IL-10-producing regulatory cells impact on celiac disease evolution.

Celiac Disease (CD) is a T-cell mediated disorder caused by immune response to gluten, although the mechanisms underlying CD progression are still elusive. We analyzed immune cell composition, plasma cytokines, and gliadin-specific T-cell responses in patients with positive serology and normal intestinal mucosa (potential-CD) or villous atrophy (acute-CD), and after gluten-free diet (GFD). We found: an inflammatory signature and the presence of circulating gliadin-specific IFN-γ+ T cells in CD patients regardless of mucosal damage; an increased frequency of IL-10-secreting dendritic cells (DC-10) in the gut and of circulating gliadin-specific IL-10-secreting T cells in potential-CD; IL-10 inhibition increased IFN-γ secretion by gliadin-specific intestinal T cells from acute- and potential-CD. On GFD, inflammatory cytokines normalized, while IL-10-producing T cells accumulated in the gut. We show that IL-10-producing cells are fundamental in controlling pathological T-cell responses to gluten: DC-10 protect the intestinal mucosa from damage and represent a marker of potential-CD.

Tolerogenic IL-10-engineered dendritic cell-based therapy to restore antigen-specific tolerance in T cell mediated diseases.

Tolerogenic dendritic cells play a critical role in promoting antigen-specific tolerance via dampening of T cell responses, induction of pathogenic T cell exhaustion and antigen-specific regulatory T cells. Here we efficiently generate tolerogenic dendritic cells by genetic engineering of monocytes with lentiviral vectors co-encoding for immunodominant antigen-derived peptides and IL-10. These transduced dendritic cells (designated DCIL-10/Ag) secrete IL-10 and efficiently downregulate antigen-specific CD4+ and CD8+ T cell responses from healthy subjects and celiac disease patients in vitro. In addition, DCIL-10/Ag induce antigen-specific CD49b+LAG-3+ T cells, which display the T regulatory type 1 (Tr1) cell gene signature. Administration of DCIL-10/Ag resulted in the induction of antigen-specific Tr1 cells in chimeric transplanted mice and the prevention of type 1 diabetes in pre-clinical disease models. Subsequent transfer of these antigen-specific T cells completely prevented type 1 diabetes development. Collectively these data indicate that DCIL-10/Ag represent a platform to induce stable antigen-specific tolerance to control T-cell mediated diseases.

Role of inflammation in pediatric irritable bowel syndrome.

BACKGROUND: IBS affects a large number of children throughout the world and is thought to be the result of disturbed neuroimmune function along with the brain-gut axis. Although the underlying pathophysiologic mechanisms are not clear, the role of low-grade inflammation and mucosal immune activation in IBS symptom generation has become evident also in subsets of pediatric patients. Animal models provided meaningful insight in the causal relationship between abnormal mucosal immune activation and changes in gastrointestinal (GI) sensory-motor function. Likewise, the development of long-standing GI symptoms fulfilling the current criteria for functional GI disorders after infection gastroenteritis and in patients with IBD or celiac disease in remission further supports this hypothesis. Immune activation, its impact on gut sensory-motor function, and potential implications for symptom generation emerged in both children and adults with IBS. PURPOSE: The aim of this review is to summarize the main evidence on the presence of low-grade inflammation and immune activation in children with IBS, its possible role in symptom generation, and its potential implication for new therapeutic strategies.

Skin Manifestations and Coeliac Disease in Paediatric Population.

Celiac disease (CD) is an immune-mediated enteropathy caused by gluten ingestion, affecting approximately 1% of the worldwide population. Extraintestinal symptoms may be present as the first signs of CD, years before the CD diagnosis is made. A great variety of extraintestinal manifestations may be associated with CD. Cutaneous manifestations represent the main extraintestinal manifestations, with dermatitis herpetiformis being the most common in patients with CD. In adults, it has been demonstrated that the role of a gluten-free diet is crucial not only for the recovery of signs and symptoms associated with CD but also for cutaneous manifestations, which often improve after gluten avoidance. In children with CD, the association with skin disorders is well documented regarding dermatitis herpetiformis, but studies considering other dermatological conditions, such as psoriasis and atopic dermatitis, are few. The prevalence and manifestations of dermatological disorders in celiac children are often different from those in adults, explaining the gap between these populations. In addition, the therapeutic role of a gluten-free diet in the improvement in skin alterations is not fully understood in children and in adult population except for dermatitis herpetiformis. Therefore, cutaneous CD symptoms need to be known and recognized by physicians despite their specialties to improve early CD diagnosis, which is critical for a better prognosis. This review describes the current scientific evidence on skin manifestations associated with CD in the pediatric population.

Isolated intestinal Ganglioneuromatosis: case report and literature review.

BACKGROUND: Intestinal Ganglioneuromatosis (IG) is a rare disorder of the enteric nervous system. In pediatric age it is often associated with genetic syndromes such as Neurofibromatosis 1 (NF1), multiple endocrine neoplasia type 2B (MEN2B) and Cowden syndrome (PTEN mutation), and ganglioneuromas (GNs) may be sometimes the first sign of the disease. Isolated GNs are rare and sporadic. Clinical symptom vary and depend on the size and on the location of the GNs. This disorder affects intestinal motility and it, consequently, causes changes in bowel habits, abdominal pain, occlusive symptoms and rarely lower gastrointestinal bleeding secondary to ulceration of the intestinal mucosa. On the other hand, patients can remain asymptomatic for many years. CASE PRESENTATION: We describe a 9-year-old boy referred to our emergency department for right lower quadrant abdominal pain. No familial history for gastrointestinal disorders. No history of fever or weight loss. At physical examination, he had diffused abdominal pain. Abdominal ultrasonography showed a hypoechoic formation measuring 41.8 mm by 35 mm in the right lower quadrant of the abdomen. Routine blood tests were normal, but fecal occult blood test was positive. Abdominal TC confirmed the hypodense formation, of about 5 cm in transverse diameter, in the right hypochondrium that apparently invaginated in the caecum-last ileal loop. Colonoscopy showed in the cecum an invaginated polypoid lesion of the terminal ileal loop. Laparoscopic resection of the polypoid lesion was performed. Histological diagnosis of the large neoplasm observed in the terminal ileum was diffuse ganglioneuromatosis. NF1, RET and PTEN gene tests resulted negative for specific mutations. At the 1 year follow-up, the patient presented good general condition and blood tests, fecal occult blood test, esophagogastroduodenoscopy, colonoscopy and MR-enterography were negative. CONCLUSIONS: Only few cases are reported in literature of IG in pediatric age. Although rare, the present case suggests that this disorder must be taken in consideration in every patient with GI symptoms such as abdominal pain, constipation, lower intestinal bleeding, in order to avoid a delayed diagnosis.

Omental Infarction: An Underrecognized Cause of Right-Sided Acute Abdominal Pain in Children.

OBJECTIVE: To evaluate the prevalence of omental infarction (OI) in children with suspected appendicitis, the role of ultrasonography (US) in its diagnosis and management and the efficacy of conservative management. METHODS: Consecutive children with suspected acute appendicitis were prospectively enrolled. Ultrasonography was performed at baseline, during follow-up, before the discharge, and at 15-day intervals until US findings of OI disappeared. All children with a diagnosis of OI were treated conservatively. RESULTS: One hundred ninety-nine children (91 male; age range, 3-15 years) were evaluated. Eighty-four patients had acute appendicitis. Omental infarctions were found in 14 children (8 male; mean age, 9.8 ± 2.6 years), with an incidence of 7%. Ultrasonography depicted an echogenic mass consistent with OI in all children. Ultrasonography detected in 8 patients a normal-looking appendix, whereas in other 6 patients, it identified neither appendix nor indirect signs of acute appendicitis. A normal appendix has been detected by US during follow-up in 2 of these 6 patients. During follow-up, US finding of OI disappeared in all cases and no signs of acute appendicitis or other disease occurred. All 14 OIs were treated conservatively, with no reported complications. CONCLUSIONS: Omental infarction is an underestimated cause of abdominal pain in children accounting for 7% of patients with suspected appendicitis. Ultrasonography is a useful method for the diagnoses and to guide clinical management of OI. Conservative therapy is a safe option for the management of OI.

Antibiotic Prophylaxis for Percutaneous Endoscopic Gastrostomy in Children: A Randomised Controlled Trial.

OBJECTIVES: Paediatric studies on the role of antibiotic prophylaxis in the prevention of postoperative infections in children undergoing percutaneous endoscopic gastrostomy (PEG) are lacking. The aim of this study was to assess if a single dose of co-amoxiclav before PEG can decrease the rate of peristomal wound and systemic infection in children. METHODS: In this prospective, randomised, double-blind, multicentre trial, children undergoing PEG were randomized to antibiotic prophylaxis with co-amoxiclav versus placebo and the rate of local and systemic infections were assessed. RESULTS: Of the 106 patients considered for inclusion, 49 patients were randomized. In the per-protocol analysis, the occurrence of wound infection was 5% (1/20) in the antibiotic group and 21% (4/19) in the placebo group (P = 0.13, 16% difference in proportions, odds ratio [OR] 0.19, 95% confidence interval [CI] 0.02-1.9). The occurrence of systemic infection was 9% (2/22) in the antibiotic group and 27.2% (6/25) in the placebo group [P = 0.17, 18% difference in proportions, OR 0.32, 95% CI 0.06%-1.80%]. Similar results were obtained in intention-to-treat analysis. Interestingly, the overall infection rate was significantly higher in the placebo group as compared with the antibiotic group (40% vs 13.6%; P = 0.04) and the duration of hospital stay was significantly longer in the placebo group as compared with the antibiotic group (4.4 ±â€Š1.6 vs 3.5 ±â€Š1.05; P = 0.02). The number-needed-to-treat (NTT) to prevent 1 peristomal infection on average are 6.7 patients. CONCLUSIONS: A preoperative dose of co-amoxiclav reduces the overall infection rate and the duration of hospital stay. Our data suggest that antibiotic prophylaxis should be recommended in every children undergoing PEG placement.

Enteroscopy in children and adults with inflammatory bowel disease.

Inflammatory bowel disease (IBD) includes Crohn's disease (CD), ulcerative colitis and unclassified entities. CD commonly involves the terminal ileum and colon but at the time of diagnosis it can be confined to the small bowel (SB) in about 30% of the patients, especially in the young ones. Management of isolated SB-CD can be challenging and objective evaluation of the SB mucosa is essential in differentiating CD from other enteropathies to achieve therapeutic decisions and to plan the follow-up. The introduction of cross-sectional imaging techniques and capsule endoscopy (CE) have significantly expanded the ability to diagnose SB diseases providing a non-invasive test for the visualization of the entire SB mucosa. The main CE limitations are the low specificity, the lack of therapeutic capabilities and the impossibility to take biopsies. Device assisted enteroscopy (DAE) enables histological confirmation when traditional endoscopy, capsule endoscopy and cross-sectional imaging are inconclusive and also allows therapeutic interventions such as balloon stricture dilation, intralesional steroid injection, capsule retrieval and more recently stent insertion. In the current review we will discuss technical aspect, indications and safety profile of DAE in children and adults with IBD.

Not only fat: omental infarction and its mimics in children. Clinical and ultrasound findings: a pictorial review.

Acute abdominal pain in children is the most common cause of emergency department admissions. Omental infarction is a rare cause of acute abdominal pain in this age group, accounting for approximately 15% of cases in children and 0.024-0.1% of cases of surgery for suspected appendicitis at the same age. Its clinical presentation may mimic similar diseases such as acute appendicitis, epiploic appendagitis, and mesenteric panniculitis. Ultrasound is the modality of choice for the initial evaluation of acute abdominal pain in pediatric patients and it can be used with confidence in the diagnosis and management of omental infarction in children. In this brief review, we focus on the main ultrasound findings and their diagnostic clue for omental infarction and its mimics.

Faecal calprotectin and ultrasonography as non-invasive screening tools for detecting colorectal polyps in children with sporadic rectal bleeding: a prospective study.

BACKGROUND: Colorectal polyps are reported in 6,1% of paediatric colonoscopies and in 12% of those performed for lower gastrointestinal bleeding. Although colonoscopy is widely used in paediatric patients, it requires bowel preparation and general anaesthesia or deep sedation, and in rare cases, it can cause complications. Non-invasive screening techniques able to predict polyps in children with isolated and sporadic rectal bleeding may play a key role in the selection of patients needing colonoscopy. METHODS: We enrolled all children undergoing colonoscopy for isolated and sporadic rectal bleeding to determine the diagnostic accuracy of faecal calprotectin, ultrasonography (US) and digital rectal examination as diagnostic methods for screening colorectal polyps. RESULTS: A total of 26 of 59 enrolled patients (44.1%) had colonic polyps, one patient had multiple polyps, and 23% of children had polyps proximal to the splenic flexure. The diagnostic accuracy of faecal calprotectin for detecting colorectal polyps was 96.6%, with a sensitivity of 100%. False-positive faecal calprotectin was shown in 2 patients with non-steroidal anti-inflammatory drug-related lesions. The diagnostic accuracy of ultrasound was 77.9%. Polyps not seen with ultrasound tended to be relatively smaller (1.5 vs 2.3, p = 0.001) and located in the rectum. The combined use of FC, US and digital rectal examination obtained a specificity and PPV of 100%. CONCLUSIONS: FC combined with US and digital rectal examination is a good and promising non-invasive screening test for detecting colorectal polyps in children with isolated and sporadic rectal bleeding.

Caustic Ingestion in Children: 1 Year Experience in 3 Italian Referral Centers.

OBJECTIVES: Despite the efforts to reduce the exposure to corrosive household products, caustic ingestion in children is currently a significant medical problem. The aims of the present study were to evaluate the clinical consequences of caustic ingestion and to identify prognostic factors that could concur in driving both diagnostic and therapeutic management. METHODS: All consecutive children referred for ingestion of a caustic substance from June 2017 to June 2018 were enrolled. Medical records, laboratory and endoscopic findings were reviewed and analyzed. RESULTS: We enrolled 44 children with caustic ingestion. Alkaline agents were ingested by 26 of 44 (59.1%) patients, whereas acid agents were ingested by 18 of 44 patients (40.9%). Alkaline rather than acid agents were associated with a worse endoscopic score (r: 0.45) and a higher probability of early esophageal stricture occurrence (r: 0.38). The specific risk of the presence of severe esophageal lesions rose progressively with increasing number of symptoms whereas no esophageal injury was found in asymptomatic patients. CONCLUSIONS: Our data suggest that endoscopic evaluation is mandatory in symptomatic patients to direct therapeutic management, but it could be avoided in asymptomatic patients after accidental ingestion, particularly if the ingestion is only suspected and patients have no oropharyngeal burns.

Eosinophilic Esophagitis in Children: Clinical Findings and Diagnostic Approach.

Eosinophilic esophagitis (EoE) is an emerging chronic immune and antigen-mediated clinicopathologic disease. During the last 2 decades, the incidence of this condition in children has increased significantly, thanks to practitioners for creating the awareness and higher use of diagnostic endoscopy. We have analysed paediatric literature on EoE focusing on the epidemiology, pathophysiology, clinical findings and diagnostic approach. EoE is pathogenically related to a Th2 inflammation characterized by a mixed IgE and non-IgEmediated reaction to food and/or environmental agents. This leads to esophageal dysfunction and remodeling accompanied by subepithelial fibrosis. EoE can be presented with several range of gastrointestinal symptoms, including regurgitation, vomiting, feeding difficulties or feeding refusal in infants and toddlers, as well as heartburn, dysphagia and food bolus impaction in older children and adults. The diagnostic suspicion is based on the presence of chronic symptoms of esophgeal dysfunction and esophageal eosinophilia characterised histologically by a significant eosinophilic infiltration of the oesophageal mucosa (>15 eosinophils per high powered field). In this review, we will provide an update on clinical presentation and diagnostic approach to EoE in children. We emphasized on the relevant aspects of the new clinical condition termed "PPI responsive esophageal eosinophilia", as entities distinct from EoE and the role of PPI trial in the diagnostic workup, therefore we proposed a new diagnostic algorithm.

Bowel preparations for colonoscopy: an RCT.

BACKGROUND: The ideal preparation regimen for pediatric colonoscopy remains elusive, and available preparations continue to represent a challenge for children. The aim of this study was to compare the efficacy, safety, tolerability, and acceptance of 4 methods of bowel cleansing before colonoscopy in children. METHODS: This randomized, investigator-blinded, noninferiority trial enrolled all children aged 2 to 18 years undergoing elective colonoscopy in a referral center for pediatric gastroenterology. Patients were randomly assigned to receive polyethylene glycol (PEG) 4000 with simethicon (PEG-ELS group) or PEG-4000 with citrates and simethicone plus bisacodyl (PEG-CS+Bisacodyl group), or PEG 3350 with ascorbic acid (PEG-Asc group), or sodium picosulfate plus magnesium oxide and citric acid (NaPico+MgCit group). Bowel cleansing was evaluated according to the Boston Bowel Preparation Scale. The primary end point was overall colon cleansing. Tolerability, acceptability, and compliance were also evaluated. RESULTS: Two hundred ninety-nine patients were randomly allocated to the 4 groups. In the per-protocol analysis, PEG-CS+Bisacodyl, PEG-Asc, and NaPico+MgCit were noninferior to PEG-ELS in bowel-cleansing efficacy of both the whole colon (P = .910) and colonic segments. No serious adverse events occurred in any group. Rates of tolerability, acceptability, and compliance were significantly higher in the NaPico+MgCit group. CONCLUSIONS: Low-volume PEG preparations (PEG-CS+Bisacodyl, PEG-Asc) and NaPico+MgCit are noninferior to PEG-ELS in children, representing an attractive alternative to high-volume regimens in clinical practice. Because of the higher tolerability and acceptability profile, NaPico+MgCit would appear as the most suitable regimen for bowel preparation in children.