New insights in the pathogenesis and in the management of Pediatric Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a world- wide health-care problem with a continually increasing incidence. The exact cause of IBD is still unknown, but is thought to be due to a combination of patient’s genetics, microbiome, immune response, and the environment that result in an excessive and abnormal immune response against commensal flora in genetically susceptible individuals. Therefore the main aims of my thesis are deepen the knowledge of IBD pathogenesis investigating genetic susceptibility and its functional implication in pediatric inflammatory bowel disease, as well as describing peculiar clinical phenotype. Moreover, I propose new therapeutic strategies for the treatment of the disease. A true understanding of IBD pathogenesis is mandatory to improve current therapeutic approaches to IBD. There is no doubt that there has been an enormous improvement in the management of IBD, however results are far from ideal, particularly in regard to rather predictable recurrence of disease. Since IBD is the result of a complex integration of different components, an effective therapy can only be achieved if an IBD integrated approach is implemented. Hopefully, the collection of large amounts of molecular data from genomic, proteomic, and microbiomic arrays could generate models that could improve patient classifications, predict clinical course, select the most logical treatment forms, and anticipate outcome

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

Comparative Evaluation of Nasal and Small Intestine Expression of ACE2, TMPRSS2 and ACE1 and in Children and in Adults

Importance: Clinical severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seems to be lower in children compared to that in adults. Defining the pathophysiological mechanisms of such disease patterns maybe relevant for development of effective public health strategies. It has been hypothesised that the lower severity of SARS-CoV-2 infection in children could be due to the differential expression of angiotensin-converting enzyme 2 (ACE2), which serves as a virus receptor. Objective: To evaluate the expression of ACE2, ACE1, and TMPRSS2 genes at the level of the two most relevant entry sites for SARS-CoV-2, the upper respiratory tract and small intestine, in healthy children and adult subjects. Design, Setting, and Participants: This prospective study included healthy individuals of both sexes, aged 1-10 years in the paediatric population (n=30) and 20-80 years in the adult population (n=30). The participants were consecutively evaluated at two tertiary centres for paediatrics, gastroenterology, and otolaryngology. Main Measures: Expression of ACE2, ACE1, and TMPRSS2 genes in samples collected from the upper respiratory tract and small intestine. Results: We found no difference in ACE2, ACE1, and TMPRSS2 expression in the nasal epithelium between children and adult subjects. ACE2 expression was more abundant in the small intestine of children compared to that in adults. ACE1 expression was higher in the small intestine of adults compared to that in children. Intestinal TMPRSS2 expression was similar in the two study populations. Conclusions and Relevance: The general lower severity of SARS-CoV-2 infection in children does not seem to be related to a lower expression of ACE2 and/or TMPRSS2 in the respiratory tract or in the gastrointestinal tract. Other co-factors may confer protection against SARS-CoV-2 in children. The exploration of such factors is of pivotal importance for development of innovative protective strategies against SARS-CoV-2. Funding Statement: This work was supported in part by a grant of Regione Campania POR FESR 2014/2020, Task Force Covid-19 DGR 140 – 17 March 2020. Declaration of Interests: The authors have no other conflict of interests that are directly relevant to the content of this manuscript, which remains their sole responsibility. Ethics Approval Statement: The study was approved by the Ethics Committee of the University Federico II of Naples, Italy. Written informed consent was obtained from the adult participants and from the parents/tutors of minors

Age-Related Differences in the Expression of Most Relevant Mediators of SARS-CoV-2 Infection in Human Respiratory and Gastrointestinal Tract

Background: Clinical features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seem to differ in children compared to that in adults. It has been hypothesized that the lower clinical severity in children could be influenced by differential expression of the main host functional receptor to SARS-CoV-2, the angiotensin-converting enzyme 2 (ACE2), but data are still conflicting. To explore the origin of age-dependent clinical features of coronavirus disease 2019 (COVID-19), we comparatively evaluated the expression in children and adult subjects of the most relevant mediators of the SARS-CoV-2 infection: ACE2, angiotensin-converting enzyme 1 (ACE1), transmembrane serine protease-2 (TMPRSS2), and neuropilin-1 (NRP1), at upper respiratory tract and small intestine level. Methods: The expression of ACE2, ACE1, TMPRSS2, and NRP1 in nasal epithelium and in small intestine epithelium was investigated by quantitative real-time PCR analysis. Results: We found no differences in ACE2, ACE1, and TMPRSS2 expression in the nasal epithelium comparing children and adult subjects. In contrast, nasal epithelium NRP1 expression was lower in children compared to that in adults. Intestinal ACE2 expression was higher in children compared to that in adults, whereas intestinal ACE1 expression was higher in adults. Intestinal TMPRSS2 and NRP1 expression was similar comparing children and adult subjects. Conclusions: The lower severity of SARS-CoV-2 infection observed in children may be due to a different expression of nasal NRP1, that promotes the virus interaction with ACE2. However, the common findings of intestinal symptoms in children could be due to a higher expression of ACE2 at this level. The insights from these data will be useful in determining the treatment policies and preventive measures for COVID-19

Differences in management of eosinophilic esophagitis in Europe : an assessment of current practice

Objectives:The aim of the study was to assess differences in the diagnosis and management of eosinophilic esophagitis (EoE) by European pediatric (PG) and adult gastroenterologists (AG), and their self-reported adherence to guidelines. Methods:A multiple-choice questionnaire gauged the diagnostic and management strategies of gastroenterologists treating children or adults in 14 European countries and the United Arab Emirates (UAE). Results:Questionnaires were completed by 465 PG and 743 AG. PG were significantly more likely to take biopsies in patients with symptoms of esophageal dysfunction (86.2% PG vs 75.4% AG, P<0.001) and to perform endoscopic follow-up (86.3% PG vs 80.6% AG, P<0.001). After failure of proton-pump inhibitors (PPIs), topical steroids were the preferred second-line therapy; however, PG opted more frequently for elimination diets (47.5% PG vs 13.7% AG, P<0.001). More PG than AG indicated having read recent guidelines (89.4% PG vs 58.2% AG, P<0.001). Geographic differences in practice were reported, with respondents from the United Kingdom, Portugal, and Spain more often adhering to recommended biopsy protocols. Physicians in the UAE, France, Lithuania, and Poland tended to opt for steroid therapy or elimination diets as first-line therapy, in contrast to most other countries. Conclusions:Significant differences in general practice between PG and AG were demonstrated with notable divergence from consensus guidelines. International practice variations are also apparent. Among other strategies, educational activities to highlight current recommendations may help harmonize and optimize clinical practice

Cyclic Vomiting Syndrome in Children

Cyclic Vomiting Syndrome (CVS) is an underdiagnosed episodic syndrome characterized by frequent hospitalizations, multiple comorbidities, and poor quality of life. It is often misdiagnosed due to the unappreciated pattern of recurrence and lack of confirmatory testing. CVS mainly occurs in pre-school or early school-age, but infants and elderly onset have been also described. The etiopathogenesis is largely unknown, but it is likely to be multifactorial. Recent evidence suggests that aberrant brain-gut pathways, mitochondrial enzymopathies, gastrointestinal motility disorders, calcium channel abnormalities, and hyperactivity of the hypothalamic-pituitary-adrenal axis in response to a triggering environmental stimulus are involved. CVS is characterized by acute, stereotyped and recurrent episodes of intense nausea and incoercible vomiting with predictable periodicity and return to baseline health between episodes. A distinction with other differential diagnoses is a challenge for clinicians. Although extensive and invasive investigations should be avoided, baseline testing toward identifying organic causes is recommended in all children with CVS. The management of CVS requires an individually tailored therapy Management of acute phase is mainly based on supportive and symptomatic care. Early intervention with abortive agents during the brief prodromal phase can be used to attempt to terminate the attack. During the interictal period, non-pharmacologic measures as lifestyle changes and the use of reassurance and anticipatory guidance seem to be effective as a preventive treatment. The indication for prophylactic pharmacotherapy depends on attack intensity and severity, the impairment of the QoL and if attack treatments are ineffective or cause side effects. When children remain refractory to acute or prophylactic treatment, or the episode differs from previous ones, the clinician should consider the possibility of an underlying disease and further mono- or combination therapy and psychotherapy can be guided by accompanying comorbidities and specific sub-phenotype. This review was developed by a joint task force of the Italian Society of Pediatric Gastroenterology Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP) to identify relevant current issues and to propose future research directions on pediatric CV

Endocannabinoids-related compounds in gastrointestinal diseases

The endocannabinoid system (ECS) is an endogenous signalling pathway involved in the control of several gastrointestinal (GI) functions at both peripheral and central levels. In recent years, it has become apparent that the ECS is pivotal in the regulation of GI motility, secretion and sensitivity, but endocannabinoids (ECs) are also involved in the regulation of intestinal inflammation and mucosal barrier permeability, suggesting their role in the pathophysiology of both functional and organic GI disorders. Genetic studies in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease have indeed shown significant associations with polymorphisms or mutation in genes encoding for cannabinoid receptor or enzyme responsible for their catabolism, respectively. Furthermore, ongoing clinical trials are testing EC agonists/antagonists in the achievement of symptomatic relief from a number of GI symptoms. Despite this evidence, there is a lack of supportive RCTs and relevant data in human beings, and hence, the possible therapeutic application of these compounds is raising ethical, political and economic concerns. More recently, the identification of several EC-like compounds able to modulate ECS function without the typical central side effects of cannabino-mimetics has paved the way for emerging peripherally acting drugs. This review summarizes the possible mechanisms linking the ECS to GI disorders and describes the most recent advances in the manipulation of the ECS in the treatment of GI diseases

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases

Dysphagia: A practical approach

Dysphagia is any disorder of the swallowing process. It can be classified according to the disordered phase of swallowing: oral dysphagia, pharyngeal dysphagia, esophageal dysphagia. Approximately 1% of children in the general population will experience swallowing difficulties, although the incidence is much higher in some clinical populations. Although oropharyngeal dysphagia may be the first symptom of a neuromuscular disorder, gastroesophageal reflux disease (GERD), functional esophageal disorders, and eosinophilic esophagitis are the most common causes of esophageal dysphagia. Treatment and management of dysphagia must be tailored to the clinical characteristics of the individual patient