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The recognition of constipation as a possible non‐Immunoglobulin E (IgE)‐mediated allergic condition is challenging because functional constipation (unrelated to food allergies) is a common health problem with a reported worldwide prevalence rate of up to 32.2% in children. However, many studies in children report challenge proven cow's milk allergy and constipation as a primary symptom and have found that between 28% and 78% of children improve on a cow's milk elimination diet. Due to the paucity of data and a focus on IgE‐mediated allergy, not all food allergy guidelines list constipation as a symptom of food allergy. Yet, it is included in all cow's milk allergy guidelines available in English language. The Exploring Non‐IgE‐Mediated Allergy (ENIGMA) Task Force (TF) of the European Academy for Allergy and Clinical Immunology (EAACI) considers in this paper constipation in the context of failure of standard treatment and discuss the role of food allergens as culprit in constipation in children. This position paper used the Delphi approach in reaching consensus on both diagnosis and management, as currently published data are insufficient to support a systematic review. [ABSTRACT FROM AUTHOR]

The term "feeding difficulties" refers to a spectrum of phenotypes characterized by suboptimal intake of food and/or lack of age‐appropriate eating habits. While it is evident that feeding difficulties are prevalent within healthy children, no consensus has been reached for those with food allergies. The aim of this study was to systematically review all the available literature reporting the prevalence of feeding difficulties within food allergic children. We searched eight international electronic databases for all published studies until June 2022. International experts in the field were also contacted for unpublished and ongoing studies. All publications were screened against pre‐defined eligibility criteria and critically appraised by established instruments. The substantial heterogeneity of included studies precluded meta‐analyses, so narrative synthesis of quantitative data was performed. A total of 2059 abstracts were assessed, out of which 21 underwent full‐text screening and 10 studies met the study criteria. In these, 12 different terms to define feeding difficulties and 11 diagnostic tools were used. Five papers included data of feeding difficulty prevalence in children with food allergies, ranging from 13.6% to 40%. Higher prevalence was associated with multiple food allergies. The current literature suggests that feeding difficulties are prevalent within food allergic children, particularly those with multiple food allergies. However, the heterogeneity of terminologies and diagnostic tools makes drawing conclusions challenging. Consensus guidelines for the diagnosis and management of feeding difficulties within food allergic children and further research on the development and perpetuation of feeding difficulties are needed to appropriately manage such patients. [ABSTRACT FROM AUTHOR]

Gastro‐oesophageal reflux (GOR) and food allergy (FA) are common conditions, especially during the first 12 months of life. When GOR leads to troublesome symptoms, that affect the daily functioning of the infant and family, it is referred to as GOR disease (GORD). The role of food allergens as a cause of GORD remains controversial. This European Academy of Allergy and Clinical Immunology (EAACI) position paper aims to review the evidence for FA‐associated GORD in young children and translate this into clinical practice that guides healthcare professionals through the diagnosis of suspected FA‐associated GORD and medical and dietary management. The task force (TF) on non‐IgE mediated allergy consists of EAACI experts in paediatric gastroenterology, allergy, dietetics and psychology from Europe, United Kingdom, United States, Turkey and Brazil. Six clinical questions were formulated, amended and approved by the TF to guide this publication. A systematic literature search using PubMed, Cochrane and EMBASE databases (until June 2021) using predefined inclusion criteria based on the 6 questions was used. The TF also gained access to the database from the European Society of Paediatric Gastroenterology and Hepatology working group, who published guidelines on GORD and ensured that all publications used within that position paper were included. For each of the 6 questions, practice points were formulated, followed by a modified Delphi method consisting of anonymous web‐based voting that was repeated with modified practice points where required, until at least 80% consensus for each practice point was achieved. This TF position paper shares the process, the discussion and consensus on all practice points on FA‐associated GORD. [ABSTRACT FROM AUTHOR]

Aim: To summarise the results from four clinical trials assessing the efficacy and safety of a thickening complex in the management of regurgitation in infants.Methods: Infants (n = 392) younger than 5 months presenting with at least five regurgitations per day were recruited in four open-label, interventional, single-group, multi-centric clinical trials sharing an identical design. The efficacy of four different formulae thickened with different thickening complexes of pectin, starch and locust bean gum, was evaluated on regurgitation at days 3, 14 and 90, and stools and growth at days 14 and 90.Results: The daily number of regurgitation episodes was significantly reduced at days 3 and 14 vs baseline in all studies (P < .001), with the largest decrease with the formula having the highest pectin content (study 1; P < .001). In all studies, growth was within normal range. A trend towards stool normalisation for consistency was observed in three studies at day 90 vs baseline and was significant in study 1 (P < .001). Stool frequency was unchanged by the interventions.Conclusion: The four tested thickened formulae reduced regurgitation and were proven to be safe. The formula with the largest amount of pectin and lowest starch content showed the best efficacy. [ABSTRACT FROM AUTHOR]

It is well‐established that food proteins, such as egg, soya, cow's milk and wheat, are detectable in breastmilk for many hours or days after ingestion. Exposure to these proteins is important to the process of developing tolerance but can also sometimes elicit IgE‐mediated and non–IgE‐mediated allergic symptoms in breastfed infants. Non–IgE‐mediated allergy, outside of food protein‐induced allergic proctocolitis and eosinophilic oesophagitis, is not well understood, leading to variations in the diagnosis and management thereof. A primary objective of the European Academy for Allergy and Clinical Immunology is to support breastfeeding in all infants, including those with food allergies. A Task Force was established, to explore the clinical spectrum of non–IgE‐mediated allergies, and part of its objectives was to establish diagnosis and management of non–IgE‐mediated allergies in breastfed infants. Eight questions were formulated using the Patient, Intervention, Comparison, Outcome (PICO) system and Scottish Intercollegiate Guideline Network (SIGN) criteria for data inclusion, and consensus was achieved on practice points through the Delphi method. This publication aims to provide a comprehensive overview on this topic with practice points for healthcare professionals. [ABSTRACT FROM AUTHOR]

We linearize the inverse branches of the iterates of holomorphic endomorphisms of Pk and thus overcome the lack of Koebe Distortion theorem in this setting when k⩾2. We review several applications of this result in holomorphic dynamics. [ABSTRACT FROM AUTHOR]

Aim This French study assessed a quick, noninvasive, immuno-chromatographic, Helicobacter pylori ( H. pylori) stool antigen test for detecting infections in children. Methods We enrolled 158 children, with a median age of 8.5 years (range eight months to 17 years), with digestive symptoms suggesting upper gastrointestinal tract disease. Upper digestive endoscopy was performed with gastric biopsy specimens for histology, a rapid urease test, culture test and quantitative real-time polymerase chain reaction. The H. pylori stool antigen test was performed twice for each child and the results were compared to the reference method. Results The reference methods showed that 23 (14.6%) of the 158 children tested were H. pylori positive. The H. pylori stool antigen test showed 91.3% sensitivity, with a 95% confidence interval (95% CI) of 86.9-95.6 and 97% specificity (95% CI 94.3-99.6), 30.84 positive likelihood ratio and 0.09 negative likelihood ratio. The test accuracy was 96.2% (95% CI 93.2-99.1). The two blinded independent observers produced identical H. pylori stool antigen test results and the Kappa coefficient for the H. pylori stool antigen test was one. Conclusion The H. pylori stool antigen test was found to be a consistent, reliable, quick and specific test for detecting the H. pylori infection in children. [ABSTRACT FROM AUTHOR]

A large number of studies investigating various biomarkers for allergy have been published over the past decades. The aim of this review was to evaluate these biomarkers on their diagnostic and/or predictive value. To this date, no single or specific biomarker for allergy has been identified. As allergy is not one disease, but a collection of a number of allergic conditions, it is more plausible a combination of clinical history, clinical readouts, and diagnostic markers will be needed. [ABSTRACT FROM AUTHOR]

Clinicians with expertise in managing children with gastrointestinal problems and/or atopic diseases attended a workshop in Brussels in September 2014 to review the literature and determine whether a clinical score derived from symptoms associated with the ingestion of cow's milk proteins could help primary healthcare providers. The Cow's Milk-related Symptom Score (CoMi SS), which considers general manifestations, dermatological, gastrointestinal and respiratory symptoms, was developed as an awareness tool for cow's milk-related symptoms. It can also be used to evaluate and quantify the evolution of symptoms during therapeutic interventions, but does not diagnose cow's milk protein allergy and does not replace a food challenge. Its usefulness needs to be evaluated by a prospective randomised study. Conclusion The CoMi SS provides primary healthcare clinicians with a simple, fast and easy-to-use awareness tool for cow's milk-related symptoms. [ABSTRACT FROM AUTHOR]

Aim Eosinophilic oesophagitis ( EO) is an emerging worldwide disease, closely associated with male gender and allergic disorders. This study investigated the distribution of allergy markers in a cohort of children with EO. Methods We analysed allergy markers in 91 children (62 males and 29 females) with EO and a control group of 45 age-matched children who had non- EO gastrointestinal allergic symptoms. The markers analysed were serum cow's milk-specific and hen's egg-specific IgE, thymic stromal lymphopoietin ( TSLP), thymus-regulated and activation-regulated chemokine ( TARC/ CCL17) and immunoglobulin free light chain (Ig- fLC). Results In the EO group, cow's milk-specific IgE levels were detectable in 41.9% of males and 62.1% of females and hen's egg-specific levels in 25% of males and 26.9% of females. There was no gender difference in increased TSLP or TARC levels. Kappa Ig- fLC were increased in 5.6% of males and 20.8% of females (p = 0.058) and lambda Ig- fLC in 1.9% of males and 33.3% of females (p = 0.000). No gender differences were found in the control group. Conclusion Our findings suggest that serum TSLP might be a potential marker of EO and TARC of non- EO gastrointestinal food allergies. In EO, serum Ig- fLC appeared higher in females, adding another gender difference to the biology of EO. [ABSTRACT FROM AUTHOR]

In a child that is allergic to milk, the natural next step, following the elimination diet, is the reintroduction of cow's milk. Several questions may arise. When feasible, this reintroduction has many benefits for the child and his family. However, the disease needs to be well defined by physicians and explained to parents. They need to understand that there are different types of allergy to cow's milk, specifically Ig E- and non- Ig E-mediated, and each of these may exhibit both a variable duration and frequently an incomplete recovery. Deciding where to first reintroduce cow's milk to a child who has previously followed a milk-free diet, whether it be at home or in a hospital, also frequently presents an issue. Following this first reintroduction, the progressive increase of milk into the diet needs to be managed properly, as not all children will go back to a normal dairy products intake. Recent studies show that most children with milk allergy tolerate products containing baked milk and that their consumption might speed up recovery. Hence, the purpose of the milk challenge in a child on a milk-free diet is becoming, even in a child still reactive to milk, the first step of gradual and individually adapted reintroduction of milk or dairy products. When reintroduction of cow's milk does not work, immunotherapy becomes an option, and this is carried out in specialized centers. [ABSTRACT FROM AUTHOR]

Background. The aim of this study was to compare the efficacy of epicutaneous immunotherapy (EPIT) to sublingual immunotherapy (SLIT) in a model of mice sensitized to Phleum pratense pollen. Methods. BALB/c mice were sensitized by subcutaneous route to pollen protein extract mixed treated for 8 weeks, using sham, EPIT, or SLIT. Measurements involved the serological response and cytokine profile from reactivated splenocytes, plethysmography after aerosol challenge to pollen, cell, and cytokine contents in the bronchoalveolar lavages (BALs). Results. After immunotherapy, sIgE was significantly decreased in the treated groups compared to sham (P < 0.001), whereas sIgG2a increased with EPIT and SLIT (P < 0.001 and P < 0.005 versus sham). Reactivated splenocytes secreted higher levels of Th2 cytokines with sham (P < 0.01). Penh values were higher in sham than EPIT and SLIT. Eosinophil recruitment in BAL was significantly reduced only by EPIT (P < 0.01). Conclusion. In this model of mice sensitized to pollen, EPIT was at least as efficient as SLIT. [ABSTRACT FROM AUTHOR]

Background: The aim of our study was to assess the different mutations involved in clarithromycin-resistant Helicobacter pylori strains isolated from French children and their temporal trends. Methods: The point mutations of H. pylori were detected by PCR followed by RFLP technique in 50 clarithromycin-resistant strains collected between 1993 and 2004 in France. Results: Clarithromycin resistance was observed in 23% (50/217) of H. pylori isolates. Two mutations A2143G and A2142G in the 23S rRNA genes of H. pylori were detected. The former was found in 45/50 (90%) of isolates. The rate of resistance increased with time from 18.6% in the period 1993–1996 to 41.6% in 2001–2004. No significant difference was observed in the distribution of mutations during the same periods. No correlation was found between any mutation and age, sex, and ethnic origin of children. Furthermore, no significant differences in minimal inhibitory concentrations level were observed according to the different point mutations. In all cases, only one point mutation was present, except in two cases where two different mutations were found in two different clones from the same biopsy. Conclusion: The mutation A2143G is predominant in clarithromycin-resistant H. pylori strains isolated from children in France. We report for the first time the presence of two clarithromycin-resistant clones harboring two different mutations of the 23S rRNA genes present in the same biopsy specimen and genotypically identical as demonstrated by RAPD fingerprinting. [ABSTRACT FROM AUTHOR]

Objectives: To assess the safety of a polyethylene glycol (PEG) 4000 laxative without additional salts in pediatric patients.Study Design: This was a 3-month multicenter, randomized, double-blind, double-dummy, lactulose-controlled, parallel study enrolling 96 ambulatory constipated children aged 6 months to 3 years, treated daily with 4-8 g PEG or 3.33 g-6.66 g lactulose. Total protein, albumin, iron, electrolytes, and vitamins B9 (folates), A and D (25OHD3) were measured in blood before and after treatment (day 84) in a central laboratory.Results: The percentage of children with at least one value out of normal range at day 84 with respect to baseline status (with or without at least one value out of normal range), i.e. the primary endpoint, was 87% and 90% in the PEG and lactulose groups, respectively, without any difference between groups. The whole blood parameters showed no qualitative or quantitative treatment-related changes. Vitamin A values were above normal range in 56% and 41% of children at baseline versus 33% and 36% at day 84 in the PEG and lactulose groups, respectively. Iron values were similarly under normal range in 47% and 51% at baseline versus 42% and 51% at day 84. Clinical tolerance was similar for both treatments except for vomiting and flatulence, which were significantly higher with lactulose. Significantly higher improvements were evidenced with PEG regarding stool consistency, appetite, fecaloma and use of additional laxatives.Conclusion: This 3-month study in 96 constipated children aged 6 months to 3 years confirms the long-term tolerance of PEG 4000 in pediatrics and indicates a PEG efficacy similar to or greater than that of lactulose. [ABSTRACT FROM AUTHOR]

Since the introduction of flexible fiberoptic endoscopy in the early 1970s, esophagogastro-duodenoscopy and colonoscopy have become established procedures for the diagnosis, evaluation and treatment of gastrointestinal tract disease in the pediatric population. The development of safe fiberoptic endoscopes specially designed for neonates has allowed visualization of lesions occurring in the first days of life. Despite an increased understanding of neonatal digestive disorders deriving from this new diagnostic modality, there is little consensus on the appropriate use of endoscopic procedures in routine care of neonates. It is the feeling of the authors that widening the indications of endoscopy in the neonatal period might lead to diagnosis of discrete clinical abnormalities, which might improve the care of neonates. The techniques for performing neonatal endoscopies, the appropriate indications, the common normal and pathologic findings and the complications of these procedures are reviewed. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the impact of development on the pharmacokinetics and pharmacodynamics of nizatidine.Methods: Children (age range, 5 days-18 years) and adults (age range, 18-50 years) were enrolled in four open-label trials. Nizatidine formulation and dose were determined by age: infants received 2 or 4 mg/kg i.v., children 2.5 or 5 mg/kg in one of three oral liquid formulations, and adolescents and adults received a fixed 150-mg capsule. Nizatidine and N-desmethylnizatidine concentrations were measured in serial post-dose plasma samples by a high-performance liquid chromatographic assay with mass spectrometric detection. Intragastric pH was recorded during a 24-hour post-dose interval.Results: Data on 93 subjects were combined with previous values from 36 individuals to cover an age group not adequately captured and to control for formulation effects. Dose-normalized exposure estimates revealed no apparent age dependence; however, maximum plasma concentration (298.5 +/- 100.7 v 552.8 +/- 152.4 ng/mL per mg/kg dose) and AUC0-infinity (954.4 +/- 379.8 v 1,573.0 +/- 347.4 ng*hour/mL per mg/kg dose) were reduced in extemporaneous formulations in apple juice. The apparent modest age dependence observed for total body clearance (Cl/F) (r = 0.365) and Vss/F (r = 0.221) reflected a formulation-dependent decrease in bioavailability rather than a true age effect. The age-associated changes in lambda z observed for nizatidine and its metabolite were predictable and consistent with developmental acquisition of renal function. Mean and median pH, as well as fraction of time that the dosing interval remained above target pH values, were significantly greater with administration of the drug than without.Conclusions: The biodisposition of nizatidine in children and adults is similar; however, response after a comparable weight-based dose is equal and potentially greater in children. [ABSTRACT FROM AUTHOR]

The article discusses the use of ketotifen in the treatment of atopic dermatitis and other food allergy diseases. The pharmacological properties of ketotifen make it suitable for the treatment of asthma, allergic rhinitis, conjunctivitis, acute and chronic urticaria, food allergy and food intolerance. In the study presented, ketotifen was well tolerated. No side effects were registered, even drowsiness which affects 10% to 15% of adult patients in the first week of treatment, subsequently passes. Sedation is observed less frequently in children.

Porcine vasoactive intestinal peptide stimulated adenosine 3′:5′-monophosphate (cyclic AMP) production in rat intestinal epithelial cells. The stimulation was dependent on time and temperature and was potentiated by the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine. Under optimal conditions (at 15 °C, with 0.2 mM 3-isobutyl-l-methylxanthine, at a cell concentration up to 18 μg DNA/ml), the cyclic AMP production produced by vasoactive intestinal peptide was constant for 10 min and stopped after 15 min incubation, at either low (1 nM) or high (30 nM) concentration of the peptide. This plateau effect was demonstrated not to be due to an inactivation of vasoactive intestinal peptide in the medium nor to an alteration of receptors for the peptide. Cyclic AMP production was sensitive to a concentration as low as 0.1 nM vasoactive intestinal peptide. Maximal stimulation of cyclic AMP levels by vasoactive intestinal peptide was observed with 30 nM vasoactive intestinal peptide and represented an 11-fold increase above basal. The dose-response curve was monophasic with a Km of 2.3 × 10-9 M. No cooperative effects were detected by Hill analysis. The positive non-linear relationship observed between stimulation of cyclic AMP production and occupancy of binding sites was not time-dependent as indicated by experiments performed after 15, 45 and 120 min incubation. Maximal and half-maximal responses were obtained at about 70% and 7% occupation of binding sites, respectively. Chicken vasoactive intestinal peptide and porcine secretin were agonists of porcine vasoactive intestinal peptide with a 6-times higher and a 120-times lower potency, respectively. Among secretin analogs that were found to have low affinity for vasoactive intestinal peptide binding sites, [4-alanine, 5-valine]secretin, that resembles vasoactive intestinal peptide at the first seven amino acids at the N-terminal end, was a partial agonist of vasoactive intestinal peptide and others failed to stimulate cyclic AMP production. Glucagon (10μM), gastric inhibitory peptide (0.1μM), substance P, neurotensin, octapeptide of cholecystokinin, bovine pancreatic polypeptide, human gastrin I with leucine at residue 15, Leu-enkephalin and somatostatin (1 μM) did not alter cyclic AMP levels. Non-peptide mediators such as dopamine, serotonin, acetylcholine and histamine, tested at 10 μM, were also ineffective. Prostaglandins E2, El and isoproterenol, tested at 10 μM, induced an increase of cyclic AMP levels above basal but were 9.5, 13.7 and 17.5 times less efficient than vasoactive intestinal peptide, respectively. Thus vasoactive intestinal peptide is a unique stimulus of cyclic AMP production in rat intestinal epithelial cells. [ABSTRACT FROM AUTHOR]

The article cites a study that investigated the fecal calprotectin levels of preterm infants beginning from birth to hospital discharge. The researchers conducted their nine-month study at the neonatal department of Saint Vincent de Paul Hospital in Paris, France where fecal samples from 34 newborn infants were collected. The subjects of the study included 22 boys and 12 girls with a median gestational age of 30 weeks and results of the study indicated that no correlation was established between fecal calprotectin level and either gestational age, birth weight, sex, mode feeding, or postnatal age.

Background: Food Protein-Induced Enterocolitis Syndrome (FPIES) is considered to be a non-IgE mediated food allergy. However, its pathogenesis remains poorly understood and biomarkers are lacking. We aimed to perform in-depth characterization of humoral and cellular immune responses in children with cow's milk (CM)-FPIES and investigated whether there is a FPIES metabolomic signature. Methods: Children with CM-FPIES and control subjects with an IgE-mediated CM allergy (IgE-CMA), both avoiding CM, were recruited on the day of an oral food challenge. Blood samples were collected before the challenge. Total and specific levels of IgE, IgG1-4, IgA, IgM and IgD to various whey and casein allergens and to their gastroduodenal digestion products were measured in plasma, using plasma from CM-tolerant peanut allergic patients (IgE-PA, not avoiding CM) as additional controls. Cytokine secretion and cellular proliferation were analyzed after stimulation of PBMC with different CM allergens. Metabolomic profiles were obtained for plasma samples using liquid chromatography coupled to high-resolution mass spectrometry. Results: Nine children with CM-FPIES and 12 control subjects (6 IgE-CMA and 6 IgE-PA) were included. In children with CM-FPIES, total Ig concentrations were lower than in control subjects, specific Ig against CM components were weak to undetectable, and no specific IgE against CM digestion products were detected. Moreover, in CM-FPIES patients, we did not find any Th cell proliferation or associated cytokine secretion after allergen reactivation, whereas such responses were clearly found in children with IgE-CMA. Plasma metabolic profiles were different between CM allergic patients, with significantly lower concentrations of various fatty acids and higher concentrations of primary metabolites such as amino acids in CM-FPIES compared to IgE-CMA patients. Conclusions: In CM-FPIES, both humoral and cellular specific immune responses are weak or absent, and this is not related to CM avoidance. A metabolomic signature was identified in patients with CM-FPIES that may be useful for the diagnosis and management of this disease. [ABSTRACT FROM AUTHOR]