Symptoms and management of cow's milk allergy: perception and evidence.

Introduction: The diagnosis and management of cow's milk allergy (CMA) is a topic of debate and controversy. Our aim was to compare the opinions of expert groups from the Middle East (n = 14) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) (n = 13). Methods: These Expert groups voted on statements that were developed by the ESPGHAN group and published in a recent position paper. The voting outcome was compared. Results: Overall, there was consensus amongst both groups of experts. Experts agreed that symptoms of crying, irritability and colic, as single manifestation, are not suggestive of CMA. They agreed that amino-acid based formula (AAF) should be reserved for severe cases (e.g., malnutrition and anaphylaxis) and that there is insufficient evidence to recommend a step-down approach. There was no unanimous consensus on the statement that a cow's milk based extensively hydrolysed formula (eHF) should be the first choice as a diagnostic elimination diet in mild/moderate cases. Although the statements regarding the role for hydrolysed rice formula as a diagnostic and therapeutic elimination diet were accepted, 3/27 disagreed. The votes regarding soy formula highlight the differences in opinion in the role of soy protein in CMA dietary treatment. Generally, soy-based formula is seldom available in the Middle-East region. All ESPGHAN experts agreed that there is insufficient evidence that the addition of probiotics, prebiotics and synbiotics increase the efficacy of elimination diets regarding CMA symptoms (despite other benefits such as decrease of infections and antibiotic intake), whereas 3/14 of the Middle East group thought there was sufficient evidence. Discussion: Differences in voting are related to geographical, cultural and other conditions, such as cost and availability. This emphasizes the need to develop region-specific guidelines considering social and cultural conditions, and to perform further research in this area.

Use of Limosilactobacillus reuteri DSM 17938 in paediatric gastrointestinal disorders: an updated review.

Strains of lactobacilli are the most widely used probiotics and can be found in a large variety of food products and food supplements throughout the world. In this study, the evidence on Limosilactobacillus reuteri DSM 17938 (LR DSM 17938) has been reviewed. This species secretes reuterin and other substances singularly or in microvesicles, inhibiting pathogen growth and interacting with the intestinal microbiota and mucosa, restoring homeostasis. The use of LR DSM 17938 has been exploited in several pathological conditions. Preclinical research has shown that this probiotic can ameliorate dysbiosis and, by interacting with intestinal mucosal cells, can raise the pain threshold and promote gastrointestinal motility. These aspects are amongst the significant components in functional gastrointestinal disorders, such as colic and regurgitation in infants, functional abdominal pain and functional constipation in children and adolescents. This strain can decrease the duration of acute diarrhoea and hospitalization for acute gastroenteritis but does not seem to prevent nosocomial diarrhoea and antibiotic-associated diarrhoea. Because of its ability to survive in the gastric environment, it has been tested in Helicobacter pylori infection, showing a significant decrease of antibiotic-associated side effects and a tendency to increase the eradication rate. Finally, all these studies have shown the excellent safety of LR DSM 17938 even at higher dosages. In conclusion data from various clinical trials here reviewed can guide the clinician to find the correct dose, frequency of administration, and therapy duration.

Randomized Double-Blind Placebo-Controlled Crossover Trial for the Diagnosis of Non-Celiac Gluten Sensitivity in Children.

OBJECTIVES: Non-celiac gluten sensitivity (NCGS) is characterized by intestinal and extra-intestinal symptoms that are related to the ingestion of gluten in subjects who are not affected by either celiac disease (CD) or wheat allergy (WA). In this multicenter study, we aim for the first time to evaluate the prevalence of NCGS in pediatric subjects with chronic functional gastrointestinal symptoms associated with gluten ingestion using a double-blind placebo-controlled (DBPC) gluten challenge with crossover. METHODS: Among 1,114 children with chronic gastrointestinal symptoms (negative CD and WA), those exhibiting a positive correlation between symptoms and gluten ingestion were eligible for a diagnostic challenge including the following phases: run-in, open gluten-free diet (GFD) and DBPC crossover gluten challenge. Patients were randomized to gluten (10 g/daily) and placebo (rice starch) for 2 weeks each, separated by a washout week. The gluten challenge was considered positive in the presence of a minimum 30% decrease of global visual analogue scale between gluten and placebo. RESULTS: Out of 1,114 children, 96.7% did not exhibit any correlation with gluten ingestion. Thirty-six children were eligible; after the run-in and open GFD, 28 patients entered the gluten challenge. Eleven children (39.2%; 95% CI: 23.6-53.6%) tested positive. CONCLUSIONS: This is the first demonstration of the existence of NCGS in children that reinforce the need for a DBPC for the diagnosis as the diagnosis is ruled out in >60% of cases. The registration identifier in ClinicalsTrials.gov is NCT02431585.

Probiotics for prevention of atopic diseases in infants: systematic review and meta-analysis.

Growing evidence underlines the pivotal role of infant gut colonization in the development of the immune system. The possibility to modify gut colonization through probiotic supplementation in childhood might prevent atopic diseases. The aim of the present systematic review and meta-analysis was to evaluate the effect of probiotic supplementation during pregnancy and early infancy in preventing atopic diseases. PubMed, Embase and Cochrane Library were searched for randomized controlled trials evaluating the use of probiotics during pregnancy or early infancy for prevention of allergic diseases. Fixed-effect models were used, and random-effects models where significant heterogeneity was present. Results were expressed as risk ratio (RR) with 95% confidence interval (CI). Seventeen studies, reporting data from 4755 children (2381 in the probiotic group and 2374 in the control group), were included in the meta-analysis. Infants treated with probiotics had a significantly lower RR for eczema compared to controls (RR 0.78 [95% CI: 0.69-0.89], P = 0.0003), especially those supplemented with a mixture of probiotics (RR 0.54 [95% CI: 0.43-0.68], P < 0.00001). No significant difference in terms of prevention of asthma (RR 0.99 [95% CI: 0.77-1.27], P = 0.95), wheezing (RR 1.02 [95% CI: 0.89-1.17], P = 0.76) or rhinoconjunctivitis (RR 0.91 [95% CI: 0.67-1.23], P = 0.53) was documented. The results of the present meta-analysis show that probiotic supplementation prevents infantile eczema, thus suggesting a new potential indication for probiotic use in pregnancy and infancy.

Prevention of functional gastrointestinal disorders in neonates: clinical and socioeconomic impact.

Infantile colic, gastro-oesophageal reflux and constipation are the most common functional gastrointestinal disorders (FGIDs) affecting infants during the first months of life. Despite infantile colic, functional constipation and regurgitation had a self-limited pattern, they are considered a risk factor for developing different disorders later in life. The pathophysiology of these functional diseases is still controversial but there is growing evidence that an abnormal gut microbiota colonisation may play a crucial role. An early probiotic supplementation could determine a change in colonisation and may represent a new strategy for preventing FGIDs.

Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN Working Group for Probiotics and Prebiotics

The use of probiotics has been suggested in the treatment of acute gastroenteritis (AGE) in addition to early rehydration and avoidance of dietary restrictions. This document provides recommendations for the use of probiotics for the treatment of AGE in previously healthy infants and children based on a systematic review of previously completed systematic reviews and of randomized controlled trials (RCTs) published subsequently to these reviews. The recommendations were formulated only if at least 2 RCTs that used a given probiotic (with strain specification) were available. The GRADE system developed by the Grading of Recommendations, Assessment, Development, and Evaluations Working Group, was used to grade the strength of evidence and grades of recommendations used in these guidelines. It offers 4 categories of the quality of the evidence (high, moderate, low, and very low) and 2 categories of the strength of recommendation (strong or weak). The use of the following probiotics (in alphabetical order) may be considered in the management of children with AGE in addition to rehydration therapy: Lactobacillus rhamnosus GG (low quality of evidence, strong recommendation) and Saccharomyces boulardii (low quality of evidence, strong recommendation). Less compelling evidence is available for Lactobacillus reuteri DSM 17938 (very low quality of evidence, weak recommendation) and heat-inactivated Lactobacillus acidophilus LB (very low quality of evidence, weak recommendation). The latter, although traditionally discussed with other probiotics, does not fit with the definition of probiotics. Other strains or combinations of strains have been tested, but evidence of their efficacy is weak or preliminary.

Randomised clinical trial: Lactobacillus reuteri DSM 17938 vs. placebo in children with acute diarrhoea--a double-blind study.

BACKGROUND: Probiotics may be of help for the management of acute diarrhoea, however, the effect is strain specific and efficacy needs to be proven. AIM: To test the efficacy and safety of Lactobacillus reuteri DSM 17938 derived from L. reuteri ATCC 55730 in children with acute diarrhoea. Primary outcomes were the rate of unresolved diarrhoea after 3 days of treatment and duration of diarrhoea. METHODS: Children (6-36 months), hospitalised in three paediatric hospitals in Southern Italy for acute diarrhoea with clinical signs of dehydration were randomised to receive in a double-blind fashion either L. reuteri (dose of 4 × 10(8) colony-forming units/die) or placebo. RESULTS: Out of 96 eligible children, 74 were enrolled, five patients were withdrawn; 35 in the L. reuteri group and 34 in the placebo group. Lactobacillus reuteri significantly reduced the duration of watery diarrhoea as compared with placebo (2.1 ± 1.7 days vs. 3.3 ± 2.1 days; P < 0.03); on day two and three of treatment watery diarrhoea persisted in 82% and 74% of the placebo and 55% and 45% of the L. reuteri recipients respectively (P < 0.01; P < 0.03). Finally, children receiving L. reuteri had a significantly lower relapse rate of diarrhoea (15% vs. 42%; P < 0.03). There was not a significant difference in hospital stay between the groups. No adverse events were recorded. CONCLUSION: Our study shows that L . reuteri DSM 17938 as an adjunct to rehydration therapy is efficacious in the treatment of acute diarrhoea reducing the frequency, duration and recrudescence rate of the disease.

The effect of prebiotics in the management of neonatal hyperbilirubinaemia.

BACKGROUND: Breast milk oligosaccharides such as galacto-oligosaccharides (scGOS) and fructo-oligosaccharides (lcFOS) can influence the intestinal microbial flora. The latter, in turn, can modulate several intestinal and extraintestinal functions, including bilirubin metabolism. Supplementing infant formula with a prebiotic mixture might then be a novel and safe intervention to manage mild neonatal hyperbilirubinaemia. AIM: To investigate the effect of dietary supplementation with prebiotics on moderate hyperbilirubinaemia in healthy, term infants. METHODS: A prospective, double-blind, clinical trial was performed on seventy-six consecutive newborns who were randomly assigned to receive a formula containing 0.8 g/dL of a mixture from scGOS and lcFOS (ratio 9:1), or maltodextrines as placebo for 28 days. Bilirubin levels were determined by the transcutaneous bilirubin measurement within 2 h after birth (T1), at 24, 48 and 72 h and at 5, 7, 10 and 28 days of life. The number of stool per day was also recorded. RESULTS: Neonates receiving prebiotics showed a larger number of stools over all the duration of dietary intervention compared to that of those on placebo (Repeated Measures ANOVA p < 0.001; day 28 3.4 +/- 0.0.9 vs 1.7 +/- 0.9, respectively; Dunn test p < 0.05). Neonates whose formula was supplemented with prebiotics showed a lower transcutaneous bilirubin that was statistically significant from 72 h of life (5.46 +/- 1.6 vs 7.07 +/- 2.49, post hoc Dunn test, p < 0.05) throughout the duration of the dietary intervention (day 28 2.41 +/- 0.4 vs 2.85 +/- 0.5, post hoc Dunn test, p < 0.05). CONCLUSION: The addition of prebiotics to standard infant diet might represent a novel strategy to help control neonatal hyperbilirubinaemia.

Effects of probiotic and prebiotic on gastrointestinal motility in newborns.

To fortify the biological role of milk formula has been suggested to use probiotics and prebiotics as functional components to mimic the effect of breast milk. The aim of this study was to evaluate the effects of prebiotic, probiotic added to a standard formula on gastrointestinal motility respect to placebo-formula. Cutaneous electrogastrography (EGG) and ultrasound gastric emptying (GE) were performed in 49 preterm newborns. 17 newborns were exclusively breast-fed; 32 were randomly assigned to receive prebiotic-added formula (0.8 g/dl of a mixture from scGOS and lcFOS, ratio 9:1) (10), a probiotic-added formula (L. reuteri at dose of 1x10(8) colony forming units (CFU) per day) (10), a formula with placebo (12) for 30 days. No difference was seen in the nutritional parameters and no adverse events were reported. After the intervention period, the prebiotic, probiotic, and breast milk groups showed a higher percentage of EGG slow wave propagation and faster gastric half emptying time respect to placebo group (ANOVAon ranks p<0.001; Dunn test vs control: prebiotic, probiotic and breast-milk vs placebo formula p<0.05; and ANOVA on ranks p=0.005; Dunn test vs control: prebiotic, probiotic and breast-milk vs placebo formula p<0.05, respectively). Feeding preterm infants with a formula supplemented with prebiotics or probiotics may stimulate gastric emptying and improve maturation of the EGG activity mimicking the effect of breast milk.

Multichannel intraluminal impedance to detect relationship between gastroesophageal reflux and apnoea of prematurity.

BACKGROUND: The association between gastroesophageal reflux and apnoea of prematurity is still controversial. Available data are biased by the heterogeneity of the infants enrolled as regard to some confounding factors and by the use of the traditional pH monitoring that is unable to detect non acid reflux events which might be prevalent in infants receiving frequent milk feeding. Multichannel intraluminal impedance has been recently introduced as a pH-independent method to investigate the bolus transport in hollow organs. OBJECTIVE: To assess if combined multichannel intraluminal impedance-pH study could be useful to detect an association between gastroesophageal reflux and apnoea of prematurity. METHODS: We prospectively evaluated a group of premature infants with apnoea of prematurity in absence of any confounding factors (ventilatory support, treatment with caffeine, permanent nasogastric tube, post-natal age older than 30 days) by simultaneous recording of 24-h multichannel intraluminal impedance-pH and cardiorespiratory monitoring. A temporal relationship between an apnoea and a reflux event was considered if both commenced within 20s of each other. RESULTS: Six premature infants [three male; median gestational age 31 weeks (range 27-36); birth weight 1335g (range 1200-2350); age at study 17 days (range 7-28)] were studied. A total of 405 reflux events [306 (76%) weakly acid and 99 acid reflux] and 142 apnoeas were detected. The frequency of apnoeas occurring during the reflux events period was significantly greater than the one calculated for reflux-free period [0.42/min (0.00-1.28) versus 0.016/min (0.003-0.028); p<0.05]. The sub-analysis based on chemical composition and duration of refluxate showed that the frequency of apnoeas associated with weakly acid reflux events was significantly greater than the one calculated for reflux-free period [0.416/min (0.00-1.30) versus 0.016/min (0.003-0.028), respectively; p<0.05] and that the frequency of apnoeas occurring during reflux events longer than 30s was significantly higher than those occurring during shorter reflux events (22% versus 11%; p<0.004). CONCLUSION: Our data show that weakly acidic reflux events are more prevalent than acid reflux events in premature infants, confirming the need for the use of multichannel intraluminal impedance-pH monitoring for diagnosis of gastroesophageal reflux in those patients. Gastroesophageal reflux and apnoea of prematurity are both common occurrences and, in our experience, may be temporally related especially as regard to weakly acid refluxate and reflux events longer than 30s.

Calprotectin levels in meconium.

AIM: To evaluate the effect of gender, gestational age, birthweight, mode of delivery, 5'-Apgar score and maternal conditions on calprotectin concentrations in meconium. METHODS: Calprotectin was measured in 131 neonates, in the first passed meconium. RESULTS: Calprotectin levels (mean +/- SD) resulted in 145.2 +/- 78.5 mg kg(-1) meconium, significantly correlated with birthweight (r = -0.333; p < 0.001), gestational age (r = -0.206; p = 0.018) and 5'-Apgar score (r = -0.243, p = 0.035). The estimated regression model was: calprotectin levels (mg kg(-1)) = 269.58-41.54 weight (kg): r = 0.383, p < 0.001. No differences were found in relation to gender, mode of delivery and maternal conditions. CONCLUSION: Calprotectin is already present in the first passed meconium, with higher levels in preterm and low birthweight neonates, as well as in neonates with some degree of perinatal asphyxia, as indicated by the negative correlation with 5'-Apgar score. These findings are probably secondary to both the immaturity of the intestinal mucosa and its hypoxic-ischaemic damage.

Gastric electrical activity and gastric emptying in preterm newborns fed standard and hydrolysate formulas.

BACKGROUND: Because infant formulas containing hydrolyzed cow milk protein are used to reduce feeding intolerance and to improve gastric emptying, the effect on gastrointestinal motility of a hydrolysate formula was compared with that of a standard preterm formula. METHODS: Thirty-six preterm newborns with a gestational age of 32.2 +/- 2.3 weeks were assigned randomly to standard formula or hydrolyzed formula. Cutaneous electrogastrography and ultrasound examination of gastric emptying were performed simultaneously to evaluate gastrointestinal motility before and after the test meal. All recording sessions were performed 1 week after infants had reached full enteral feeding. RESULTS: No significant difference in gastrointestinal symptoms was noted in the newborns fed the different formulas. In particular, regurgitation and vomiting were observed in 78% versus 64% of preterm newborns after standard and hydrolyzed formula, respectively (Fisher exact test, not significant). No differences were found in terms of gastric electrical activity and gastric emptying time between the two groups. CONCLUSIONS: It seems unnecessary to use hydrolysate formulas to improve motility in preterm infants.

Gastric electrical activity and gastric emptying in term and preterm newborns.

The aims of this study were to evaluate the gastric electrical activity and gastric emptying in preterm and term newborns and to assess the development of gastric motility by comparing newborns of different gestational ages. The cutaneous electrogastrography and the ultrasonographic study of the gastric emptying were performed before and after milk formula in three groups of infants: 12 preterm newborns with a gestational age of 28-32 weeks, 11 preterm newborns with a gestational age of 32-36 weeks, and 10 full-term newborns with a gestational age of 36-40 weeks. All recording sessions were performed 1 week after infants had reached full enteral feeding. The percentage of normal slow waves was similar in the three groups but it was not predominant compared to tachygastria in the earliest premature infants (59.3% (12.7-92.3) vs. 29.6% (3.7-78.8); P < 0.05). In addition, a progressive increase in the normal slow wave percentage (59.3% (17.4-87.4), 60.9% (38.1-89.7), 77.8% (66.4-84.8); P < 0.05) was observed as gestation advanced. As regards gastric emptying parameters, the antral area was greater and T(1/2) was longer in the preterm newborns of 28-32 weeks than preterm newborns of 32-36 weeks and full-term newborns (fasting antral area: 0.96 cm2 (0.6-1.5), 0.63 cm2 (0.4-1.2), 0.55 cm2 (0.1-0.9) respectively, P < 0.05; T(1/2): 83.4 min (76.0-108.5), 70 min (57.5-89.5) and 71.8 min (54.9-81.2), respectively P < 0.05). The comparisons of gastric emptying curves made among the three groups showed a reduced antral dilatation in preterm newborns of 28-32 weeks compared to full-term newborns at 30 and 60 min after a meal. In conclusion, although enteral feeding is important for the development process of gastrointestinal motility, gastric electrical activity and gastric emptying show an intrinsic maturation depending on the gestational age.