Pediatric nutritional surgery and its implications: results from a unicentric retrospective analysis.

PURPOSE: Existing guidelines provide weak recommendations on the surgical management of nutritional problems in children. The objective was to design a management pathway to address the best nutritional surgery (NS) procedure in a given patient. METHODS: Retrospective analysis of children treated at our department from January 2015 to December 2019. The sample was divided into two groups according to presence or absence of neurological impairment (NI). Patients with NI (Group 1) were classified in three subgroups based on presenting symptoms: A-Dysphagia without gastroesophageal reflux (GER); B-GER with or without dysphagia; C-Symptoms associated with a delayed gastric emptying. RESULTS: A total of 154 patients were included, 111 with NI. One-hundred-twenty-eight patients underwent only one procedure. Complications and mortality were superior in Group 1. In subgroup A, isolated gastrostomy was the first NS in all patients. In subgroup B most of patients were subjected to a Nissen fundoplication, while in 5 cases total esophagogastric dissociation (TEGD) was the first intervention. Considering the entire sample, 92.3% patients who underwent a TEGD did not require further procedures. CONCLUSION: NS encompasses various procedures depending on presenting symptoms and neurological status. A management flowchart for these patients is proposed.

Institution of an interdisciplinary IBD centre is associated with improved healthcare utilisation.

Despite the institution of an interdisciplinary Inflammatory Bowel Disease (IBD) centre is encouraged, how it may improve patient care is still unknown. In a 5-year period following organisation of an IBD centre, hospitalisations per patient/year decreased (0.41-0.17) and patients on biologics increased (7.7%-26.7%). Total number of hospitalisations (-18.4%) and length of hospitalisation (-29.4%) improved compared with a preceding 5-year period. These findings suggest that institution of an interdisciplinary IBD centre is associated with improved healthcare utilisation.

Clinical Course of Very Early-Onset Inflammatory Bowel Disease.

OBJECTIVES: Data on the phenotypes and disease outcomes of very early-onset inflammatory bowel disease (VEO-IBD) are limited. The aims of this study were to describe the clinical features, outcomes, and treatment response of VEO-IBD patients and to compare them with later-onset pediatric inflammatory bowel disease (P-IBD) patients. METHODS: All consecutive patients aged 0-6 years who were diagnosed with Crohn disease (CD), ulcerative colitis, or IBD unclassified (IBD-U) at 2 academic hospitals from 2010 to March 2021 were included. They were compared to sex-matched IBD patients aged 6-17 years. RESULTS: Two hundred thirty-two patients were included, 78 (34%) with VEO-IBD and 154 (66%) with P-IBD. IBD-U was the most common diagnosis in the VEO-IBD group compared to P-IBD (28% vs 3%, P < 0.001), while CD was predominant in older children (27% vs 52%, P < 0.001). The VEO-IBD group showed lower rates of clinical remission after induction with steroids compared to older children (82% vs 93%, P = 0.01), higher rates of steroid resistance (14% vs 5%, P = 0.02), and steroid dependence (27% vs 8%, P < 0.001). The number of patients who started anti-tumor necrosis factor (TNF)-α agents was similar between the groups. Anti-TNF-α retention was lower in the VEO-IBD group at 1 and 2 years (59% vs 85%, P = 0.003; 16% vs 55%, P < 0.001, respectively). Surgical risk appeared to be higher for VEO-IBD (32% vs 14%, P < 0.001). CONCLUSIONS: When compared to P-IBD patients, patients with VEO-IBD may have a more severe disease course, a poorer response to steroids and anti-TNF-α agents, and require more frequent surgical procedures.

Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy.

Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities.

Type I interferon activation in RAS-associated autoimmune leukoproliferative disease (RALD).

RAS-associated autoimmune leukoproliferative disease (RALD) is a rare immune dysregulation syndrome caused by somatic gain-of-function mutations of either NRAS or KRAS gene in hematopoietic cells. We describe a 27-year-old patient presenting at 5 months of age with recurrent infections and generalized lymphadenopathy who developed a complex multi-organ autoimmune syndrome with hypogammaglobulinemia, partially controlled with oral steroids, hydroxichloroquine, mofetil mycophenolate and IVIG prophylaxis. Activation of type I interferon pathway was observed in peripheral blood. Since 18 years of age, the patient developed regenerative nodular hyperplasia of the liver evolving into hepatopulmonary syndrome. Whole exome sequencing analysis of the peripheral blood DNA showed the NRAS p.Gly13Asp mutation validated as somatic. Our report highlights the possibility of detecting somatic NRAS gene mutations in patients with inflammatory immune dysregulation and type I interferon activation.

Thalidomide as treatment of crohn-like disease occurred after allogeneic hematopoietic stem cell transplantation in a pediatric patient.

BACKGROUND: Autoimmune diseases may occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and inflammatory bowel disease (IBD or Crohn disease) is rarely described. We describe a child who developed CD after allo-HSCT, successfully treated with thalidomide. CASE REPORT: A child affected by mucopolysaccharidosis type I received two allogeneic HSCTs for rejection after the first one. After cutaneous and intestinal chronic GvHD and 6 months after HSCT, the patients developed a trilinear autoimmune cytopenia successfully treated with rituximab and sirolimus. Due to persisting intestinal symptoms, colonoscopies were performed and histological findings demonstrated a picture of CD. Based on this observation and according to the recommendations for the treatment of CD, thalidomide was started. A complete stable clinical response was obtained 8 weeks after start of thalidomide. Colonoscopy performed 4.8 years later demonstrated a complete endoscopic and histological remission of CD. DISCUSSION: In this case, the diagnosis of CD after HSCT was based on histological findings. Indeed, repeated colonscopies were necessary for diagnosis, since both clinical and endoscopic features are often common to chronic GvHD and CD. Thalidomide was started at the dose of 1.7 mg/Kg/day, and it was well tolerated. Mild peripheral neurotoxicity occurred 5 years later but disappeared completely with the dose reduction. Currently, the patient is in complete remission from CD, despite the discontinuation of all the immunosuppressive therapies. CONCLUSIONS: Thalidomide could represent a therapeutic option to treat CD as autoimmune disease after allogeneic HSCT.

Scoring Endoscopy in Pediatric Inflammatory Bowel Disease: A Way to Improve Quality.

OBJECTIVES AND STUDY: There is a large interobserver variability in evaluating mucosal lesions of inflammatory bowel disease (IBD), especially in pediatric patients. This multicenter prospective observational study aims to evaluate interobserver agreement (IOA) among pediatric endoscopists in assigning validated IBD endoscopic scores in children. METHODS: Fifteen videos of follow-up ileocolonoscopies in children with IBD were recorded and selected as cases. Eleven pediatric endoscopists from different centers blindly evaluated all videos and calculated scores: either Ulcerative Colitis Endoscopic Index of Severity (UCEIS) or Simple Endoscopic Score for Crohn Disease (SES-CD). Scores from all reviewers were compared in order to calculate IOA for general videos and specific sections. Scores from an expert adult reader were used to calculate possible reviewer's characteristics affecting scores' reliability. RESULTS: Intraclass correlation was 0.298 (95% confidence interval [CI]: 0.13-0.55) for ulcerative colitis (UC) and 0.266 (0.11-0.52) for Crohn disease (CD). When a disease activity categorization was adopted (remission, mild, moderate, severe activity) Fleiss kappa coefficient was 0.408 (0.29-0.53) for UC and 0.552 (0.43-0.73) for CD. When stratified by item, vascular pattern of UC was the most reliable item IC: 0.624 (0.321-0.854). In multivariable analysis, none of the reviewer's characteristics affected the readers' errors. CONCLUSIONS: This multicenter study shows low agreement among pediatric endoscopists in evaluating endoscopic scores in children with IBD. By using disease activity categorization, agreement slightly increased, mostly for CD. All readers showed a low-grade concordance with the expert adult gastroenterologist's evaluations. Future-specific training programs should be considered to increase IOA in using IBD endoscopic activity scores.

Parental Psychological Factors and Quality of Life of Children With Inflammatory Bowel Disease.

OBJECTIVES: Parents have a central role in the management of children with inflammatory bowel disease (IBD). Alterations in parental psychological well-being may affect the patient's health-related quality of life (HRQoL). This study aimed to evaluate the correlation between maternal and paternal distress, anxiety, depression and pain catastrophizing and the HRQoL of patients with IBD. METHODS: Children with IBD ages 8 to 18 years and their parents were prospectively recruited. Children answered questionnaires on HRQoL while parents completed an assessment of distress, anxiety, depression, and pain catastrophizing. Univariate and multivariate regression models analysis were used to evaluate correlations between parental measures and patient's HRQoL and between the factors related to children health and parental psychological suffering. RESULTS: One hundred patients (45 Crohn disease, 55 ulcerative colitis), 90 mothers and 62 fathers were enrolled. Parents had high levels of distress while anxiety, depression, and pain catastrophizing levels were relatively low. Parental distress had the most substantial correlation with children's HRQoL and was associated with patients' disease activity and recent flares. On multivariate regression analysis, parental factors explained less than 20% of the variance in the children's HRQoL scores. Mothers suffered from psychological alterations more frequently than fathers, but the parental inter-rater agreement was strong in regards to distress and anxiety. CONCLUSIONS: Parental distress is high and correlates with the HRQoL of children with IBD. Interventions aimed at evaluating and managing parental distress should be considered during the management of children with IBD.

Unusual Late-onset Enteropathy in a Patient With Lipopolysaccharide-responsive Beige-like Anchor Protein Deficiency.

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.

Characteristic of COVID-19 infection in pediatric patients: early findings from two Italian Pediatric Research Networks.

Detailed data on clinical presentations and outcomes of children with COVID-19 in Europe are still lacking. In this descriptive study, we report on 130 children with confirmed COVID-19 diagnosed by 28 centers (mostly hospitals), in 10 regions in Italy, during the first months of the pandemic. Among these, 67 (51.5%) had a relative with COVID-19 while 34 (26.2%) had comorbidities, with the most frequent being respiratory, cardiac, or neuromuscular chronic diseases. Overall, 98 (75.4%) had an asymptomatic or mild disease, 11 (8.5%) had moderate disease, 11 (8.5%) had a severe disease, and 9 (6.9%) had a critical presentation with infants below 6 months having significantly increased risk of critical disease severity (OR 5.6, 95% CI 1.3 to 29.1). Seventy-five (57.7%) children were hospitalized, 15 (11.5%) needed some respiratory support, and nine (6.9%) were treated in an intensive care unit. All recovered.Conclusion:This descriptive case series of children with COVID-19, mostly encompassing of cases enrolled at hospital level, suggest that COVID-19 may have a non-negligible rate of severe presentations in selected pediatric populations with a relatively high rates of comorbidities. More studies are needed to further understand the presentation and outcomes of children with COVID-19 in children with special needs. What is Known: • There is limited evidence on the clinical presentation and outcomes of children with COVID-19 in Europe, and almost no evidence on characteristics and risk factors of severe cases. What is New: • Among a case series of 130 children, mostly diagnosed at hospital level, and with a relatively high rate (26.2%) of comorbidities, about three-quarter had an asymptomatic or mild disease. • However, 57.7% were hospitalized, 11.5% needed some respiratory support, and 6.9% were treated in an intensive care unit.

Efficacy and Safety of Adalimumab in Pediatric Ulcerative Colitis: A Real-life Experience from the SIGENP-IBD Registry.

OBJECTIVES: The aim of this study was to evaluate the effectiveness and safety of adalimumab (ADA) in children with ulcerative colitis (UC) previously treated with infliximab (IFX). METHODS: Retrospective study including children with UC from a national registry who received ADA therapy. The primary endpoint was the rate of corticosteroid-free remission at week 52. Secondary outcomes were the rate of sustained clinical remission, primary nonresponse, and loss of response at weeks 12, 30, and 52 and rate of mucosal healing and side effects at week 52. RESULTS: Thirty-two children received ADA (median age 10 ±â€Š4 years). Median disease duration before ADA therapy was 27 months. All patients received previous IFX (43% intolerant, 50% nonresponders [37.5% primary, 42.5% secondary nonresponders], 6.7% positive anti-IFX antibodies). Fifty-two weeks after ADA initiation, 13 patients (41%) were in corticosteroid-free remission. Mucosal healing occurred in 9 patients (28%) at 52 weeks. The cumulative probability of a clinical relapse-free course was 69%, 59%, and 53% at 12, 30, and 52 weeks, respectively. Ten patients (31%) had a primary failure and 5 (15%) a loss of response to ADA. No significant differences in efficacy were reported between not-responders and intolerant to IFX (P = 1.0). Overall, 19 patient (59%) maintained ADA during 52-week follow-up. Seven patients (22%) experienced an adverse event, no serious side effects were observed and none resulted in ADA discontinuation. CONCLUSIONS: Based on our data, ADA seems to be effective in children with UC, allowing to recover a significant percentage of patients intolerant or not-responding to IFX. The safety profile was good.

Endoscopic and Histologic Healing in Children With Inflammatory Bowel Diseases Treated With Thalidomide.

BACKGROUND & AIMS: Mucosal healing, determined by endoscopic evaluation, is one of the most important prognostic markers for patients with inflammatory bowel diseases. Findings from histologic evaluation, however, could complement findings from endoscopy in assessing mucosal responses to treatment. We analyzed long-term results of children treated with thalidomide to determine the association between clinical response and histology and endoscopy findings. METHODS: We collected data from 2 multicenter trials of 70 children with refractory Crohn's disease (CD) or ulcerative colitis (UC) (2-18 years old; ileocolonic or colonic disease) given thalidomide or placebo (NCT00720538). Clinical remission and clinical response at 8 weeks were defined as a pediatric CD activity index scores 10 points or lower and a decrease of at least 50% from baseline, respectively, for patients with CD; and as a pediatric UC activity index score below 10 and a decrease of at least 20 points from baseline, respectively, for patients with UC. Patients with a clinical response to 8 weeks' treatment with thalidomide underwent endoscopic examination with biopsy collection at study weeks 12 and 52. Severity of inflammation in patients with UC was assessed by Mayo score and in patients with CD by 4-grade system. Biopsies were assessed for signs of active inflammation, erosion or ulceration, and crypt abscesses and assigned a histologic score. RESULTS: Clinical remission was observed in 42 patients (60.0%) and clinical response in 45 patients (64.2%) at Week 8. At Week 52, a total of 38 patients (54.3%) were still in clinical remission or still had a clinical response; 29 patients (41.4%) had mucosal healing, defined as complete healing of erosions or ulcerations, and 20 patients (27.7%) had histologic healing, defined as complete absence of markers of inflammation. Of patients with clinical remission or clinical response, 75.3% also had mucosal healing and 52.6% also had histologic healing. The probability of achieving mucosal healing decreased significantly with increasing values of erythrocyte sedimentation rate (adjusted odds ratio, 0.96; 95% CI, 0.93-0.98; P = .006). CONCLUSIONS: In a long-term analysis of data from 2 clinical trials of pediatric patients with CD or UC, 52 weeks' treatment with thalidomide led to clinical remission in 54.3% of patients with ileocolonic or colonic disease; of these patients, 75.3% had mucosal healing and 52.6% also had histologic healing. Further studies are needed to determine how thalidomide therapy affects long-term progression of inflammatory bowel diseases. (ClinicalTrials.gov number NCT00720538).

Morbidity and Risk Factors of Laparoscopic-Assisted Ileostomies in Children With Ulcerative Colitis.

INTRODUCTION: Laparoscopic-assisted ileostomy (LAI) represents a cornerstone for the staged approach to ulcerative colitis (UC). The aim is to determine stoma morbidity in a series of pediatric patients and possibly identify specific risk factors. METHODS: All of the patients who underwent LAI for UC between January 2008 and December 2014 were included. The following data were collected: patient demographics, preoperative medical treatment, body mass index (BMI) at surgery, Pediatric UC Index (PUCAI), and stoma-related complications. In this series of patients, a staged approach has been adopted (subtotal colectomy + ileostomy; restorative proctocolectomy with J-pouch ileo-rectal anastomosis + ileostomy; ileostomy closure). RESULTS: Seventy-two LAIs were fashioned in 37 pediatric patients with UC. Median age at surgery was 12 years (range 5-14.8 years). Boy to girl ratio was 0.85:1. Mortality was zero. Complications occurred after 8 procedures after a median of 31 days postoperatively (range 8-60 days). Those were significantly more frequent in the case of BMI-z score >-0.51 (deleted in revised manuscript, ie, relatively overweight patients) and in the case of preoperative azathioprine administration. Pediatric UC Index score, sex, number of preoperative medications, and other preoperative parameters did not correlate with the incidence of complications. CONCLUSIONS: Our study suggests to keep a prudent behavior in the case of patients with a BMI-z score >-0.51 and received preoperative azathioprine administration. Parents should be adequately acknowledged on this regard.

Clinical Features and Risk Factors of Autoimmune Liver Involvement in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Autoimmune liver disease is reported in up to 7.8% of children with inflammatory bowel disease. A distinct inflammatory bowel disease phenotype has been suggested in adults and in small pediatric cohorts. The aim of the study was to evaluate the features of inflammatory bowel disease associated with autoimmune liver diseases and to analyze the characteristics of the liver disease. METHODS: Information on patients was obtained from the Italian Pediatric Inflammatory Bowel Disease Registry. Data of patients with and without autoimmune liver disease were compared. RESULTS: Autoimmune liver disease was detected in 6.8% of the 677 patients enrolled and was significantly associated with the diagnosis of ulcerative colitis (83%), with pancolonic involvement (84%), and with perinuclear antineutrophil cytoplasmic antibody positivity (41%) (all Ps < 0.05). Autoimmune liver disease was defined as sclerosing cholangitis in 61% of the patients and as an overlap syndrome in 33%. Concomitant intra- and extrahepatic biliary involvement was reported in 61% of cases, whereas exclusive extrahepatic lesions were reported in 21%. Hepatobiliary complications were observed in 9% of the patients during follow-up. CONCLUSIONS: Autoimmune liver disease, especially sclerosing cholangitis, was significantly more common in patients with extensive ulcerative colitis. Although complications are relatively rare in the pediatric age, monitoring is recommended.

Long-term outcome and need of re-operation in gastro-esophageal reflux surgery in children.

BACKGROUND: Fundoplication is considered a mainstay in the treatment of gastro-esophageal reflux. However, the literature reports significant recurrences and limited data on long-term outcome. AIMS: To evaluate our long-term outcomes of antireflux surgery in children and to assess the results of redo surgery. METHODS: We retrospectively analyzed all patients who underwent Nissen fundoplication in 8 consecutive years. Reiterative surgery was indicated only in case of symptoms and anatomical alterations. A follow-up study was carried out to analyzed outcome and patients' Visick score assessed parents' perspective. RESULTS: Overall 162 children were included for 179 procedures in total. Median age at first intervention was 43 months. Comorbidities were 119 (73 %), particularly neurological impairments (73 %). Redo surgery is equal to 14 % (25/179). Comorbidities were risk factors to Nissen failure (p = 0.04), especially children suffering neurological impairment with seizures (p = 0.034). Follow-up datasets were obtained for 111/162 = 69 % (median time: 51 months). Parents' perspectives were excellent or good in 85 %. CONCLUSIONS: A significant positive impact of redo Nissen intervention on the patient's outcome was highlighted; antireflux surgery is useful and advantageous in children and their caregivers. Children with neurological impairment affected by seizures represent significant risk factors.

The diagnostic challenge of very early-onset enterocolitis in an infant with XIAP deficiency.

BACKGROUND: Aggressive course and resistance to treatments usually characterize very early onset inflammatory bowel disease (VEO-IBD). Some VEO-IBD cases are due to monogenic immune defects and can benefit from hematopoietic stem cell transplantation (HSCT). CASE PRESENTATION: We describe a Caucasian male baby who presented in the first months of life macrophage activation syndrome, followed by intractable colitis, recurrent episodes of fever and mild splenomegaly. After several immunological, genetic and clinical investigations, subsequently a therapeutic attempt with colectomy, analysis of VEO-IBD-associated genes, revealed a causative mutation in XIAP. The genetic diagnosis of a primary immune deficiency allowed curing the boy with hematopoietic stem cell transplantation. CONCLUSION: Our report, together with novel findings from recent literature, should contribute to increase awareness of monogenic immune defects as a cause of VEO-IBD. Comprehensive genetic analysis can allow a prompt diagnosis, resulting in the choice of effective treatments and sparing useless and damaging procedures.

Diagnostic accuracy of upper gastrointestinal series in children with suspected intestinal malrotation.

Intestinal malrotation (IM) results from an altered or incomplete rotation of the fetal midgut around the superior mesenteric artery axis. The abnormal anatomy of IM is associated with risk of acute midgut volvulus which can lead to catastrophic clinical consequences. The upper gastro-intestinal series (UGI) is addressed as the gold standard diagnosis procedure, but a variable failure degree has been described in literature. The aim of the study was to analyze the UGI exam and describe which features are the most reproducible and reliable in diagnosing IM. Medical records of patients surgically treated for suspected IM between 2007 and 2020 at a single pediatric tertiary care center were retrospectively reviewed. UGI inter-observer agreement and diagnostic accuracy were statistically calculated. Images obtained with antero-posterior (AP) projections were the most significant in terms of IM diagnosis. Duodenal-Jejunal Junction (DJJ) abnormal position resulted to be the most reliable parameter (Se = 0.88; Sp = 0.54) as well as the most readable, with an inter-reader agreement of 83% (k = 0.70, CI 0.49-0.90). The First Jejunal Loops (FJL), caecum altered position and duodenal dilatation could be considered additional data. Lateral projections demonstrated an overall low sensitivity (Se = 0.80) and specificity (Sp = 0.33) with a PPV of 0.85 and a NPV of 0.25. UGI on the sole AP projections ensures a good diagnostic accuracy. The position of the third portion of the duodenum on lateral views showed an overall low reliability, therefore it was not helpful but rather deceiving in diagnosing IM.