B. Malamisura

Therapy With Gastric Acidity Inhibitors Increases the Risk of Acute Gastroenteritis and Community-Acquired Pneumonia in Children

OBJECTIVE. Gastric acidity (GA) inhibitors, including histamine-2 receptor antagonists (H2 blockers) and proton pump inhibitors (PPIs), are the mainstay of gastroesophageal reflux disease (GERD) treatment. A prolonged GA inhibitor–induced hypochlorhydria has been suggested as a risk factor for severe gastrointestinal infections. In addition, a number of papers and a meta-analysis have shown an increased risk of pneumonia in H2-blocker–treated intensive care patients. More recently, an increased risk of community-acquired pneumonia associated with GA inhibitor treatment has been reported in a large cohort of adult patients. These findings are particularly relevant to pediatricians today because so many children receive some sort of GA-blocking agent to treat GERD. To test the hypothesis that GA suppression could be associated with an increased risk of acute gastroenteritis and pneumonia in children treated with GA inhibitors, we conducted a multicenter, prospective study. METHODS. The study was performed by expert pediatric gastroenterologists from 4 pediatric gastroenterology centers. Children (aged 4–36 months) consecutively referred for common GERD-related symptoms (for example, regurgitation and vomiting, feeding problems, effortless vomiting, choking), from December 2003 to March 2004, were considered eligible for the study. Exclusion criteria were a history of GA inhibitors therapy in the previous 4 months, Helicobacter pylori infection, diabetes, chronic lung or heart diseases, cystic fibrosis, immunodeficiency, food allergy, congenital motility gastrointestinal disorders, neuromuscular diseases, or malnutrition. Control subjects were recruited from healthy children visiting the centers for routine examinations. The diagnosis of GERD was confirmed in all patients by standard criteria. GA inhibitors (10 mg/kg ranitidine per day in 50 children or 1 mg/kg omeprazole per day in 50 children) were prescribed by the physicians for 2 months. All enrolled children were evaluated during a 4-month follow-up. The end point was the number of patients presenting with acute gastroenteritis or community-acquired pneumonia during a 4-month follow-up study period. RESULTS. We obtained data in 186 subjects: 95 healthy controls and 91 GA-inhibitor users (47 on ranitidine and 44 on omeprazole). The 2 groups were comparable for age, gender, weight, length, and incidence of acute gastroenteritis and pneumonia in the 4 months before enrollment. Rate of subjects presenting with acute gastroenteritis and community-acquired pneumonia was significantly increased in patients treated with GA inhibitors compared with healthy controls during the 4-month follow-up period. In the GA inhibitor-treated group, the rate of subjects presenting with acute gastroenteritis and community-acquired pneumonia was increased when comparing the 4 months before and after enrollment. No differences were observed between H2 blocker and PPI users in acute gastroenteritis and pneumonia incidence in the previous 4 months and during the follow-up period. On the contrary, in healthy controls, the incidence of acute gastroenteritis and pneumonia remained stable. CONCLUSIONS. This is the first prospective study performed in pediatric patients showing that the use of GA inhibitors was associated with an increased risk of acute gastroenteritis and community-acquired pneumonia in GERD-affected children. It could be interesting to underline that we observed an increased incidence of intestinal and respiratory infection in otherwise healthy children taking GA inhibitors for GERD treatment. On the contrary, the majority of the previous data showed that the patients most at risk for pneumonia were those with significant comorbid illnesses such as diabetes or immunodeficiency, and this points to the importance of GA suppression as a major risk factor for infections. In addition, this effect seems to be sustained even after the end of therapy. The results of our study are attributable to many factors, including direct inhibitory effect of GA inhibitors on leukocyte functions and qualitative and quantitative gastrointestinal microflora modification. Additional studies are necessary to investigate the mechanisms of the increased risk of infections in children treated with GA inhibitors, and prophylactic measures could be considered in preventing them.

Natural History of Potential Celiac Disease in Children

BACKGROUND & AIMS The presence of celiac disease-associated autoantibodies (antiendomysium and antitissue transglutaminase [anti-TG2]) with normal jejunal mucosa indicate potential celiac disease. We performed a prospective, 3-year cohort study to determine the natural history of potential celiac disease in children. METHODS The study included 106 children with potential celiac disease, based on serology analysis and normal duodenal architecture. All but 2 carried the HLA-DQ2 and/or DQ8 haplotype. In all children, every 6 months, growth, nutritional parameters, celiac disease serology, and autoimmunity were investigated. In biopsies, γδ intraepithelial-, CD3-, and lamina propria CD25-positive cells were counted; duodenal deposits of anti-TG2 immunoglobulin A were detected. Biopsy analysis was repeated after 2 years on patients with persistent positive serology and/or symptoms. RESULTS Celiac disease was detected primarily in first-degree relatives and patients with autoimmune disorders (40.6%). A gluten-free diet was prescribed to 20/106 patients because of symptoms, which were relieved in only 11. Eighty-nine of the 106 patients entered the follow-up study, with normal daily consumption of gluten. During the follow-up antibodies disappeared in 14.6% and fluctuated in 32.6%. Villous atrophy was observed in 12/39 patients (30.8%) who underwent a repeat biopsy. CONCLUSIONS Most children with potential celiac disease remain healthy. After 3 years, approximately 33% of patients develop villous atrophy. Intestinal deposits of anti-TG2 IgA identify children at risk for villous atrophy.

Reintroduction of gluten following flour transamidation in adult celiac patients: a randomized, controlled clinical study.

A lifelong gluten-free diet (GFD) is mandatory for celiac disease (CD) but has poor compliance, justifying novel strategies. We found that wheat flour transamidation inhibited IFN-γ secretion by intestinal T cells from CD patients. Herein, the primary endpoint was to evaluate the ability of transamidated gluten to maintain GFD CD patients in clinical remission. Secondary endpoints were efficacy in prevention of the inflammatory response and safety at the kidney level, where reaction products are metabolized. In a randomized single blinded, controlled 90-day trial, 47 GFD CD patients received 3.7 g/day of gluten from nontransamidated (12) or transamidated (35) flour. On day 15, 75% and 37% of patients in the control and experimental groups, respectively, showed clinical relapse (P = 0.04) whereas intestinal permeability was mainly altered in the control group (50% versus 20%, P = 0.06). On day 90, 0 controls and 14 patients in the experimental group completed the challenge with no variation of antitransglutaminase IgA (P = 0.63), Marsh-Oberhuber grading (P = 0.08), or intestinal IFN-γ mRNA (P > 0.05). Creatinine clearance did not vary after 90 days of treatment (P = 0.46). In conclusion, transamidated gluten reduced the number of clinical relapses in challenged patients with no changes of baseline values for serological/mucosal CD markers and an unaltered kidney function.

High Sodium and Low Potassium Intake among Italian Children: Relationship with Age, Body Mass and Blood Pressure

Background Hypertension is the leading cause of death in developed countries and reduction of salt intake is recommended as a key preventive measure. Objective To assess the dietary sodium and potassium intakes in a national sample of Italian children and adolescents and to examine their relationships with BMI and blood pressure (BP) in the framework of the MINISAL survey, a program supported by the Italian Ministry of Health. Population and Methods The study population included 1424 healthy subjects (766 boys, 658 girls) aged 6-18 years (mean age: 10.1±2.9) who were consecutively recruited in participating National Health Service centers in 10 Italian regions. Electrolyte intake was estimated from 24 hour urine collections tested for completeness by the concomitant measurement of creatinine content. Anthropometric indices and BP were measured with standardized procedures. Results The average estimated sodium intake was 129 mmol (7.4 g of salt) per day among boys and 117 mmol (6.7 g of salt) among girls. Ninety-three percent of the boys and 89% of the girls had a consumption higher than the recommended age-specific standard dietary target. The estimated average daily potassium intakes were 39 mmol (1.53 g) and 36 mmol (1.40 g), respectively, over 96% of the boys and 98% of the girls having a potassium intake lower than the recommended adequate intake. The mean sodium/potassium ratio was similar among boys and girls (3.5 and 3.4, respectively) and over 3-fold greater than the desirable level. Sodium intake was directly related to age, body mass and BP in the whole population. Conclusions The Italian pediatric population is characterized by excessive sodium and deficient potassium intake. These data suggest that future campaigns should focus on children and adolescents as a major target in the framework of a population strategy of cardiovascular prevention.

Oats in the Diet of Children with Celiac Disease: Preliminary Results of a Double-Blind, Randomized, Placebo-Controlled Multicenter Italian Study

A gluten-free diet (GFD) is currently the only available treatment for patients with celiac disease (CD). Several clinical trials have demonstrated that most celiac patients can tolerate a medium-high quantity of oats without any negative clinical effects; however, the inclusion of oats in GFD is still a matter of debate. In this study, Italian children with CD were enrolled in a 15-month, randomized, double-blind, placebo-controlled multicenter trial. Participants were randomized in two groups following either A-B treatment (6 months of diet “A”, 3 months of standard GFD, 6 months of diet “B”), or B-A treatment (6 months of diet “B”, 3 months of standard GFD, 6 months of diet “A”). A and B diets included gluten-free (GF) products (flour, pasta, biscuits, cakes and crisp toasts) with either purified oats or placebo. Clinical data (Gastrointestinal Symptoms Rate Scale [GSRS] score) and intestinal permeability tests (IPT), were measured through the study period. Although the study is still blinded, no significant differences were found in GSRS score or the urinary lactulose/mannitol (L/M) ratio between the two groups after 6 months of treatment. These preliminary results suggest that the addition of non-contaminated oats from selected varieties in the treatment of children with CD does not determine changes in intestinal permeability and gastrointestinal symptoms.

Safety of Oats in Children with Celiac Disease: A Double-Blind, Randomized, Placebo-Controlled Trial

Objective To evaluate the long‐term validity and safety of pure oats in the treatment of children with celiac disease. Study design This noninferiority clinical trial used a double‐blind, placebo‐controlled, crossover design extended over 15 months. Three hundred six children with a biopsy‐proven diagnosis of celiac disease on a gluten‐free diet for ≥2 years were randomly assigned to eat specifically prepared gluten‐free food containing an age‐dependent amount (15‐40 g) of either placebo or purified nonreactive varieties of oats for 2 consecutive 6‐month periods separated by washout standard gluten‐free diet for 3 months. Clinical (body mass index, Gastrointestinal Symptoms Rating Scale score), serologic (IgA antitransglutaminase antibodies, and IgA anti‐avenin antibodies), and intestinal permeability data were measured at baseline, and after 6, 9, and 15 months. Direct treatment effect was evaluated by a nonparametric approach using medians (95% CI) as summary statistic. Results After the exclusion of 129 patients who dropped out, the cohort included 177 children (79 in the oats–placebo and 98 in the placebo–oats group; median, 0.004; 95% CI, −0.0002 to 0.0089). Direct treatment effect was not statistically significant for clinical, serologic, and intestinal permeability variables (body mass index: median, −0.5; 95% CI, −0.12 to 0.00; Gastrointestinal Symptoms Rating Scale score: median, 0; 95% CI, −2.5 to 0.00; IgA antitransglutaminase antibodies: median, −0.02; 95% CI, −0.25 to 0.23; IgA anti‐avenin antibodies: median, −0.0002; 95% CI, −0.0007 to 0.0003; intestinal permeability test: median, 0.004; 95% CI, −0.0002 to 0.0089). Conclusions Pure nonreactive oat products are a safe dietary choice in the treatment of children with celiac disease. Trial registration ClinicalTrials.gov: NCT00808301.

PP21 DAILY LIFE WITHOUT GLUTEN IN A GROUP OF ADOLESCENT TEENS

child, whose parents were consanguineous. He was admitted to our hospital for bloody diarrhoea, asthenia, fever and a severe anaemia (haemoglobin 3.7 g/dl). Macroscopical signs of inflammation with a severe diffuse friability were discovered by gastrointestinal endoscopy and histological analysis suggested a diagnosis of UC. He was treated with blood transfusion, antibiotics and steroid therapy without improvement. We then started a rescue therapy ciclosporin followed by mesalazine and azathioprine. His clinical history was characterized by relapsing symptoms and by the lack of response to drugs. In view of an IL10R mutations involvement, we analyzed the IL10R1 and IL10R2 mRNA of the proband and his parents, by using a combination of reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time polymerase chain reaction. We observed a very lower level of IL10R1 mRNA expression in the proband of 0.1 fold change, compared to his father and mother that showed a value of 1 and 0.7 fold change respectively. No IL10R1 and IL10R2 mutations were found in any of the analyzed subjects. The SNPs analysis revealed that proband has homozygous G/G for SNPs rs.:2256111 and rs.:2229113 (located in a region responsible for receptor stability) and homozygous A/A for SNP rs.:9610, while his parents were both heterozygous A/G for these SNPs. In addition, the proband and his parents were heterozygous for the IL10RB K47E polymorphism, described to be associated with persistence of HBV infection and low level of IL10RB mRNA expression. Further studies are necessary to clarify the molecular mutations responsible for our patients disease; however, our data suggest that alterations of IL10R1 expression could be involved. It is possible that a specific SNPs haplotype contributes to disease manifestations with or without other mutations.