were observed in 84%, 62%, and 56% of the children, respectively. Normal C-reactive protein and fecal calprotectin (FC) <150 mcg/g were achieved in 75% and 50%, respectively. Combined CFR and FC remission was observed in 18/46 (39%) children with available data at 8 weeks. AEs were recorded in 37 children, including one serious AE of an appendiceal neuroendocrine tumor. The most frequent AEs were hyperlipidemia (n=13), acne (n=12), and infections (n=10, five of whom with herpes viruses)., Conclusion: Upadacitinib is an effective induction therapy for refractory pediatric UC and IBD-U. Efficacy should be weighed against the potential risks of AEs., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Aims: Upper endoscopy (UE) procedures (EGD and ERCP) are an established standard of care in pediatric gastroenterology. The Pediatric Endoscopy Quality Improvement Network (PEnQuIN) recently published its pediatric-specific endoscopy quality guidelines. This study, initiated by the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition, aims to evaluate the adherence of Italian pediatric endoscopy centers (PECs) to these established quality standards., Methods: Conducted between April 2019 and March 2021, this nationwide study used a smartphone-based app approach. Data encompassing pediatric endoscopy facilities, patient profiles, endoscopy indications, 17 procedure-related PEnQuIN indicators, and a patient satisfaction questionnaire (Group Health Association of America-9) were systematically collected., Results: A comprehensive analysis of 3582 procedures from 24 centers revealed that 2654 (76%) were UEs. The majority of centers (75%) involved >1 operator, with 9 centers incorporating adult endoscopists, responsible for 5% of UEs. Overall, adherence to quality standards was good; however, areas of improvement include suboptimal reporting of sedation details, adherence to disease-specific guidelines, and patient satisfaction questionnaire completeness (56%). The adverse event rate aligned with literature standards (1%), and patient satisfaction was generally high. A noteworthy observation was a 30% decreased monthly reporting rate and a shift in disease-specific patterns after the COVID-19 outbreak., Conclusions: Pediatric UE practices in Italy adhere well to established quality standards. Emphasizing the adoption of disease-specific guidelines is crucial for optimizing resources, enhancing diagnostic accuracy, and minimizing unnecessary procedures. Prioritizing patient satisfaction is important for immediate enhancements in practice as well as for future research endeavors., Competing Interests: Disclosure All authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Anemia is one of the most frequent extra-intestinal manifestations of inflammatory bowel disease. Insidious onset, variability of symptoms and lack of standardized screening practices may increase the risk of underestimating its burden in children with IBD. Despite its relevance and peculiarity in everyday clinical practice, this topic is only dealt with in a few documents specifically for the pediatric field. The aim of the current guidelines is therefore to provide pediatric gastroenterologists with a practical update to support the clinical and therapeutic management of children with IBD and anemia. A panel of 19 pediatric gastroenterologists and 1 pediatric hematologist with experience in the field of pediatric IBD was agreed by IBD Working group of the Italian Society of Gastroenterology, Hepatology and Nutrition (SIGENP) to produce the present article outlining practical clinical approaches to the pediatric patient with IBD and anemia. The levels of evidence and recommendations have been defined for each part of the statement according to the GRADE system., Competing Interests: Declaration of competing interest The authors have no conflict of interests to declare with regards to this manuscript., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease (CeD) compared to those who did not. We aim to confirm the potential protective role of one of these species, namely Bacteroides vulgatus, and to mechanistically establish the effect of bacterial bioproducts on gluten-dependent changes on human gut epithelial functions., Methods: We identified, isolated, cultivated, and sequenced a unique novel strain (20220303-A2) of B. vulgatus found only in control subjects. Using a human gut organoid system developed from pre-celiac patients, we monitored epithelial phenotype and innate immune cytokines at baseline, after exposure to gliadin, or gliadin plus B. vulgatus cell free supernatant (CFS)., Results: Following gliadin exposure, we observed increases in epithelial cell death, epithelial monolayer permeability, and secretion of pro-inflammatory cytokines. These effects were mitigated upon exposure to B. vulgatus 20220303-A2 CFS, which had matched phenotype gene product mutations. These protective effects were mediated by epigenetic reprogramming of the organoids treated with B. vulgatus CFS., Conclusions: We identified a unique strain of B. vulgatus that may exert a beneficial role by protecting CeD epithelium against a gluten-induced break of epithelial tolerance through miRNA reprogramming., Impact: Gut dysbiosis precedes the onset of celiac disease in genetically at-risk infants. This dysbiosis is characterized by the loss of protective bacterial strains in those children who will go on to develop celiac disease. The paper reports the mechanism by which one of these protective strains, B. vulgatus, ameliorates the gluten-induced break of gut epithelial homeostasis by epigenetically re-programming the target intestinal epithelium involving pathways controlling permeability, immune response, and cell turnover., (© 2024. The Author(s).)

Purpose: Pediatric liver transplant surgery is burdened by arterial complications whose endovascular treatment is not standardized. We report the outcomes of a cohort of pediatric recipients with hepatic artery complications treated by endoluminal procedures., Materials and Methods: From December 2019 to December 2022, consecutive transplanted pediatric patients who underwent endovascular treatment of hepatic artery complications were reviewed. The analysis included: type of complication (occlusion, stenosis, pseudoaneurysm); onset (acute =  < 15 days, subacute = 15-90 days, late =  > 90 days); endovascular technique (angioplasty, stenting); complications and outcomes. Technical success was defined as the opacification of the hepatic artery at the final angiogram with < 50% residual stenosis and no pseudoaneurysms. Clinical success was defined by graft's and patient's survival., Results: Seventeen patients (8 males; median age 33 months, IQR 9-103) underwent 21 hepatic arteriography procedures for predominantly acute or subacute occlusions (n = 7) or stenosis (n = 11) with concurrent pseudoaneurysms (n = 4). Primary and secondary technical success was achieved in 13/18 and 3/3 procedures, respectively, with overall technical success of 76%. Angioplasty alone was successful in 5/21 procedures; stent-retriever thrombectomy was performed in one occlusion with thrombosis; stenting was required in 9/17 (53%) patients. Clinical success was obtained in 14/17 (82%) patients with hepatic artery patency after a median of 367 days (IQR 114.5-500). Clinical failure occurred in 3 permanent occlusions, with 2 deaths and 1 re-transplantation. Procedure-related complications included minor events in 3/17 (18%) patients and 1/17 (6%) death., Conclusion: In liver transplanted children with hepatic artery complications, endovascular treatment may provide clinical success, with stenting often required in acute and subacute conditions., Level of Evidence: Level 4., (© 2023. The Author(s).)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Anti-tumor necrosis factor alpha (anti-TNFα) inhibitors are used extensively for the management of moderate to severe inflammatory bowel disease (IBD) in both adult and pediatric patients. Unfortunately, not all patients show an optimal response to induction therapy, while others lose their response over time for reasons yet poorly understood. We report on a pharmacokinetic/pharmacogenetic approach to monitor the therapy with anti-TNFα in a real-world cohort of seventy-nine pediatric patients affected by IBD that was analyzed retrospectively. We evaluated plasma concentrations of infliximab, adalimumab, and related anti-drug antibodies (ADAs), and single nucleotide polymorphisms (SNPs) in genes involved in immune processes and inflammation on the anti-TNFα response. We found a significant association between the SNP in TNFα promoter (-308G>A) and clinical remission without steroids in patients on infliximab therapy. Additionally, a potential connection between HLA-DQA1*05 genetic variant carriers and a higher risk of anti-TNFα immunogenicity emerged., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Venous outflow obstruction (VOO) is a known cause of graft and patient loss after pediatric liver transplantation (LT). We analyzed the incidence, risk factors, diagnosis, management, and outcome of VOO in a large, consecutive series of left lateral segment (LLS) split LT with end-to-side triangular venous anastomosis., Methods: We evaluated data collected in our prospective databases relative to all consecutive pediatric liver transplants performed from January 2006 to December 2021. We included in this study children undergoing LLS split liver transplant with end-to-side triangular anastomosis. Diagnosis of VOO was based on clinical suspicion and radiological confirmation., Results: VOO occurred in 24/279 transplants (8.6%), and it was associated with lower graft weight (p = .04), re-transplantation (p = .008), and presence of two hepatic veins (p < .0001). In presence of two segmental veins' orifices, the type of reconstruction (single anastomosis after venoplasty or double anastomosis) was not significantly related to VOO (p = .87). Multivariable analysis indicated VOO as a risk factor for graft lost (hazard ratio 3.21, 95% confidence interval 1.22-8.46; p = .01). Percutaneous Transluminal Angioplasty (PTA) was effective in 17/22 (77%) transplants. Surgical anastomosis was redone in one case. Overall six grafts (25%) were lost., Conclusion: VOO after LLS split LT with end-to-side triangular anastomosis is an unusual but critical complication leading to graft loss in a quarter of cases. The occurrence of VOO was associated with lower graft weight, re-transplantation, and presence of two hepatic veins. PTA was safe and effective to restore proper venous outflow in most cases., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Management of children with acute liver failure is challenging. In this retrospective study, paediatric patients diagnosed with ALF at our centre, in the last 26 years, were divided into two groups (G1 = diagnosed from 1997 to 2009; G2 = from 2010 to 2022) and compared to see whether they differed with regard to aetiologies, need for liver transplantation (LT), and outcome. A total of 90 children (median age 4.6 years, range 1.2-10.4; M/F = 43/47) were diagnosed with ALF, by autoimmune hepatitis (AIH) in 16 (18%), paracetamol overdose in 10 (11%), Wilson disease in 8 (9%), and other causes in 19 (21%); 37 (41%) had indeterminate ALF (ID-ALF). Comparing the two periods, the clinical features, aetiologies, and median peak values of INR [3.8 (2.9-4.8) in G1 vs. 3.2 (2.4-4.8) in G2] were similar ( p > 0.05). The percentage of ID-ALF tended to be higher in G1 compared to G2 (50% vs. 32% in G2, p = 0.09). The overall percentage of patients diagnosed with Wilson disease, inborn errors of metabolism, neonatal hemochromatosis or viral infection was higher in G2 (34% vs. 13% in G1, p = 0.02). A total of 21/90 patients (23%; 5 with indeterminate ALF) were treated with steroids; 12 (14%) required extracorporeal liver support treatment. The need for LT was significantly higher in G1 compared to G2 (56% vs. 34%; p = 0.032). Among 37 children with ID-ALF, 6 (16%) developed aplastic anaemia (all in G2, p < 0.001). The survival rate at last follow up was of 94%. On a KM curve, the transplant-free survival was lower in G1 compared to G2. In conclusion, we report a lower need for LT in children diagnosed with PALF during the most recent period compared to the first era. This suggests improvements over time in the diagnosis and management of children with PALF.

Introduction: The purpose of this study was to identify possible serum biomarkers predicting celiac disease (CD) onset in children at risk., Methods: A subgroup from an ongoing, international prospective study of children at risk of CD was classified according to an early trajectory of deamidated gliadin peptides (DGPs) immunoglobulin (Ig) G and clinical outcomes (CD, potential CD, and CD autoimmunity)., Results: Thirty-eight of 325 children developed anti-tissue transglutaminase IgA antibody (anti-tTG IgA) seroconversion. Twenty-eight of 38 children (73.6%) showed an increase in anti-DGPs IgG before their first anti-tTG IgA seroconversion., Discussion: Anti-DGPs IgG can represent an early preclinical biomarker predicting CD onset in children at risk., (Copyright © 2023 by The American College of Gastroenterology.)

Background: Cyclic Vomiting Syndrome (CVS) is a rare functional gastrointestinal disorder, which has a considerable burden on quality of life of both children and their family. Aim of the study was to evaluate the diagnostic modalities and therapeutic approach to CVS among Italian tertiary care centers and the differences according to subspecialties, as well as to explore whether potential predictive factors associated with either a poor outcome or a response to a specific treatment., Methods: Cross-sectional multicenter web-based survey involving members of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP)., Results: A total of 67 responses were received and analyzed. Most of the respondent units cared for less than 20 patients. More than half of the patients were referred after 3 to 5 episodes, and a quarter after 5 attacks. We report different diagnostic approaches among Italian clinicians, which was particularly evident when comparing gastroenterologists and neurologists. Moreover, our survey demonstrated a predilection of certain drugs during emetic phase according to specific clinic, which reflects the cultural background of physicians., Conclusion: In conclusion, our survey highlights poor consensus amongst clinicians in our country in the diagnosis and the management of children with CVS, raising the need for a national consensus guideline in order to standardize the practice., (© 2022. The Author(s).)

Background: Although biliary complications after orthotopic liver transplantation represent a common source of morbidity and mortality, decreasing graft survival, consensus is lacking on their management in the pediatric population., Objective: The aim of this study was to present the prevalence of such biliary complications and their interventional radiologic management with representative images., Materials and Methods: This retrospective study reports our experience with percutaneous transhepatic cholangiography in the management of biliary complications after orthotopic liver transplantation in pediatric patients. This study enrolled all pediatric patients (<18 years old) who underwent percutaneous transhepatic cholangiography for the management of biliary complications after orthotopic liver transplantation at a tertiary care center between January 2010 and December 2020. Diagnosis of biliary complications and indication to perform percutaneous transhepatic cholangiography were based on clinical, laboratory or radiologic data., Results: Among the 301 orthotopic liver transplantations, 78 (26%) developed biliary complications that were managed by interventional radiology: these included 52 (17.3%) biliary strictures, 19 (6.3%) bile leaks, 5 (1.7%) biliary stones, 1 (0.3%) iatrogenic biliary obstruction and 1 (0.3%) vanishing syndrome. The median time interval between orthotopic liver transplantation and the diagnosis of biliary complications was 6.0 years (interquartile range [IQR] 8.2 years). Percutaneous transhepatic cholangiography and biliary duct catheterization were successful in all cases, with low rates of complications that were variable among subgroups., Conclusion: A wide spectrum of biliary complications can occur after pediatric orthotopic liver transplantation. In this large single-center experience, we highlight the value of percutaneous transhepatic cholangiography in their diagnosis and management. Percutaneous treatments in pediatric patients are safe and effective, providing resolution or serving as a bridge to surgery, including re-transplantation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose of the Review: The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged and caused a massive global health crisis. The aim of this review is first, to provide the latest evidence on what is known about the pathophysiology and the transmission of SARS-CoV-2 and then to focus on the manifestations of the gastrointestinal (GI) tract in children with COVID-19. Lastly, we summarise the impact of COVID-19 on patients with preexisting GI diseases., Recent Findings: Even though the virus is mostly transmitted from human to human via respiratory droplets, ACE2 is known to be expressed throughout the GI tract, and SARS-CoV-2 ribonucleic acid has been isolated from patients' stools. GI symptoms including abdominal pain, diarrhoea and vomiting are frequently reported in paediatric patients. Interestingly, a small number of patients seem to exhibit solely GI symptoms. In addition, a multisystem inflammatory syndrome in children (MIS-C) related to SARS-COV-2 described in children, has a high rate of GI involvement. Several etiopathogenetic mechanisms have been postulated to explain the GI involvement of COVID-19., Summary: Clinicians should not underestimate or disregard these early or mild GI symptoms, because the patients may be infected and transmit the virus, or develop a more severe condition such as MIS-C., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Aim of the present report was to investigate the repercussions of COVID-19 pandemic on the procedural volumes and on the main indications of pediatric digestive endoscopy in Italy., Methods: An online survey was distributed at the beginning of December 2020 to Italian digestive endoscopy centers. Data were collected comparing two selected time intervals: the first from 1st of February 2019 to 30th June 2019 and the second from 1st February 2020 to 30th June 2020., Results: Responses to the survey came from 24 pediatric endoscopy Units. Globally, a reduction of 37.2% was observed between 2019 and 2020 periods with a significant decrease in median number of procedures (111 vs 57, p < 0.001). Both the median number of procedures performed for new diagnoses and those for follow-up purposes significantly decreased in 2020 (63 vs 36, p < 0.001 and 42 vs 21, p< 0.001, respectively). We reported a drastic reduction of procedures performed for suspected Celiac Disease and Functional Gastrointestinal Disorders (55.1% and 58.0%, respectively). Diagnostic endoscopies for suspected IBD decreased of 15.5%, whereas procedures for Mucosal Healing (MH) assessment reduced of 48.3%., Conclusions: Our study provides real-world data outlining the meaningful impact of COVID-19 on pediatric endoscopy practice in Italy., Competing Interests: Conflict of interest None declared., (Copyright © 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

To test the impact of celiac disease (CD) and depression symptoms on quality of life in adolescent patients., Methods: We conducted a prospective survey of 12- to 18-year-old celiac patients and their caregivers between January 2015 and November 2016. Enrolled parents and youth completed standard measures of adjustment to celiac disease, depression, and quality of life., Results: We enrolled 105 patients with CD and their parents. Both parents and youth reported high levels of depression symptoms. There were no associations between age, duration of CD, or following a gluten-free diet (GFD) and quality of life. No significant associations were found between adolescent perception of CD state and quality of life; parental report of adolescent's adjustment to CD; and youth report of quality of life were modestly associated (r = 0.19, P ≤ 0.05). Moderate associations were observed between adolescent reports of depression and quality of life (r = 0.59, P < 0.01) and between parental reports of adolescent depression and quality of life (r = 0.41, P  = 0.01). Only depressive symptoms by youth and parent report, however, and not adjustment to celiac, explained unique variance in quality of life., Conclusion: Adolescents with CD report levels of depression comparable to those reported by adolescents seeking mental health services. Length of time living with CD, or on GFD, age at diagnosis and perception of disease state do not appear to contribute to depression. High rates of depression may impact CD prognosis, therefore, screening for depression in adolescents with CD appears critical. Identification and intervention of depression may lead to improved adherence to the GFD during emerging adulthood., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: During Coronavirus Disease 2019 (COVID-19) outbreak in Lombardia, people were recommended to avoid visiting emergency departments and attending routine clinic visits. In this context, it was necessary to understand the psychological reactions of patients with chronic diseases. We evaluated the psychological effects on patients with chronic respiratory conditions and inflammatory bowel disease (IBD) through the analysis of their spontaneous contacts with their referral centres., Methods: Cross-sectional study was conducted from February 23 to April 27, 2020 in patients, or their parents, who contacted their multidisciplinary teams (MDT). E-mails and phone calls directed to the MDT of the centre for cystic fibrosis (CF) in Milano and for paediatric IBD in Bergamo, were categorised according to their contents as information on routine disease management, updates on the patient's health status, COVID-19 news monitoring, empathy towards health professionals, positive feedback and concern of contagion during the emergency., Results: One thousand eight hundred and sixteen contacts were collected during the study period. In Milano, where the majority of patients were affected by CF, 88.7% contacted health professionals by e-mail, with paediatricians receiving the largest volume of emails and phone calls compared with other professionals (P< .001). Compared with Milano, the centre for IBD in Bergamo recorded more expression of empathy towards health professionals and thanks for their activity in the COVID-19 emergency (52.4% vs 12.7%, P< .001), as well as positive feedback (64.3% vs 2.7%, P = .003)., Conclusion: One of the most important lessons we can learn from COVID-19 is that it is not the trauma itself that can cause psychological consequences but rather the level of balance, or imbalance, between fragility and resources. To feel safe, people need to be able to count on the help of those who represent a bulwark against the threat. This is the role played, even remotely, by health professionals., (© 2021 John Wiley & Sons Ltd.)

Objectives: In the era of Coronavirus 2019 (COVID-19), concern has been raised for immunosuppressed patients, including children with inflammatory bowel diseases (IBD). We aimed to collect data from IBD tertiary centers of Lombardy during pandemic. Methods: A cross-sectional survey enrolling IBD children has been completed by seven major IBD centers in Lombardy during lockdown. The clinical form included questions on any symptom consistent with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the IBD adherence treatment. Furthermore, we have reviewed all IBD medical records including new IBD diagnoses and flares in known IBD patients after the lockdown. Results: Questionnaires of 290 IBD children were returned during lockdown. Out of them, 24 children (8%) complained of mild symptoms suspicious of SARS-CoV-2 infection without needing hospitalization or changing IBD treatment. During the lockdown, one patient presented with IBD flare and one had infectious colitis, with no new IBD cases. Conversely, after lockdown, 12/290 (4%) children relapsed and 15 children were newly diagnosed with IBD. Last year, in the same timeframe, 20/300 (7%) children presented with IBD flare, while 17 children had IBD onset with no statistical difference. Conclusions: Our data on children with IBD in a high COVID-19 prevalence region are reassuring. Only a minority of IBD children had mild symptoms, and no hospitalization or treatment modification was needed. Standard IBD treatments including biologics were safely continued. New IBD diagnoses and flares in known IBD children occurred after the lockdown phase, although no significant difference was found compared with the previous year., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sansotta, Norsa, Zuin, Panceri, Dilillo, Pozzi, Giacomo, Moretti, Celano, Nuti, Sgaramella, Stefano, Salvatore, Arrigo, Motta and D'Antiga.)

Background. Percutaneous transhepatic cholangiography (PTC) is an established treatment in the management of biliary strictures. The aim of our study was to determine the incidence of PTC-related infectious complications in transplanted children, and identify their precise aetiol-ogy. Methods. We retrospectively reviewed all PTC performed from January 2017 to October 2020 in our center. Before the procedure, all patients received antibiotic prophylaxis defined as first line, while second line was used in case of previously microbiological isolation. Cholangitis was defined as fever (>38.5°) and elevated inflammatory markers after PTC, while sepsis included hemodynamic instability in addition to cholangitis. Results. One hundred and fifty-seven PTCs from 50 pediatric recipients were included. The overall incidence of cholangitis and sepsis after PTC was 44.6% (70/157) and 3.2% (5/157), respectively, with no fatal events. Blood cultures yielded positive results in 15/70 cases (21.4%). Enterococcus faecium and Pseudomonas aeruginosa were the most common isolated pathogens. Multidrug-resistant (MDR) pathogens were found in 11/50 patients (22%). Conclusion. PTC is associated with a relatively high rate of post-procedural cholangitis, although with low rate of sepsis and no fatal events. Blood cultures allowed to find a precise aetiology in roughly a quarter of the cases, showing prevalence of Enterococcus faecium and Pseudomonas aeruginosa .

We aimed to evaluate the role of liver biopsy to predict subclinical biliary strictures (BS) and assess the impact of BS on long-term allograft dysfunction following liver transplantation in children (LT). We reviewed all liver biopsies performed from 2012-2018. Percutaneous transhepatic cholangiography (PTC) was performed in patients presenting cholangiolar proliferation on cytokeratin-7 stained sections. We performed 271 biopsies in 161 children (86% with a left lateral segment); 44/161 (27%) presented with diffuse or multifocal cholangiolar proliferation. Among them, a tight BS was confirmed in 38/44 (86%, 24% of total) and it was managed by balloon dilatation. Cholangiolar proliferation showed a positive predictive value (PPV) for BS of 86.4%. Levels of alkaline phosphatase >325 IU/L predicted BS (P = .007). Dilatation of intrahepatic bile ducts on ultrasound was found only in 44% of patients with BS. Following a median follow-up of 9.2 years, only 15/38 (39%) patients resolved the BS. In conclusion subclinical BS is very common and probably underdiagnosed in these patients. Histological evidence of cholangiolar proliferation detectable by cytokeratin-7 immunostain should be preferred to liver function tests and ultrasound to suspect BS. BS in this setting should be regarded as a main cause of long-term allograft dysfunction., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: The aim of the study was to assess changes in clinical phenotype, and identify determinants of outcome in children with chronic hepatitis B virus (HBV) infection born in HBV-endemic countries followed in 2 Italian tertiary care centers after immigration or adoption., Methods: A prospective observational study on hepatitis B e-antibodies-negative chronic hepatitis B children started on 2002. Patients with liver fibrosis, or those needing antiviral treatment were excluded. Immune active patients were defined those with raised transaminases (alanine aminotransferase > 40 IU/L), immune tolerants those having normal alanine aminotransferase, both exhibiting substantial viral replication (HBV DNA >2000 IU/mL)., Results: Sixty-nine patients (44 boys, median age 4.7 years) had a median follow-up of 53 months. At entry, 18 (26%) children were immune tolerant, 47 (68%) immune active, and 4 had indeterminant immune status. At last follow-up, 14 (78%) of the immune-tolerant patients remained so, whereas only 23 (49%) of the immune active children maintained their initial immune phenotype. Seroconversion to hepatitis B e antibodies (SCHBe) occurred in only 2 (11%) immune tolerants, whereas 13 (28%) immune active patients achieved SCHBe.Ethnicity was the only feature independently correlated to SCHBe: Asian origin reduced by 4.1 times the probability of SCHBe (Asian vs other; odds ratio = 0.24 [95% confidence interval = 0.07-0.76]; P = 0.016) compared to other ethnicities, whereas viral genotype did not influence the outcome., Conclusions: Ethnicity and immune status phenotype against HBV, rather than HBV genotype, are the main determinants of SCHBe in foreign-born children with chronic HBV infection.

The effects of gluten free diet (GFD) on body mass index (BMI) and growth parameters in pediatric patients with celiac disease (CD) and their dependence on different socio-cultural environments are poorly known. We conducted an international retrospective study on celiac patients diagnosed at the University of Verona, Italy, and at the University of Chicago, Chicago, IL, USA, as underweight. A total of 140 celiac children and 140 controls (mean age 8.4 years) were enrolled in Chicago; 125 celiac children and 125 controls (mean age 7.3 years, NS) in Verona. At time of diagnosis, Italian celiac children had a weight slightly lower ( p = 0.060) and a BMI z-score significantly ( p < 0.001) lower than their American counterparts. On GFD, Italian celiac children showed an increased prevalence of both underweight (19%) as well as overweight (9%), while American children showed a decrease prevalence of overweight/obese. We concluded that while the GFD had a similar impact on growth of celiac children in both countries, the BMI z-score rose more in American than in Italian celiac children. Additionally, in Italy, there was an alarming increase in the proportion of celiac children becoming underweight. We speculate that lifestyle and cultural differences may explain the observed variations., Competing Interests: The authors declare no conflict of interest.

Background: The aim of this study is to compare the performance of antitissue transglutaminase (atTG) chemiluminescence immunoassay (CLIA) with the standard enzyme-linked immunosorbent assay (ELISA) methods in monitoring celiac children after the start of gluten-free diet (GFD)., Methods: Celiac children diagnosed between 2005 and 2016 at our centre were classified into 2 groups based on serum assay (ELISA vs CLIA) used for atTG monitoring, and were compared on percentage of decrease and time to normalization of atTG on GFD., Results: Among 260 included children, the rate of normalization of atTG levels at 30 months' follow-up was 86% and 70% in ELISA and CLIA group, respectively (P < 0.01). Median time to normalization was 11.7 and 14.7 months in ELISA and CLIA group respectively (P = 0.003). Marsh score at diagnosis was not associated with time to atTG normalization (P = 0.770), whereas older age at diagnosis and higher baseline atTG predicted longer time to atTG normalization (P = 0.01, P < 0.01)., Conclusions: The percentage and the time of the atTG normalization in celiac children on GFD should be interpreted according to the utilized assay: at 30 months' follow-up children tested by CLIA are less likely to normalize atTG levels compared to those tested by ELISA. Younger age at diagnosis and lower baseline atTG are predictors of earlier atTG normalization, regardless of the adopted assay.

Purpose of Review: There is growing evidence encouraging the use of probiotics in many conditions in children. However, given the wide number of probiotics available and contradictory data in the literature, the health-care provider is often faced with uncertainness about whether or not to use probiotics and which one(s) to choose. We here review current hypotheses regarding the efficacy and safety of probiotics and evaluate the available data on the use of probiotics in most common diseases in children. Considering that probiotics have strain-specific effects, we will focus on individual probiotic strains rather than on probiotics in general., Recent Findings: Strain-specific efficacy was clearly demonstrated with Lactobacillus rhamnosus GG and Saccharomyces boulardii I-745 in the treatment of acute infectious diarrhea, Lactobacillus reuteri DSM 17938 in infantile colics, Lactobacillus rhamnosus GG, and VSL#3 in irritable bowel syndrome. In addition, encouraging results are seen for use of probiotics in necrotizing enterocolitis, food allergy, and nonalcoholic fatty liver disease. However, the data available for constipation are to be considered somewhat equivocal., Summary: The clinical relevance of these findings indicates that healthcare providers need to take strain-specificity and disease specificity of probiotics into consideration when recommending probiotic for their patients.

Objective: The aim of the study was to determine the effects of the gluten-free diet (GFD) on body mass indexes (BMIs) in children with celiac disease at University of Chicago before and after 2011, when processed gluten-free foods became readily available on the market., Methods: We conducted a retrospective chart review of children seen at University of Chicago Celiac Center from January 2002 to May 2016. BMI was recorded upon GFD initiation in addition to at least 1 other timepoint: 6 months, 1 year, 2 years, 3 years, and 4+ years. We compared the rate of BMI increase in children who were diagnosed before versus after 2011., Results: A total of 147 children (66% girls) with biopsy-confirmed celiac disease were included in the study. The mean BMI at diagnosis was 17.8 (standard deviation 3.9) for those diagnosed before 2011 and 17.1 (standard deviation 2.7) for those diagnosed after 2011. Based on a mixed-effects random-intercept random-slope regression model, there was no evidence for significant difference in BMI change over time between the 2 groups (P value = 0.36). BMI values overall were noted to increase after starting the GFD, even at the first appointment. Serologies were monitored after patients started the GFD and approached normal values, allowing us to conclude that patients were adherent to the GFD., Conclusions: Although overall we observed no significant changes in BMI before and after 2011, we did notice that in adolescent celiac patients there was a trend toward a higher postdiagnosis BMI in the years after 2011. We speculate that teenagers may be especially vulnerable to choosing quick and easy processed gluten-free options over more healthy, natural alternatives leading to a rise in their BMIs after the 2011 surge in production of processed gluten-free foods on the market. Therefore, special attention must be paid to this population to insure ongoing healthy food choices even after many years on the GFD.

While considerable progress has been made in the treatment of inflammatory bowel diseases (IBD), alternative options are constantly sought by adult patients as well as frustrated parents of young patients. These include dietary modifications, food supplements, and, more recently, probiotics.Their potential use is based on the demonstrated role of the altered mucosal immune response to bacterial agents that eventually leads to the chronic intestinal inflammation that characterized IBD. In fact, probiotics might conceivably be beneficial due to multiple mechanisms: stimulation of anti-inflammatory cytokines, inhibition of inflammatory cytokines, strengthening of intestinal barrier, and antagonistic action on pathogens. Such mechanisms have been largely extensively investigated in animal models both in vitro and in vivo.Despite such premise, a relatively scarce number of clinical trials are available, and of them only a handful in pediatric age. Overall, available evidence is very disappointing in the treatment of Crohn's disease (CD), where no recommendation for probiotic use can be made. In ulcerative colitis (UC), on the other hand, there is clinical evidence of efficacy for some specific strains and especially for multi-strain preparations.In summary, more data are needed very likely to yield a better understanding on what strains and in what doses should be used in different specific clinical settings.

Objective: The aim of the study was to evaluate the efficacy of the gluten-free diet (GFD) on gastrointestinal (GI) and extra-intestinal (EI) symptom resolution and identify predictors for persistence of symptoms in all celiac patients at the University of Chicago., Methods: We conducted a retrospective chart review from 2002 to 2015. GI symptoms included abdominal pain, bloating, constipation, diarrhea, failure to thrive/weight loss, nausea, reflux, and vomiting. EI symptoms included abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia, stomatitis, myalgia, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility., Results: A total of 554 patients (227 children) with celiac disease (CeD) were included. Abdominal pain, diarrhea and failure to thrive were the most common GI symptoms in children whereas diarrhea, bloating, and abdominal pain were most common in adults. Short stature, fatigue, and headache were the most common EI symptoms in children whereas iron deficiency anemia, fatigue, and headache/psychiatric disorders were most common in adults. Children had significantly higher rates of EI and GI symptom resolution as compared to adults, with greater rates of improvements in GI versus EI symptoms at more than 24 months. Long duration of symptoms, female sex, and non-adherence to a GFD were the most important significant predictors of failure to clinically improve., Conclusions: On a strict GFD, children report greater rates of both GI and EI symptom resolution as compared to adults with greater rates of improvement in GI over EI symptoms. Early recognition of CeD and close attention to diet adherence may help in symptom resolution.

Objective: The aim of the study was to evaluate the effectiveness of the gluten-free diet (GFD) on extraintestinal symptoms in pediatric and adult celiac populations at the University of Chicago., Methods: We conducted a retrospective chart review of the University of Chicago Celiac Center clinic charts from January 2002 to October 2014. Demographics, serologic testing, intestinal biopsies, and extraintestinal symptoms at presentation, 12, 24, and >24 months were recorded. Extraintestinal symptoms included abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia, stomatitis, myalgias, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility., Results: A total of 737 patients with biopsy-confirmed celiac disease or skin biopsy-confirmed dermatitis herpetiformis were included. Patients lost to follow-up, or with insufficient data were excluded leaving 328 patients (157 pediatrics younger than 18 years). For pediatrics, the female to male ratio was 2:1 and the mean age at diagnosis was 8.9 years. For adults, 4:1 and 40.6 years old. Extraintestinal symptom rates were similar in children (60%) and adults (62%). Short stature (33%), fatigue (28%), and headache (20%) were most common in children. Iron deficiency anemia (48%), fatigue (37%), and headache/psychiatric disorders (24%) were common in adults. Children had faster/higher rates of symptom resolution compared with adults. Twenty-eight percent of children with unresolved short stature on a GFD were found to have other comorbidities., Conclusions: Children and adults with celiac disease have similar rates of extraintestinal manifestations. In children short stature, fatigue, and headache were most common, whereas anemia, fatigue, and headache/psychiatric disorders were most common in adults. Children on a strict GFD showed faster and higher rates of symptom resolution as compared to adults. Unresponsive children with short stature must be assessed for comorbidities.

Objective: To test the hypothesis that children with celiac disease (CD) on gluten-free diet are at increased risk of abdominal pain (AP) associated-functional gastrointestinal disorders (FGIDs)., Study Design: This was a multinational cross-sectional study performed from 2014 to 2015. Patients 4-18 years of age with CD on gluten-free diet for longer than 6 months were recruited from pediatric CD clinics in US and Italy. Control groups included siblings of children with CD (with normal tissue transglutaminase levels) and unrelated controls. Subjects or parents completed the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III., Results: Children (n = 289) were recruited (55% US, 45% Italy): 96 children with CD, 96 sibling controls, and 97 unrelated controls. Chronic AP was present in 30 (30.9%) subjects with CD, 22 (22.7%) sibling controls, and 21 (21.6%) unrelated controls (P = .26 patients with CD vs siblings; P = .18 patients with CD vs unrelated; P = .96 siblings vs unrelated). AP-FGIDs were present in 8 (8.2%) subjects with CD, 8 (8.2%) sibling controls, and 2 (2.1%) unrelated controls (P = 1.00 subjects with CD vs sibling controls; P = .06 subjects with CD vs unrelated controls; P = .06 sibling controls vs unrelated controls)., Conclusion: This multinational study evaluated the prevalence of chronic abdominal pain and AP-FGIDs in the pediatric population with CD. We found that subjects with CD and controls have a similar prevalence of chronic AP and AP-FGIDs. This suggests that not all types of gastrointestinal inflammation result in AP-FGIDs in children., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Strategies to prevent or reduce the risk of allergic diseases are needed. The time of exclusive breastfeeding and introduction of solid foods is a key factor that may influence the development of allergy. For this reason, the aim of this review was to examine the association between exposure to solid foods in the infant's diet and the development of allergic diseases in children. Classical prophylactic feeding guidelines recommended a delayed introduction of solids for the prevention of atopic diseases. Is it really true that a delayed introduction of solids (after the 4th or 6th month) is protective against the development of eczema, asthma, allergic rhinitis and food or inhalant sensitisation? In recent years, many authors have found that there is no statistically significant association between delayed introduction of solids and protection for the development of allergic diseases. Furthermore, late introduction of solid foods could be associated with increased risk of allergic sensitisation to foods, inhalant allergens and celiac disease in children. Tolerance may be driven by the contact of the mucosal immune system with the allergen at the right time of life; the protective effects seem to be enhanced by the practice of the breastfeeding at the same time when weaning is started. Therefore, recent guidelines propose a "window" approach for weaning practice starting at the 17th week and introducing almost all foods within the 27th week of life to reduce the risk of chronic diseases such as allergic ones and the celiac disease. Guidelines emphasize the role of breastfeeding during the weaning practice., (Copyright © 2012 SEICAP. Published by Elsevier Espana. All rights reserved.)

Adverse drug reactions or side effects are usually expected, dose dependent, and occur at therapeutic doses. Anaphylactic and anaphylactoid reactions are unexpected and dose independent and can occur at the first exposure to drugs used during anesthesia. Perioperative anaphylaxis is a severe and rapid clinical condition that can be lethal even in previously healthy patients. The initial diagnosis of anaphylaxis is presumptive. A precise identification of the drug responsible for the adverse reaction is more difficult to establish in the case of anaphylactoid reaction because the adverse reaction could result from additive side effects of different drugs injected simultaneously. The timing of the reaction in relation to events, e.g. induction, start of surgery, administration of other drugs, i.v. fluids, is essential for the diagnosis. Generally, reactions are predominant in the induction and recovery phases, and manifested mainly as cutaneous symptoms. Reactions to drugs coincide with the phases when they are administered. Reactions to antibiotics are more frequent in the induction phase, to neuromuscular agents in the initiation and maintenance phases and to non-steroidal anti-inflammatory agents in the recovery phase. The differential diagnosis of any adverse reaction during or following anesthesia should include the possibility of anaphylaxis.

The most common agents that are responsible for intraoperative anaphylaxis are muscle relaxants. In fact, neuromuscular blocking agents (NMBAs) contribute to 50-70 percent of allergic reactions during anaesthesia. The main mechanism of hypersensitivity reactions to NMBAs is represented by acute type I allergic reactions and the most severe form is anaphylaxis. The rate of non IgE mediated immediate hypersensitivity reactions usually varies between 20 percent and 35 percent of the reported cases in most large series. In a recent report, non allergic suspected reactions to NMBAs occurred with almost the same frequency as did those with an allergic component. Although the precise mechanisms of these reactions remain difficult to ascertain, they usually result from direct non specific mast cell and basophil activation. After diagnostic procedures, regardless of the specific IgE results, NMBAs are contraindicated if the skin tests were positive. In view of the constantly evolving anesthesiologic practices, and of the complexity of allergy investigation, an active policy to identify patients at risk and to provide any necessary support to anaesthetists and allergologists should be promoted. The high frequency of IgE anaphylactic reactions and the feasibility of skin tests in children justify systematic allergy testing whenever hypersensitivity reaction occurs during general anaesthesia.

Background: Accuracy of intraepithelial lymphocytes counts for diagnosing mild enteropathy coeliac disease in absence of villous atrophy can be limited by inappropriate controls included in the studies., Aim: To determine the diagnostic accuracy of intraepithelial lymphocytes counts utilising controls lacking HLA coeliac disease-associated alleles., Methods: Intraepithelial lymphocytes counting at villus tip and per 100 enterocytes was performed at haematoxylin and eosin (H&E) and CD3-stainings in: 29 cases (21 with potential coeliac disease and 8 affected by latent coeliac disease) representing the patient population and 14 noncoeliac controls lacking HLA-DQ2/DQ8 alleles., Results: Threshold (mean+2 s.d.) of duodenal intraepithelial lymphocytes at villus tip and per 100 enterocytes in noncoeliac controls was respectively: 3.5 and 18 at H&E, 3.2 and 17 following CD3-staining. Considering the whole patient population, the sensitivity of tip intraepithelial lymphocytes in detecting mild enteropathy coeliac disease was 90% (95% CI=72.6-97.8) both at H&E and CD3-stainings. The sensitivity of intraepithelial lymphocytes per 100 enterocytes was 93% (95% CI=77.2-99.2) both at H&E and CD3-staining. Specificity of both intraepithelial lymphocytes counts was 100% (95% CI=76.8-100). Using a threshold of 25 intraepithelial lymphocytes per 100 enterocytes could miss 59% of cases at H&E and 48% following CD3-staining., Conclusions: Intraepithelial lymphocytes counts are diagnostic feasible tools to detect mild enteropathy coeliac disease. Threshold of duodenal intraepithelial lymphocytes may be lower than currently accepted., (© 2011 Blackwell Publishing Ltd.)