An algorithm for the classification of mRNA patterns in eosinophilic esophagitis: Integration of machine learning.

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 Th2-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.

Pediatric Colonic Xanthomas, a Previously Unreported Colonoscopic Finding.

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.

Extensively Hydrolyzed Formula Improves Allergic Symptoms in the Short Term in Infants with Suspected Cow's Milk Protein Allergy.

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.

Short-term symptom improvement in infants with suspected cow's milk protein allergy using amino acid formula: a prospective cohort analysis.

Background: Cow'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). Objective: This study aimed to determine the short-term effects of managing suspected CMPA in infants aged 6 months and under using a commercial AAF. Methods: Healthcare 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). Results: Gastrointestinal (94%), skin (87%), respiratory (86%), and uncategorized symptoms (89%) improved from AAF initiation, and these findings were consistent across different follow-up visit durations. Conclusion: This 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.

Clinician Experience with Using Hypoallergenic Formulas to Treat Infants with Suspected Cow's Milk Protein Allergy: A Secondary Analysis of a Prospective Survey Cohort.

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.

New prebiotic blend of polydextrose and galacto-oligosaccharides has a bifidogenic effect in young infants.

OBJECTIVE: The aim of the study was to evaluate the effect of infant formula with polydextrose (PDX) and galacto-oligosaccharides (GOS) on fecal microbiota and secretory IgA (sIgA). MATERIALS AND METHODS: In the present double-blind, randomized study, term infants received control (Enfamil Lipil) or the same formula with PDX/GOS (4 g/L, 1:1 ratio; PDX/GOS) for 60 days; a reference breast-fed group was included. Formula intake, tolerance, and stool characteristics were collected via electronic diary and analyzed by repeated measures analysis of variance. Anthropometric measurements and stool samples were obtained at baseline and after 30 and 60 days of feeding. Fecal sIgA was measured by enzyme-linked immunosorbent assay and fecal bacteria by fluorescent in situ hybridization and quantitative real-time polymerase chain reaction (qPCR); both were analyzed by Wilcoxon rank sum test. RESULTS: Two hundred thirty infants completed the study. Infants consuming PDX/GOS had softer stools than control at all times (P < 0.001). Using qPCR, counts in PDX/GOS were closer to the breast-fed group, tended to be higher than control for total bifidobacteria (P = 0.069) and Bifidobacterium longum (P = 0.057) at 30 days, and were significantly higher for total bifidobacteria and B longum at 60 days and B infantis at 30 days (P = 0.002). No significant differences were detected between PDX/GOS and control in changes from baseline to 30 or 60 days for sIgA or total bifidobacteria by fluorescent in situ hybridization or qPCR; however, significantly higher changes from baseline were detected between PDX/GOS and control for B infantis at 30 days and B longum at 60 days (P ≤ 0.035). CONCLUSIONS: Infant formula with PDX/GOS produces soft stools and a bifidogenic effect closer to breast milk than formula without PDX/GOS.

Stool pattern changes in toddlers consuming a follow-on formula supplemented with polydextrose and galactooligosaccharides.

Healthy 9- to 48-month-old children (n = 133) were randomized to receive a cow's-milk-based follow-on formula (control) or the same formula with polydextrose and galactooligosaccharides (PDX/GOS) for 108 days. Pediatricians assessed diarrheal disease, stool pattern, acute respiratory infection, systemic antibiotic use, and growth. The 2 groups had similar weight-for-length/height z score and similar odds of having diarrheal disease, acute respiratory infection, and systemic antibiotic use; however, PDX/GOS had greater odds of increased defecation than control (P ≤ 0.01). Addition of PDX and GOS to a follow-on formula was well tolerated and induced a pattern of more frequent and softer stools in toddlers.

Bifidobacterium longum Subspecies infantis (B. infantis) in Pediatric Nutrition: Current State of Knowledge.

Abstract: 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.

Probiotics in the United States.

Probiotics are live microbial products that have a defined health benefit. Scientific research has established that there are validated indications for the use of some probiotics available in the United States; however, in many cases, they are often used for conditions for which no benefit has been established. This article will review the uses of probiotics in the United States, as well as the current state of regulatory issues surrounding probiotics. Although the use and scientific understanding of probiotics are rapidly increasing, it is evident that there is a need to clarify the regulatory issues, which, at present, are unclear and subject to misinterpretation. In addition to efficacy, safety issues must be considered in determining when and how probiotics are to be used.

Probiotics in allergy management.

The gut contains a diverse bacterial flora that is acquired at birth and has a number of physiological functions. Administration of prebiotics or probiotics may favourably alter this gut microflora. Prebiotics are poorly digested oligosaccharides that promote the growth of desirable bacteria and may have other beneficial gastrointestinal and systemic effects. Probiotics are "helpful" human bacteria that provide a variety of health benefits when administered exogenously. Probiotics produce beneficial effects in the prevention and treatment of traveller's diarrhoea, viral diarrhoea, and diarrhoea in day care centres. Moreover, probiotics have been shown to reduce relapses associated with Clostridium difficile, and Lactobacilli are effective in the prevention of antibiotic-associated diarrhoea. Probiotics may also be efficacious in the treatment of gastroenteritis. Clinical studies of probiotics in inflammatory bowel disease have proved disappointing, but beneficial effects in adults with irritable bowel syndrome have been reported with Bifidobacterium infantis 35624. Lactobacilli GG reduces the incidence of gastrointestinal symptoms and gut permeability in patients with atopic dermatitis, and administration of probiotics reduces the frequency and severity of atopic eczema when administered to pregnant women and then to newborn infants. In conclusion, probiotics are effective in the treatment and/or prevention of a number of conditions, including diarrhoea, irritable bowel syndrome and atopic dermatitis, and the product used should be selected based on the particular indication.

Hypoallergenicity and effects on growth and tolerance of a new amino acid-based formula with DHA and ARA.

Nutramigen AA is an amino acid-based formula for infants with multiple food protein intolerance or severe cow's milk allergy. Similar growth, tolerance, and safety profiles were found in a study comparing Nutramigen AA with a control formula (Nutramigen LIPIL) in healthy, term, formula-fed infants in a randomised study. Moreover, no allergic reactions were observed in a double-blind, placebo-controlled food challenge in infants or children randomised to receive Nutramigen AA or placebo (Neocate). In conclusion, Nutramigen AA sustains growth and is well tolerated in babies with cow's milk allergy.

A Distinct Esophageal mRNA Pattern Identifies Eosinophilic Esophagitis Patients With Food Impactions.

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.

Term infants fed formula supplemented with selected blends of prebiotics grow normally and have soft stools similar to those reported for breast-fed infants.

OBJECTIVES: The present study was designed to evaluate the effect of 2 different combinations of prebiotic ingredients, polydextrose (PDX), galactooligosaccharides (GOS), and lactulose (LOS), at 2 different intake levels on the overall growth and tolerance in healthy term infants up to 120 days of age. PATIENTS AND METHODS: Healthy, formula-fed, term infants (n = 226) were randomly assigned to 1 of 3 study formula groups: control group (n = 76), PG4 group (control formula supplemented with 4 g/L of a prebiotic blend, n = 74), or PGL8 group (control formula supplemented with 8 g/L of a prebiotic blend, n = 76). Anthropometric measurements were taken at 14, 30, 60, 90, and 120 days of age, and 24-hour dietary recall and 24-hour tolerance recall were recorded at 30, 60, 90, and 120 days of age. Adverse events were recorded throughout the study. RESULTS: There were no statistically significant differences among the 3 formula groups for weight growth rate or length growth rate at any time point. Significant differences in stool consistency were detected among the 3 formula groups at 30, 60, and 90 days of age (P < 0.001, P = 0.025, P = 0.004, respectively), with the supplemented formula groups having looser stools than the control group. The PGL8 group had significantly higher stool frequency compared with the control and PG4 groups at 30 days of age (P = 0.021 and P = 0.017, respectively), but all of the groups were similar at 60, 90, and 120 days of age. A statistical difference was detected among the formula groups in 3 categories of adverse events: diarrhea (control vs PG4, 4% vs 18%, P = 0.008), eczema (PG4 vs control, 18% vs 7%, P = 0.046; PG4 vs PGL8, 18% vs 4%, P = 0.008), and irritability (control vs PGL8, 4% vs 16%, P = 0.027). CONCLUSIONS: Infants fed formula supplemented with a prebiotic mixture achieved normal growth and stool characteristics more similar to those of breast-fed infants in comparison with infants fed an unsupplemented formula. A pediatrician needs to consider the risk of possible intolerance against the benefits of prebiotics.

A randomized, double-blind trial of Lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn's disease.

Probiotics are widely used by patients with Crohn's disease (CD) in an attempt to improve their health, but few controlled studies have been done to evaluate the efficacy of these therapies. We conducted a randomized, placebo-controlled trial of the probiotic Lactobacillus rhamnosus strain GG (LGG) to see if the addition of LGG to standard therapy prolonged remission in children with CD. Concomitant medications allowed in the study included aminosalicylates, 6-mercaptopurine, azathioprine, and low-dose alternate day corticosteroids. Seventy-five children (age range, 5-21 yr) with CD in remission were randomized to either LGG (n=39) or placebo (n=36) and followed for up to 2 years. The median time to relapse was 9.8 months in the LGG group and 11.0 months in the placebo group (P=0.24); 31% (12/39) of patients in the LGG group developed a relapse compared with 6/36 (17%) of the placebo group (P=0.18). The LGG was well tolerated, with a side effect profile comparable with placebo. This study suggests that LGG does not prolong time to relapse in children with CD when given as an adjunct to standard therapy.

Enteral and parenteral nutrition in the care of patients with short-bowel syndrome.

Short-bowel syndrome is a challenging entity for the gastroenterologist, requiring integration of medical, nutritional, surgical and psychological therapies. Treatment must be based on the patient's age, remaining gastrointestinal anatomy, baseline nutritional status and underlying general health as well as the numerous complications which may arise. This chapter reviews physiological alterations that occur with short-bowel syndrome and how therapies can be tailored to most adequately meet the needs of these patients. Emphasis on early stages of therapy to enhance intestinal adaptation is focused on as management during this time has a significant impact on the long-term outcome of these patients.

Lactobacillus GG in inducing and maintaining remission of Crohn's disease.

BACKGROUND: Experimental studies have shown that luminal antigens are involved in chronic intestinal inflammatory disorders such as Crohn's disease and ulcerative colitis. Alteration of the intestinal microflora by antibiotic or probiotic therapy may induce and maintain remission. The aim of this randomized, placebo-controlled trial was to determine the effect of oral Lactobacillus GG (L. GG) to induce or maintain medically induced remission. METHODS: Eleven patients with moderate to active Crohn's disease were enrolled in this trial to receive either L. GG (2 x 10(9) CFU/day) or placebo for six months. All patients were started on a tapering steroid regime and received antibiotics for the week before the probiotic/placebo medication was initiated. The primary end point was sustained remission, defined as freedom from relapse at the 6 months follow-up visit. Relapse was defined as an increase in CDAI of >100 points. RESULTS: 5/11 patients finished the study, with 2 patients in each group in sustained remission. The median time to relapse was 16 +/- 4 weeks in the L. GG group and 12 +/- 4.3 weeks in the placebo group (p = 0.5). CONCLUSION: In this study we could not demonstrate a benefit of L. GG in inducing or maintaining medically induced remission in CD.

New and emerging therapies for short bowel syndrome in children.

This review provides an overview of traditional as well as emerging therapies useful in the management of pediatric short bowel syndrome. Pediatric short bowel syndrome is relatively uncommon; however, when it does occur, it presents a unique challenge to medical care providers. The use of parenteral and enteral nutrition to maximize growth and enhance intestinal adaptation so as to increase absorptive surface area has been the primary focus of therapy. In recent years, the advent of pharmacologic advances, including the use of antibacterial drugs, anti-motility drugs and hormonal therapies, has had a significant impact on this condition. At times, surgery may be indicated for dealing with complications, or providing alternative therapy such as transplantation. With ongoing research, it is likely that improved pharmacologic therapy will be available for enhanced intestinal adaptation, control of gut motility, treatment of small bowel bacterial overgrowth, and treatment of rejection following small intestinal transplantation.