Alfredo Guarino

European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases Evidence-Based Guidelines for the Management of Acute Gastroenteritis in Children in Europe: Update 2014

Objectives: These guidelines update and extend evidence-based indications for the management of children with acute gastroenteritis in Europe. Methods: The guideline development group formulated questions, identified data, and formulated recommendations. The latter were graded with the Muir Gray system and, in parallel, with the Grading of Recommendations, Assessment, Development and Evaluations system. Results: Gastroenteritis severity is linked to etiology, and rotavirus is the most severe infectious agent and is frequently associated with dehydration. Dehydration reflects severity and should be monitored by established score systems. Investigations are generally not needed. Oral rehydration with hypoosmolar solution is the major treatment and should start as soon as possible. Breast-feeding should not be interrupted. Regular feeding should continue with no dietary changes including milk. Data suggest that in the hospital setting, in non–breast-fed infants and young children, lactose-free feeds can be considered in the management of gastroenteritis. Active therapy may reduce the duration and severity of diarrhea. Effective interventions include administration of specific probiotics such as Lactobacillus GG or Saccharomyces boulardii, diosmectite or racecadotril. Anti-infectious drugs should be given in exceptional cases. Ondansetron is effective against vomiting, but its routine use requires safety clearance given the warning about severe cardiac effects. Hospitalization should generally be reserved for children requiring enteral/parenteral rehydration; most cases may be managed in an outpatients setting. Enteral rehydration is superior to intravenous rehydration. Ultrarapid schemes of intravenous rehydration are not superior to standard schemes and may be associated with higher readmission rates. Conclusions: Acute gastroenteritis is best managed using a few simple, well-defined medical interventions.

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.

Oral Bacterial Therapy Reduces the Duration of Symptoms and of Viral Excretion in Children with Mild Diarrhea

BACKGROUND Oral administration of live Lactobacillus casei strain GG is associated with the reduction of duration of diarrhea in children admitted to the hospital because of diarrhea. The purposes of this work were to investigate the clinical efficacy of oral administration of Lactobacillus in children with mild diarrhea who were observed as outpatients, and to see whether Lactobacillus GG can reduce the duration of rotavirus excretion. METHODS Duration of diarrhea was recorded in 100 children seen by family pediatricians and randomly assigned to receive oral rehydration or oral rehydration followed by the administration of lyophilized Lactobacillus casei, strain GG. Rotavirus was looked for in the stools of all children and in those in whom results were positive, stools were examined again 6 days after the onset of diarrhea. RESULTS In 61 children results were positive for rotavirus and in 39 results were negative. Duration of diarrhea was reduced from 6 to 3 days in children receiving Lactobacillus GG, with a similar pattern in rotavirus-positive and -negative children. Six days after the onset of diarrhea, stools in only 4 out of 31 children that received Lactobacillus GG were positive for rotavirus compared with positive findings in 25 out of 30 control subjects. CONCLUSIONS Oral administration of Lactobacillus GG is effective in rotavirus-positive and rotavirus-negative ambulatory children with diarrhea. Furthermore, it reduces the duration of rotavirus excretion.

Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations

Objective To compare the efficacy of five probiotic preparations recommended to parents in the treatment of acute diarrhoea in children. Design Randomised controlled clinical trial in collaboration with family paediatricians over 12 months. Setting Primary care. Participants Children aged 3-36 months visiting a family paediatrician for acute diarrhoea. Intervention Childrens parents were randomly assigned to receive written instructions to purchase a specific probiotic product: oral rehydration solution (control group); Lactobacillus rhamnosus strain GG; Saccharomyces boulardii; Bacillus clausii; mix of L delbrueckii var bulgaricus, Streptococcus thermophilus, L acidophilus, and Bifidobacterium bifidum; or Enterococcus faecium SF68. Main outcome measures Primary outcomes were duration of diarrhoea and daily number and consistency of stools. Secondary outcomes were duration of vomiting and fever and rate of admission to hospital. Safety and tolerance were also recorded. Results 571 children were allocated to intervention. Median duration of diarrhoea was significantly shorter (P<0.001) in children who received L rhamnosus strain GG (78.5 hours) and the mix of four bacterial strains (70.0 hours) than in children who received oral rehydration solution alone (115.0 hours). One day after the first probiotic administration, the daily number of stools was significantly lower (P<0.001) in children who received L rhamnosus strain GG and in those who received the probiotic mix than in the other groups. The remaining preparations did not affect primary outcomes. Secondary outcomes were similar in all groups. Conclusions Not all commercially available probiotic preparations are effective in children with acute diarrhoea. Paediatricians should choose bacterial preparations based on effectiveness data. Trial registration number Current Controlled Trials ISRCTN56067537.

Intestinal inflammation is a frequent feature of cystic fibrosis and is reduced by probiotic administration

Aims : To assess the incidence of intestinal inflammation in children with cystic fibrosis and to investigate whether probiotics decrease it.

Hospital-Based Surveillance to Estimate the Burden of Rotavirus Gastroenteritis Among European Children Younger Than 5 Years of Age

OBJECTIVES. Rotavirus is the leading cause of acute gastroenteritis requiring hospitalization in young children. Data on the burden of rotavirus gastroenteritis are needed to guide recommendations for rotavirus vaccine use. This study was undertaken to estimate the burden of rotavirus gastroenteritis in European children <5 years of age. METHODS. This prospective, study was conducted in 12 hospitals in France, Germany, Italy, Spain, and the United Kingdom. A sample of all children aged <5 years presenting to emergency departments or hospitalized because of community-acquired acute gastroenteritis was enrolled for parental interview and stool collection. Acute gastroenteritis was defined as diarrhea (≥3 loose stools per 24 hours) for <14 days. Rotavirus was detected by enzyme-linked immunosorbent assay and typed by reverse-transcriptase polymerase chain reaction. RESULTS. Between February 2005 and August 2006, 3734 children with community-acquired acute gastroenteritis were recruited and retained for analysis (55.9% via the emergency department, 41.8% hospitalized). Of the 2928 community-acquired acute gastroenteritis cases for which stool samples were available, 43.4% were rotavirus-positive by enzyme-linked immunosorbent assay (32.8% emergency department, 56.2% hospitalized). Of these rotavirus gastroenteritis cases 80.9% occurred in children aged <2 years and 15.9% among infants aged <6 months. Acute gastroenteritis was more severe in rotavirus-positive subjects (Vesikari score ≥ 11 in 53.3% compared with 31.0% of rotavirus-negative subjects). All 1271 rotavirus-positive strains were genotyped (G1P[8]: 40.3%; G9P[8]: 31.2%; G4P[8]: 13.5%; G3P[8]: 7.1%). CONCLUSIONS. Rotavirus gastroenteritis places high demands on European health care systems, accounting for 56.2% of hospitalizations and 32.8% of emergency department visits because of community-acquired acute gastroenteritis in children aged <5 years. Most community-acquired rotavirus gastroenteritis occurs in children aged <2 years, and a high proportion occurs in infants aged <6 months. Cases were also observed among very young infants <2 months of age. Rotavirus vaccination is expected to have a major impact in reducing morbidity and the pressure on hospital services in Europe.

A formula containing galacto- and fructo-oligosaccharides prevents intestinal and extra-intestinal infections: an observational study.

BACKGROUND & AIM The addition of prebiotics to infant formula modifies the composition of intestinal microflora. Aim of the study was to test the hypothesis that prebiotics reduce the incidence of intestinal and respiratory infections in healthy infants. METHODS A prospective, randomized, placebo-controlled, open trial was performed. Healthy infants were enrolled and randomized to a formula additioned with a mixture of galacto- and fructo-oligosaccharides or to a control formula. The incidence of intestinal and respiratory tract infections and the anthropometric measures were monitored for 12 months. RESULTS Three hundred and forty two infants (mean age 53.7+/-32.1 days) were enrolled. The incidence of gastroenteritis was lower in the supplemented group than in the controls (0.12+/-0.04 vs. 0.29+/-0.05 episodes/child/12 months; p=0.015). The number of children with more than 3 episodes tended to be lower in prebiotic group (17/60 vs. 29/65; p=0.06). The number of children with multiple antibiotic courses/year was lower in children receiving prebiotics (24/60 vs. 43/65; p=0.004). A transient increase in body weight was observed in children on prebiotics compared to controls during the first 6 months of follow-up. CONCLUSIONS Prebiotic administration reduce intestinal and, possibly, respiratory infections in healthy infants during the first year of age.

Probiotics as prevention and treatment for diarrhea

Purpose of review To critically appraise evidence on probiotic use for prevention and treatment of diarrhea in children and adults. Recent findings Several randomized controlled trials and meta-analyses suggested that probiotics are effective in primary and secondary prevention of gastroenteritis and its treatment. Selected Lactobacillus strains had a modest, although significant effect in primary prevention. Saccharomyces boulardii was effective in antibiotic-associated and in Clostridium difficile diarrhea. There is evidence that it might prevent diarrhea in day-care centers. Lactobacillus rhamnosus GG was associated with reduced diarrheal duration and severity, more evident in case of childhood Rotavirus diarrhea. Similar, although weaker, evidence was obtained with S. boulardii. Both strains are included in evidence-based recommendations for gastroenteritis management in children. Data on other Lactobacillus strains are preliminary. Probiotic efficacy was related to cause, early administration and bacterial load, and their mechanisms were associated with antiinfectious action in the intestine or, indirectly, to modulation of innate and adaptive immunity. Summary Probiotics have gained a role as adjunctive treatment of infantile gastroenteritis together with rehydration. Their efficacy is less convincing in adults, but promising in antibiotic-associated diarrhea. However, evidence of efficacy is limited to a few strains.

Foreword: ESPGHAN/ESPID evidence-based guidelines for the management of acute gastroenteritis in children in Europe.

It is widely recognized that rotavirus is the main cause of acute gastroenteritis (AGE) in children in the world and, of course, in Europe. In fact, all children in Europe are expected to experience episodes of gastroenteritis in the first 3 years of life. Thus, pediatricians continue to see numerous cases in their daily practice. The overall burden of AGE in human terms and in terms of costs is overwhelming. One of the aims of scientific societies is to give guidance and support to their members regarding unsettled or controversial issues. It was in this context that the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and the European Society for Paediatric Infectious Diseases (ESPID) joined forces to draw up guidelines for pediatricians who must deal with AGE practically on a daily basis. This joint venture was prompted by the excellent collaboration between ESPGHAN and ESPID in drawing up the ESPID/ESPGHAN Evidence-Based Recommendations for Rotavirus Vaccination in Europe, our sister paper that is included in this supplement. The 2 societies agreed to collaborate on this ambitious enterprise to produce recommendations for both the prevention and management of gastroenteritis. Consequently, the vaccination recommendations and the AGE management guidelines represent an example of 2 authoritative societies joining together to promote good-quality health care for children in Europe. We wanted these guidelines to be a tool to meet 2 needs: first, as a guide in day-to-day practice (in some cases, demolishing entrenched myths; for example, the notion that feeding should be modified or delayed in children with AGE), and second, to reduce the financial burden of AGE as regards unnecessary treatment and hospitalization. We hope that, ultimately, these guidelines will improve the quality of health care of children with AGE in Europe and beyond. Over the years, various guidelines have been produced for the management of AGE in childhood; however, the defining feature of our guidelines is that the recommendations made stem from state-of-the-art evidence obtained through a thorough process of identifying and

Lactoferrin Induces Concentration-Dependent Functional Modulation of Intestinal Proliferation and Differentiation

Human milk stimulates intestinal development through the effects of various moieties. Lactoferrin (LF) is a glycoprotein of human milk whose concentration is highest in colostrum decreasing in mature milk. LF promotes enterocyte growth in intestinal cell lines. We tested the hypothesis that LF induces a distinct effect on enterocyte proliferation and differentiation, depending on its concentration. We examined the dose-related effects by human-native LF (N-LF) in Caco-2 (human colon adenocarcinoma) cells. At high concentrations, N-LF stimulated cell proliferation in immature Caco-2 cells, as judged by 3H-thymidine incorporation. In contrast, sucrase and lactase activities were increased at low but not high LF concentrations and their mRNA were also increased, indicating a transcriptional effect. Because iron binds specific LF sites, we compared the potency of N-LF and iron-saturated LF (I-LF) and found the native form more potent. Finally, we tested the effects by bovine LF (bLF) in the same system and found the latter more potent than the human isoform in inducing cell growth and lactase expression. These results suggest that LF directly induces enterocyte growth and proliferation, depending on its concentration, thereby regulating the earlyx postnatal intestinal development. bLF could be added to infant formula as a growth factor in selected intestinal diseases.