IntroductionLacticaseibacillus rhamnosus GG (LGG) is a well-studied probiotic with a history of safe use.MethodsIn this double-blind, prospective study, growth and tolerance were evaluated in healthy term infants randomized to: marketed, routine intact cow's milk protein-based formula (Control, n = 172) or a similar investigational formula with added LGG (INV-LGG, n = 179; 106 CFU LGG®/g powder) from 14 to 120 days of age. Anthropometrics, stool characteristics, fussiness, and gassiness were evaluated through Day 120. Medically confirmed adverse events were recorded throughout the study period. The primary outcome was rate of weight gain from Day 14–120.ResultsOf 351 infants enrolled, 275 completed (Control, n = 131; INV-LGG, n = 144). No significant group differences in rate of weight gain from Day 14–120 were detected. Study formula acceptance and tolerance was good with no significant differences in study discontinuation due to study formula or parent-reported gassiness, stool frequency, or stool consistency; however mean fussiness relative to normal was significantly lower for INV-LGG vs Control at Days 60 and 90.DiscussionIn healthy term infants, a routine intact cow's milk protein-based formula with added LGG supported adequate growth and was well tolerated. Further studies are needed to evaluate potential benefits for fussiness and efficacy outcomes. Clinical Trial RegistrationClinicaltrials.gov, identifier (NCT01897922).

Gastrointestinal xanthomas are benign, usually sessile, polypoid lesions occasionally incidentally seen in adults, usually in the stomach, but have not been reported in the large intestine in children. We identified xanthomas in the sigmoid colon of the 15-year-old girl confirmed histologically. Our findings suggest that colonic xanthomas may occur as an incidental finding in pediatric patients. They have a characteristic visual and histologic appearance but do not appear to be associated with any symptoms or illness and do not require follow-up.

Although extensively hydrolyzed formula is widely accepted for managing cow’s milk protein allergy (CMPA) long-term, there is a lack of evidence on its short-term efficacy. This study’s objective was to investigate the short-term symptom changes (within 3–6 weeks) of infants diagnosed with CMPA and managed with extensively hydrolyzed formula containing Lactobacillus rhamnosus at their subsequent physician visit. Healthcare providers treating 202 patients diagnosed with CMPA under six months old completed de-identified surveys, which were then analyzed in this prospective study. After their first visit, the patients were started on extensively hydrolyzed formula, and their baseline symptoms were scored on a severity scale of 0–3. Patients were then reevaluated at their next follow-up visit to assess changes in symptom severity. The study found statistically significant improvements in gastrointestinal (93%), skin (83%), respiratory (73%), and uncategorized symptoms (90%). These symptom improvements were consistent across different follow-up visit durations. This study is the largest prospective analysis conducted in the United States evaluating short-term change in CMPA symptoms severity in infants under six months old using extensively hydrolyzed formula. These findings suggest that extensively hydrolyzed formula is associated with clinical symptom relief, which is often noticeable by the next follow-up visit. However, additional randomized control trials are needed to validate these results.

Clinical trials are essential to the advancement of modern evidence-based medicine. The number of healthcare professionals (HCPs) participating in clinical research is continuously declining. Collecting patient data for clinical research can be challenging and time-consuming. This study aimed to evaluate the use of the ZS Moments mobile phone application (app) as a real-time data collection tool in a survey of Healthcare Professionals (HCPs) treating patients with cow's milk protein allergy (CMPA). A secondary analysis of prospectively collected de-identified survey data obtained from HCPs treating patients with CMPA in an outpatient setting was conducted. HCPs downloaded the ZS Moments app to their mobile device. After evaluating a patient and recommending a clinical management strategy (visit 1), HCPs completed a 10-minute survey using the ZS Moments app to document patient symptoms in real time. At the next follow-up visit (visit 2), the HCP completed a second survey assessing how symptoms changed since initiating treatment. Data from 404 patients (808 visits) were collected from 61 HCPs using the ZS Moments app. Of the 61 HPCs, 52 (85%) were included in the analysis. The most common reason for HCP exclusion was incomplete or non-submission of data. Of the 404 patient surveys collected, 75 (19%) were excluded due to the absence of visit 2 information, the discrepancy between the collected information on visit 1 and visit 2, or the poor quality of responses. Twenty-three patients were excluded from final symptom analysis calculations due to treatment switching but were included in the overall sample size. The study found that a majority of healthcare professionals successfully completed surveys for both visit 1 and visit 2 using the ZS Moments mobile app. The use of high-quality, real-time data collection software like ZS Moments may help to simplify the process of data entry and increase HCPs’ participation in clinical research. This highlights the potential benefits of technology in improving data collection and promoting clinical research.

Purpose: Cow's milk protein allergy (CMPA) is a common condition in infants, but little is known about healthcare providers' clinical experience treating infants with CMPA. To address this gap, we analyzed prospectively collected data from healthcare providers (HCPs) who treated infants under six months old with suspected CMPA using hypoallergenic formulas. The study focused on a commercial extensively hydrolyzed formula containing Lactobacillus rhamnosus GG (ATCC53103) (eHF-LGG) or a commercial amino acid formula (AAF).Methods: In this secondary analysis of prospectively collected survey data, 52 HCPs treated 329 infants under six months old with suspected CMPA using hypoallergenic formulas. A series of two de-identified surveys per patient were collected by HCPs to assess short-term symptom relief in the patients and HCP's satisfaction with the management strategies. The initial survey was completed at the initiation of treatment of CMPA, and the second survey was completed at a follow-up visit.Results: The majority of HCPs (87%) in the study were general pediatricians, and most saw 2 to 10 CMPA patients weekly. Results showed that clinicians reported satisfaction with treatment in 95% of patients in the EHF cohort and 97% of patients in the AAF cohort and achieved expected clinical results in 93% and 97% of patients using eHF and AAF, respectively. Furthermore, few patients were switched from the hypoallergenic formula once initiated.Conclusion: The study provides new insights into HCP perspectives on treating infants with CMPA and supports using hypoallergenic formulas to manage this condition. However, additional prospective controlled studies are needed to confirm these initial findings.

BackgroundCow’s milk protein allergy (CMPA) occurs commonly in infants. While the long-term efficacy of amino acid formulas for managing CMPA is well-established, there is limited data on the short-term symptom improvement of using amino acid formula (AAF).ObjectiveThis study aimed to determine the short-term effects of managing suspected CMPA in infants aged 6 months and under using a commercial AAF.MethodsHealthcare providers who treated infants with suspected CMPA aged 6 months or younger (n = 104) provided de-identified survey data in this prospective study. Healthcare providers scored symptoms for severity from 0 to 3 (none, low, moderate, severe) before using a commercial AAF at Visit 1 and at Visit 2 (3–6 weeks later).ResultsGastrointestinal (94%), skin (87%), respiratory (86%), and uncategorized symptoms (89%) improved from AAF initiation, and these findings were consistent across different follow-up visit durations.ConclusionThis study is the most extensive prospective analysis conducted in the United States examining the short-term change in suspected CMPA symptoms using an AAF. These findings suggest that AAF may decrease the severity of suspected CMPA symptoms in infants 6 months or younger, often by the next follow-up visit. Further randomized controlled trials are required to confirm these initial findings.

The complex microbial community of the gut microbiome plays a fundamental role in driving development and function of the human immune system. This phenomenon is named the gut microbiome-immune system axis. When operating optimally, this axis influences both innate and adaptive immunity, which orchestrates the maintenance of crucial elements of host-microorganisms symbiosis, in a dialogue that modulates responses in the most beneficial way. Growing evidence reveals some environmental factors which can positively and negatively modulate the gut microbiome-immune system axis with consequences on the body health status. Several conditions which increasingly affect the pediatric age, such as allergies, autoimmune and inflammatory disorders, arise from a failure of the gut microbiome-immune system axis. Prenatal or postnatal modulation of this axis through some interventional strategies (including diet, probiotics and postbiotics), may lead to a positive gene-environment interaction with improvement of immune-modulatory effects and final positive effect on human health. In particular probiotics and postbiotics exerting pleiotropic regulatory actions on the gut-microbiome-immune system axis provide an innovative preventive and therapeutic strategy for many pediatric conditions.

Background Early infant feeding with intact or extensively hydrolyzed (EH) proteins or free amino acids (AA) may differentially affect intestinal microbiota composition and immune reactivity. This multicenter, double-blind, controlled, parallel-group, pilot study compared stool microbiota from Baseline (1–7 days of age) up to 60 days of age in healthy term infants who received mother’s own milk (assigned to human milk [HM] reference group) ( n = 25) or were randomized to receive one of two infant formulas: AA-based (AAF; n = 25) or EH cow’s milk protein (EHF; n = 28). Stool samples were collected (Baseline, Day 30, Day 60) and 16S rRNA genes were sequenced. Alpha (Shannon, Simpson, Chao1) and beta diversity (Bray Curtis) were analyzed. Relative taxonomic enrichment and fold changes were analyzed (Wilcoxon, DESEq2). Short/branched chain fatty acids (S/BCFA) were quantified by gas chromatography. Mean S/BCFA and pH were analyzed (repeated measures ANOVA). Results At baseline, alpha diversity measures were similar among all groups; however, both study formula groups were significantly higher versus the HM group by Day 60. Significant group differences in beta diversity at Day 60 were also detected, and study formula groups were compositionally more similar compared to HM. The relative abundance of Bifidobacterium increased over time and was significantly enriched at Day 60 in the HM group. In contrast, a significant increase in members of Firmicutes for study formula groups were detected at Day 60 along with butyrate-producing species in the EHF group. Stool pH was significantly higher in the AAF group at Days 30 and 60. Butyrate increased significantly from Baseline to Day 60 in the EHF group and was significantly higher in study formula groups vs HM at Day 60. Propionate was also significantly higher for EHF and AAF at Day 30 and AAF at Day 60 vs HM. Total and individual BCFA were higher for AAF and EHF groups vs HM through Day 60. Conclusions Distinct patterns of early neonatal microbiome, pH, and microbial metabolites were demonstrated for infants receiving mother’s own milk compared to AA-based or extensively hydrolyzed protein formula. Providing different sources of dietary protein early in life may influence gut microbiota and metabolites. Trial registration ClinicalTrials.gov Identifier: NCT02500563 . Registered July 28, 2015.

Since originally isolated in 1899, the genus Bifidobacterium has been demonstrated to predominate in the gut microbiota of breastfed infants and to benefit the host by accelerating maturation of the immune response, balancing the immune system to suppress inflammation, improving intestinal barrier function, and increasing acetate production. In particular, Bifidobacterium longum subspecies infantis (B. infantis) is well adapted to the infant gut and has co-evolved with the mother-infant dyad and gut microbiome, in part due to its ability to consume complex carbohydrates found in human milk. B. infantis and its human host have a symbiotic relationship that protects the preterm or term neonate and nourishes a healthy gut microbiota prior to weaning. To provide benefits associated with B. infantis to all infants, a number of commercialized strains have been developed over the past decades. As new ingredients become available, safety and suitability must be assessed in preclinical and clinical studies. Consideration of the full clinical evidence for B. infantis use in pediatric nutrition is critical to better understand its potential impacts on infant health and development. Herein we summarize the recent clinical studies utilizing select strains of commercialized B. infantis.

Introduction: Cow's milk allergy (CMA) is a common diagnosis in infants, requiring the exclusion of cow's milk until tolerance is recovered. In the present study, we aim to determine which factors are associated with the development of tolerance. Methods: Retrospective, observational study of subjects who underwent the same clinical follow-up methodology. We studied 245 cases of CMA (125 IgE-mediated and 120 non-IgE-mediated). The following variables were analysed: age at diagnosis, gender, type of delivery, type of feeding received, feeding during the first months of life, clinical features, and type of feed received as treatment: casein hydrolysates or casein hydrolysates with Lactobacillus rhamnosus GG (LGG). Results: Factors associated with earlier tolerance were non-IgE-mediated CMA (HR = 2.92; 95% CI: 2.20-3.88) and patients receiving casein hydrolysate with LGG (HR = 1.79; 95% CI: 1.33-2.42). Later tolerance was associated with caesarean delivery (HR = 0.78; 95% CI: 0.58-1.05) and breastfeeding for a period of at least 3 days (HR = 0.64; 95% CI: 0.44-0.93). The multivariate study shows that the type of formula (HR = 1.61; 95% CI: 1.19-2.18) and the type of CMA (HR = 2.82; 95% CI: 2.12-3.85) have an effect on the recovery time. Casein hydrolysates with LGG reduces the recovery time in IgE-mediated (HR = 1.88; 95% CI: 1.17-3.01) and non-IgE-mediated CMA (HR = 1.46; 95% CI: 0.98-2.17). Conclusions: Tolerance acquisition is faster in non-IgE-mediated CMA subjects and in those who received casein hydrolysate with LGG.

Infant feeding practices play a central role in development of gut microbiome and community structure. Our goal was to test the hypothesis that diets with intact or extensively hydrolyzed proteins or free amino acids may differentially affect the intestinal microbiota composition and immune reactivity. This multicenter, double-blind, controlled, parallel-group, pilot study compared stool microbiota outcomes from Baseline (1-7 days of age) up to 60 days of age in healthy term infants. Infants received mother’s own milk (assigned to human milk [HM] reference group) (n = 25) or were randomized to receive one of two infant formulas: amino-acid based (AAF; n = 25) or extensively hydrolyzed cow’s milk protein (EHF; n = 28). Neither study formula included added Lactobacillus rhamnosus GG. DNA was extracted (Baseline, Day 30, Day 60), 16S rRNA genes were amplified and sequenced (Illumina MiSeq), and exact amplicon sequence variants (ASV) were assigned using the DADA2 model. Alpha (Shannon, Simpson, Chao1) and beta diversity (Bray Curtis distance) and differential abundance in taxa were analyzed. Relative ASV enrichment (Baseline vs Day 60) was visualized using heat maps and taxa abundance was analyzed by DESEq2 in R (ver 3.4.3). Complete stool data (all study time points) were available for 49 participants. Baseline alpha diversity measures were similar among groups. The HM group remained stable throughout the study. However, alpha diversity measures by Day 60 were significantly higher for AAF and EHF groups compared to HM. Significant group differences in beta diversity at Day 60 were detected (P < 0.001); AAF and EHF clustered more closely compared to the HM group. Relative Bifidobacterium abundance increased over time and was significantly enriched at Day 60 in the HM group (Figure, A). At Day 60, a significant increase in members of Firmicutes was detected for AAF and EHF groups; a decrease in Enterobacteriaceae (Escherichia) was observed for EHF (Figure, B). Distinct patterns of early neonatal microbiome establishment were demonstrated for infants receiving mother’s own milk compared to amino acid-based or extensively hydrolyzed protein infant formulas. Providing different sources of dietary protein early in life may impact gut microbiome development. Mead Johnson Pediatric Nutrition Institute.

Infant feeding influences early development of the gut microbiome, colonization pattern, and community structure. Metabolites, including short- and branched-chain fatty acids (S/BCFA) (e.g., butyrate, propionate), produced by colonic bacteria serve as signaling molecules, influence immunity, and reduce luminal pH in the gastrointestinal environment. The objective of this study was to evaluate stool S/BCFA and pH in infants fed with different sources of dietary protein. In this multicenter, double-blind, controlled, parallel-group, pilot study, healthy term infants were randomized to receive one of two infant formulas (IF): amino-acid based (AAF; n = 25) or extensively hydrolyzed cow’s milk protein (EHF; n = 28) from Baseline (1-7 days of age) up to 60 days of age. A human milk reference group (HM; n = 25) received mother’s own milk over the same period. Diethyl ether extractions of S/BCFA from stool samples (Baseline, Day 30, and Day 60) were quantified by gas chromatography (Clarus 580; PerkinElmer) using a fused silica capillary column (Nukol 30m × 0.25mm id × 0.25μm film). Mean stool S/BCFA (μmol/g) and pH were analyzed by repeated measures analysis of variance (ANOVA). Complete stool data (all study time points) were available for 49 participants. Stool pH (∼6) was similar among groups at Baseline with no significant changes for HM and EHF groups through Day 60. The AAF group was significantly higher at Days 30 and 60 (Figure 1). Total SCFA were similar for all groups through Day 60. Butyrate increased significantly from Baseline to Day 60 in the EHF group (P = 0.026) and was significantly higher vs HM at Days 30 and 60 (P = 0.0009 and 0.0004 respectively). Butyrate was significantly higher for AAF vs HM at Day 60 only (P = 0.038). Propionate was significantly higher for EHF and AAF at Day 30 (P = 0.0009 and < 0.0001 respectively) and AAF only at Day 60 (P = 0.005) vs HM. Total and individual BCFA increased for AAF and EHF groups vs HM through Day 60. Distinct patterns of pH and microbial metabolites were demonstrated for infants receiving mother’s own milk compared to amino acid-based or extensively hydrolyzed protein formula. Providing different sources of dietary protein early in life may influence gut microbiota and metabolites. Mead Johnson Pediatric Nutrition Institute.

This chapter is based on the memories of those who shaped the relationship between the European and the North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition. The first joint meeting of the 2 Societies took place in Paris in 1978, followed by 1 in New York in 1985, 1 in Amsterdam in 1990, 1 in Houston in 1994, and the last one in Toulouse in 1998. The formation of the Federation of the International Societies for Pediatric Gastroenterology, Hepatology and Nutrition (FISPGHAN) preceded the First World Congress of all Societies, which took place in Boston in 2000. The success of this meeting was followed by world congresses in Paris in 2004, Iguassu in 2008, Taiwan in 2012, and Montreal in 2016. NASPGHAN and ESPGHAN jointly took on the direction of the Journal of Pediatric Gastroenterology and Nutrition in 1991. Communication between the 2 Societies is extremely active, with members participating in many joint projects.

Eosinophilic esophagitis (EoE), a Th2-type allergic immune disorder characterized by an eosinophil-rich esophageal immune infiltrate, is often associated with food impaction (FI) in pediatric patients but the molecular mechanisms underlying the development of this complication are not well understood. We aim to identify molecular pathways involved in the development of FI. Due to large variations in disease presentation, our analysis was further geared to find markers capable of distinguishing EoE patients that are prone to develop food impactions and thus expand an established medical algorithm for EoE by developing a secondary analysis that allows for the identification of patients with food impactions as a distinct patient population. To this end, mRNA patterns from esophageal biopsies of pediatric EoE patients presenting with and without food impactions were compared and machine learning techniques were employed to establish a diagnostic probability score to identify patients with food impactions (EoE+FI). Our analysis showed that EoE patients with food impaction were indistinguishable from other EoE patients based on their tissue eosinophil count, serum IgE levels, or the mRNA transcriptome-based p(EoE). Irrespectively, an additional analysis loop of the medical algorithm was able to separate EoE+FI patients and a composite FI-score was established that identified such patients with a sensitivity of 93% and a specificity of 100%. The esophageal mRNA pattern of EoE+FI patients was typified by lower expression levels of mast cell markers and Th2 associated transcripts, such as FCERIB, CPA3, CCL2, IL4, and IL5. Furthermore, lower expression levels of regulators of esophageal motility (NOS2 and HIF1A) were detected in EoE+FI. The EoE+FI -specific mRNA pattern indicates that impaired motility may be one underlying factor for the development of food impactions in pediatric patients. The availability of improved diagnostic tools such as a medical algorithm for EoE subpopulations will have a direct impact on clinical practice because such strategies can identify molecular inflammatory characteristics of individual EoE patients, which, in turn, will facilitate the development of individualized therapeutic approaches that target the relevant pathways affected in each patient.

Background: Diagnostic evaluation of eosinophilic esophagitis (EoE) remains difficult, particularly the assessment of the patient's allergic status. Objective: This study sought to establish an automated medical algorithm to assist in the evaluation of EoE. Methods: Machine learning techniques were used to establish a diagnostic probability score for EoE, p(EoE), based on esophageal mRNA transcript patterns from biopsies of patients with EoE, gastroesophageal reflux disease and controls. Dimensionality reduction in the training set established weighted factors, which were confirmed by immunohistochemistry. Following weighted factor analysis, p(EoE) was determined by random forest classification. Accuracy was tested in an external test set, and predictive power was assessed with equivocal patients. Esophageal IgE production was quantified with epsilon germ line (IGHE) transcripts and correlated with serum IgE and the T(H)2-type mRNA profile to establish an IGHE score for tissue allergy. Results: In the primary analysis, a 3-class statistical model generated a p(EoE) score based on common characteristics of the inflammatory EoE profile. A p(EoE) >= 25 successfully identified EoE with high accuracy (sensitivity: 90.9%, specificity: 93.2%, area under the curve: 0.985) and improved diagnosis of equivocal cases by 84.6%. The p(EoE) changed in response to therapy. A secondary analysis loop in EoE patients defined an IGHE score of >= 37.5 for a patient subpopulation with increased esophageal allergic inflammation. Conclusions: The development of intelligent data analysis from a machine learning perspective provides exciting opportunities to improve diagnostic precision and improve patient care in EoE. The p(EoE) and the IGHE score are steps toward the development of decision trees to define EoE subpopulations and, consequently, will facilitate individualized therapy.

Eosinophilic esophagogastroenteritis refers to a spectrum of clinical presentations associated with eosinophilic infiltration at one or more gastrointestinal sites. Symptoms vary depending on location and degree of inflammation, and diagnosis most often entails mucosal biopsy. Treatment varies from dietary intervention to pharmacologic therapy with immunosuppressive agents. The incidence of these disorders appears to be on the rise and future treatment options will require controlled trials.