Eosinophilic esophagitis in children: current knowledge to open new horizons.

Eosinophilic Esophagitis (EoE) is a chronic immune/antigen-mediated condition which is also driven by genetic and environmental factors. It has been deeply investigated over the last years and its incidence is widely increasing in childhood. Although atopic diseases are closely linked with EoE, it does not recognize a classical IgE-mediate immune pathogenesis but it is rather a T helper type 2 inflammatory process. Familial clustering supports genetic predisposition in EoE and recent advances in understanding the genetic basis for EoE may eventually translate into targeted management of the disease. EoE diagnosis is based on clinical symptoms, micro, and macroscopic findings along with exclusion of gastroesophageal reflux disease (GERD) evidence. Management of the disease encompasses both dietary and pharmacological solutions that need to be specifically targeted on patients' history, clinical symptoms, and diagnostic evaluations. New therapies, currently not available in children, may represent the basis for future therapeutic options in the next years.

Gastrointestinal symptoms in children: Primary care and specialist interface.

AIMS: Gastrointestinal symptoms and diseases represent one of the major reasons for paediatricians' requests for specialist consultations and hospital admissions. One fourth of annual medical consultations for children younger than 6 years can be attributed to gastrointestinal symptoms. High-quality guidelines have been validated worldwide to provide clinical recommendations and support healthcare providers' practice. Nevertheless, overall compliance to standards of care is unsatisfactory, and children with gastrointestinal symptoms frequently undergo expensive, useless specialist consultations and laboratory evaluations. The aim of this study is to review the main epidemiological and clinical aspects, together with management strategies, of the most common gastrointestinal symptoms in children, pointing out pitfalls and practical tips in primary care management, and providing correct indications for specialist consultations. METHODS: For this review, articles published in English from 2000 to January 2018 were identified from the PubMed/Medline (http://www.ncbi.nlm.nih.gov/pubmed/) database and selected on the basis of quality, relevance to the illness and importance in illustrating current management pathways. The search used the following keywords: gastrointestinal symptoms, functional gastrointestinal symptoms, children, primary care, specialist consultations and management. Particular emphasis was placed on evidence-based guidelines and high-quality studies. RESULTS: Functional gastrointestinal symptoms have a high impact on the quality of life of children and families and on healthcare costs. A complete medical history and clinical examination are often sufficient to guide the primary care provider in the diagnosis, further workup or referral to a paediatric gastroenterologist. CONCLUSION: Paediatric gastroenterology outpatients' clinics are among the most crowded specialists, and functional gastrointestinal symptoms and disorders are the most frequent reason for counselling. The number of specialist consultations could be reduced if guidelines were applied in primary care settings.

Gluten-related disorders: certainties, questions and doubts.

In the last decade, the ingestion of gluten, a heterogeneous complex of proteins present in wheat, rice, barley and probably in oats, has been associated with clinical disorders, such as celiac disease, wheat allergy and recently to non-celiac gluten sensitivity or wheat intolerance syndrome. Gluten-related disorders, which are becoming epidemiologically relevant with an estimated global prevalence of about 5%, require the exclusion of gluten from the diet. For the past 5 years, an important shift in the availability of gluten-free products, together with increased consumption in the general population, has been recorded and is estimated to be about 12-25%. Many people follow a self-prescribed gluten-free diet, despite the fact that the majority have not first been previously excluded, or confirmed, as having gluten disorders. They rely on claims that a gluten-free diet improves general health. In this review, we provide an overview of the clinical disorders related to gluten or wheat ingestion, pointing out the current certainties, open questions, possible answers and several doubts in the management of these conditions. KEY MESSAGE Incidence of gluten-related disorders is increased in the last decade and self-diagnosis is frequent with inappropriate starting of a gluten-free diet. Gluten and wheat are considered as the most important triggers to coeliac disease, wheat allergy and non-celiac gluten sensitivity. Pediatricians, allergologist and gastroenterologist are involved in the management of these conditions and appropriate diagnostic protocols are required.

Intestinal Behçet and Crohn's disease: two sides of the same coin.

Behçet's disease (BD) and Crohn's disease (CD) are chronic immune-mediated, inflammatory disorders affecting many different systems (joints, skin, eyes, gastrointestinal and biliary tracts). Both disorders have fluctuating courses and when gastrointestinal symptoms are prevalent, differential diagnosis can be difficult. BD involves the gastrointestinal tract in 10-15% of cases with localized lesions in the ileocecal region. The clinical picture is heterogeneous with various clusters of disease expression. CD is a chronic inflammatory disorder, which can affect any part of the intestinal tract, as well as extra-intestinal tissue. Factors that contribute towards the pathogenesis of both disease include the host's genetic profile, and immune system, and environmental factors such as the gut microbiota. The aim of this manuscript is to provide a narrative review of clinical features of BD and CD, highlighting the importance of differential diagnosis and therapeutic approach, especially in the presence of gastrointestinal involvement. A comprehensive search of published literature using the Pubmed ( http://www.ncbi.nlm.nih.gov/pubmed/ ) database was carried out to identify all articles published in English from 1999 to October 2016, using 4 key terms: "Behçet Disease", "Intestinal Behçet's Disease", "Crohn's Disease" and" Inflammatory Bowel Disease".

Intestinal and neurological involvement in Behcet disease: a clinical case.

BACKGROUND: Behcet's disease (BD) is a chronic immune-mediated, inflammatory disorder which may affect a number of different systems (oral and genital mucosa, eyes, skin, vascular district, joints, gastrointestinal tract and nervous system). Neurological manifestations are present in 5-10%, and gastrointestinal tract involvement in 10-15% of cases. The simultaneous involvement of two systems, neurological and gastrointestinal tract, is very rare and represents the aim of our case report. CASE PRESENTATION: We describe a case of a 12-year-old girl with neurological (endocranial hypertension, papilledema, retinal vasculitis) and gastrointestinal tract (terminal ileum and cecum inflammation) involvement and with a history of recurrent oral aphthosis; therefore, according to both International Criteria for Behcet's Disease (ICBD) and Paediatric Behcet's Disease criteria (PEDBD) the diagnosis of BD was confirmed. CONCLUSIONS: This case report is one of the few described in literature with simultaneous involvement of the two systems, neurological and gastrointestinal tract, in paediatric BD. The diagnosis is really difficult because there is no specific diagnostic test. We think that our clinical case should help clinicians to suspect a BD with an unusual onset.

Functional Dyspepsia: An Enigma in a Conundrum.

As defined by Rome III, there are 4 abdominal pain-related functional gastrointestinal disorders in children: irritable bowel syndrome, functional dyspepsia (FD), abdominal migraine, and functional abdominal pain. Dyspepsia is a constellation of symptoms referable to the gastroduodenal region of the upper gastrointestinal tract. FD refers to dyspeptic symptoms that cannot currently be explained by an organic cause, and affects 25% to 40% of the adult population over a lifetime. In children, this condition results in increased specialist consultations, with reported prevalence between 3% and 27%. The Rome III criteria for pediatric FD include the presence or persistence of recurrent pain or discomfort centered in the upper abdomen, without evidence of organic disease or change in frequency of stools. Symptoms must be chronic, occurring at least weekly and over a period of at least 6 months. The goal of this article is to provide a narrative review of diagnosis and management of the FD in the pediatric population. A comprehensive search of published literature using the PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) database was carried out to identify all articles published in English from 1998 to November 2015, using 3 key terms; "FD," "functional gastrointestinal disorders," and "children."

Effect of Early Versus Late Azathioprine Therapy in Pediatric Ulcerative Colitis.

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

Management of Acute Severe Colitis in Children With Ulcerative Colitis in the Biologics Era.

BACKGROUND AND OBJECTIVE: Approximately one-third of children with ulcerative colitis will experience at least 1 attack of acute severe colitis (ASC) before 15 years of age. Severe disease can be defined in children when Pediatric Ulcerative Colitis Activity Index is >65 and/or ≥6 bloody stools per day, and/or 1 of the following: tachycardia, fever, anemia, and elevated erythrocyte sedimentation rate with or without systemic toxicity. Our aim was to provide practical suggestions on the management of ASC in children. The goal of medical therapy is to avoid colectomy while preventing complications of disease, side effects of medications, and mortality. METHODS: A systematic search was carried out through Medline via PubMed to identify all articles published in English to date, based on the following keywords "ulcerative colitis," "pediatric ulcerative colitis," "biological therapy," and "acute severe colitis." Multidisciplinary clinical evaluation is recommended to identify early nonresponders to conventional treatment with intravenous corticosteroids, and to start, if indicated, second-line therapy or "rescue therapy," such as calcineurin inhibitors (cyclosporine, tacrolimus) and anti-tumor necrosis factor molecules (infliximab). RESULTS: Pediatric Ulcerative Colitis Activity Index is a valid predictive tool that can guide clinicians in evaluating response to therapy. Surgery should be considered in the case of complications or rapid clinical deterioration during medical treatment. CONCLUSIONS: Several pitfalls may be present in the management of ASC, and a correct clinical and therapeutic approach is recommended to reduce surgical risk.

Pancreatic involvement in pediatric inflammatory bowel diseases.

BACKGROUND: Inflammatory bowel diseases (IBDs) are a group of chronic diseases affecting the gastrointestinal tract, with a disabling course. The incidence of IBDs is increasing in different geographical areas, indicating its emergence as a global disease, especially in children. Many patients with IBDs develop extraintestinal manifestations (EIMs) during follow-up, as IBDs have a potential risk of systemic involvement.. DATA SOURCES: A systematic review of the literature was made to analyze latest studies on pancreatic involvement in children with IBD including our experience in assessing possible implications and its future application. RESULTS: The involvement of the hepatobiliary system is considered a rare EIM of children with IBD, with an incidence much higher than that in the general population. Isolated pancreatic hyperenzymemia, which occurs in the absence of typical symptoms and/or characteristic imaging findings, may be found in many patients with IBD. The frequent causes of pancreatitis are drugs, bilio-pancreatic disorders, immunologic disturbances and pancreatic auto-antibodies, although in some cases idiopathic forms have been described. CONCLUSIONS: It is important to establish a correct diagnostic approach based on etiology and to assess the most appropriate therapeutic strategy, thus avoiding complications and improving the quality of life of children with IBD.

Urinary sevoflurane and hexafluoro-isopropanol as biomarkers of low-level occupational exposure to sevoflurane.

OBJECTIVES: Sevoflurane is an inhalation halogenated anaesthetic widely used in day and paediatric surgery. We were interested in evaluating biological markers of exposure to sevoflurane, which should improve the health surveillance of occupationally exposed personnel. METHODS: A group of 36 subjects (13 male, 23 female) occupationally exposed to volatile anaesthetics in paediatric operating rooms was studied in a 2-week survey. Post-shift urine samples and specimens from passive samplers (for personal monitoring) were collected after 1.75-6 h morning exposure and analysed by headspace gas chromatography-mass spectrometry (GC-MS). Multiple determinations were assumed as independent values (in total, n = 78: 24 from men, 54 from women; 25 from smokers, 53 from non-smokers). RESULTS: Median sevoflurane external values were 0.13 parts per million (ppm) (range 0.03-18.82) (n = 78), urinary sevoflurane 0.6 microg/l urine (ND-18.5)(n = 76) and total urinary hexafluoro-isopropanol (HFIP) 0.49 mg/l urine (ND-6833.4) (n = 75). A lower limit of detection (LOD) was achieved for urinary sevoflurane (0.03 microg/l urine), allowing quantitation of all but one of the samples; >25% of urine samples were unquantifiable by HFIP and were assigned a value equal to half the LOD of 0.10 mg/l(urine). Urinary sevoflurane correlated well with breathing-zone data (r2 = 0.697 at log-log linear regression), whereas total urinary HFIP (r2 = 0.562 at log-log linear regression) seemed to be better described by a three-parameter logistic function and appeared to be influenced by smoking habits. Biological indices corresponding to National Institute for Occupational Safety and Health (NIOSH) exposure limits, calculated as means of linear regression slope and y intercept, were 3.9 mug/l(urine) and 1.4 microg/l urine for sevoflurane (corresponding to 2 ppm and 0.5 ppm, respectively), and 2.66 mg/l urine and 0.82 mg/l urine for HFIP. CONCLUSIONS: On the basis of our data, urinary unmodified, sevoflurane seems to be a more sensitive and reliable biomarker of short-term exposure to sevoflurane with respect to total urinary metabolite HFIP, which appears to be influenced by physiological and/or genetic individual traits, and seems to provide an estimate of integrated exposure.

Proposal for single and mixture biological exposure limits for sevoflurane and nitrous oxide at low occupational exposure levels.

OBJECTIVES: Assessment of individual exposures to sevoflurane plus nitrous oxide (N(2)O) by biological monitoring of unmodified analytes in post-shift urine of exposed personnel. METHODS: Anaesthetics in urine and breathing area were monitored in 124 subjects in 11 operating theatres. Passive samplers were collected after 2.5-7 h of exposure, at the same time as post-shift urinary samples, to evaluate the individual time-weighted average (TWA) exposures to sevoflurane and N(2)O. A static headspace sampler coupled with a gas chromatograph mass spectrometer was used for analytical determinations (sensitivity sufficient to reveal biological/environmental exposures of 0.1 microg/l(urine) and 50 ppb for sevoflurane, and 1 microg/l(urine) and 80 ppb for N(2)O). RESULTS: Median (range) post-shift urinary and environmental values were 1.2 microg/l(urine) (0.1-5.0) and 0.4 ppm (0.05-3.0) for sevoflurane ( n=107) and 10.9 microg/l(urine) (0.5-74.9) and 8.6 ppm (0.2-123.4) for N(2)O ( n=121) (all low-exposure range). At log-log regression, urinary levels closely correlated with environmental data (sevoflurane, r(2)=0.7538; N(2)O, r(2)=0.8749). Biological equivalent limits (BELs) based on National Institute for Occupational Safety and Health (NIOSH) TWA exposure limits, calculated as means of regression slope and y-intercept, were 3.6 microg/l(urine) for sevoflurane (corresponding to 2 ppm) and 22.3 microg/l(urine) for N(2)O (corresponding to 25 ppm). Individual "mixture BELs", which we calculated by applying the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) mix formula to biomarker values and using the obtained NIOSH-based BELs as a reference, closely correlated with mixture TLVs (rho=0.816, Lin's concordance test). CONCLUSIONS. We propose urinary sevoflurane as a new, specific, internal dose biomarker for routine biological monitoring of personal exposures among operating-theatre personnel, and use of reliable "mixture BELs" to provide safer levels of internal exposure for workers exposed to mixtures of sevoflurane and N(2)O, and conceivably also to other mixtures of toxicants with possible additive effects.

Enflurane as an internal standard in monitoring halogenated volatile anaesthetics by headspace gas chromatography-mass spectrometry.

Recently. we proposed the use of a run-only headspace-GC-MS method for the biological monitoring of ppb concentrations of unmodified volatile anaesthetics (isoflurane, sevoflurane and halothane, plus nitrous oxide) in post-shift urine of operating theatre personnel. The adoption of enflurane (a volatile anaesthetic no longer used in clinical practice) as a poper and viable internal standard improves intra-day and inter-day accuracy in halide quantitation, providing a GC-MS reference method useful in the practice of biomonitoring of exposure of operating theatre personnel to modern volatile anaesthetics (isoflurane. sevoflurane, halothane).