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Background/objectives: To assess the nutritional status and incidence of feeding difficulties in Polish children up to 2 years of age with cow's milk allergy (CMA) on cow's milk proteins-free diet., Methods: A cross-sectional, multi-center study included children aged 6 months to 2 years with confirmed or suspected (without oral food challenge) diagnosis of CMA on the elimination diet for at least 1 month. The primary outcomes were an assessment of proportion of children with impaired nutritional status (with the weight for length and body mass index (BMI) z-score > 1 and <-1), and feeding difficulties according to the Montreal Children's Hospital Feeding Scale. Children with confirmed and suspected CMA were assessed separately., Results: A 144 children with confirmed CMA and 88 with suspected CMA were included (57 and 78% with multiple food allergies, respectively). Among children with confirmed CMA, one-third (35.5%) of participants had any nutritional status impairment regardless of definition. Among those, most of children had mild malnutrition (10.4 vs. 9%) and possible risk of overweight (11.1 vs. 9.7%; following respectively BMI for age and weight for length z-scores). Only 16.0% of children had feeding difficulties. Feeding difficulties was identified to be a risk factor for moderate malnutrition compared to children without feeding difficulties (odds ratio 10, 95% confidence interval: 4-27)., Conclusions: Mild malnutrition and possible risk of overweight are concern in children up to 2 years of age on cow's milk proteins-free diet. Feeding difficulties are less common, however, may affect the nutritional status., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

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., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background and Objective: As oral food challenge (OFC) cannot be performed routinely in the general outpatient, this study aimed to construct a nomogram to predict the odds of food allergy in infants with idiopathic feeding problems and malnutrition., Methods: From August 2018 to December 2021, 289 infants (median age, 6 months; P25-P75, 4-8) with idiopathic feeding problems and malnutrition were enrolled from seven hospitals in Shanghai, China. Food allergy was defined as a positive response to a skin prick test or OFC, with gastrointestinal, dermatologic, or respiratory symptom improvement after 4 weeks of avoidance of the suspected food. Demographic characteristics, Cow's Milk-related Symptom Scores (CoMiSS), and blood eosinophil amounts were evaluated for their associations with food allergy. Multivariable logistic regression analysis was used to identify variables to develop a nomogram model with the bootstrapped-concordance index as an assessment metric., Results: Totally 249 of 289 infants had food allergy (86.2%). After logistic regression analysis, the feeding pattern (odds ratio [OR] = 5.28, 95% confidence interval [CI]: 2.13-13.09), a family history of allergy (OR = 1.79, 95% CI: 0.71-4.51), CoMiSS (OR = 1.45, 95% CI: 1.19-1.77), and eosinophil percentage (OR = 1.33, 95% CI: 1.11-1.60) were used to develop the model, which had a good performance with an area under the curve of 0.868 (95% CI: 0.792-0.944) and a bootstrapped-concordance index of 0.868., Conclusion: Food allergy is common in infants with idiopathic feeding problems and malnutrition. The developed nomogram may help identify infants with food allergy for further diagnosis., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Food-protein-induced allergic proctocolitis (FPIAP) is an increasingly reported transient and benign form of colitis that occurs commonly in the first weeks of life in healthy breastfed or formula-fed infants. Distal colon mucosal inflammation is caused by a non-IgE immune reaction to food allergens, more commonly to cow's milk protein. Rectal bleeding possibly associated with mucus and loose stools is the clinical hallmark of FPIAP. To date, no specific biomarker is available, and investigations are reserved for severe cases. Disappearance of blood in the stool may occur within days or weeks from starting the maternal or infant elimination diet, and tolerance to the food allergen is typically acquired before one year of life in most patients. In some infants, no relapse of bleeding occurs when the presumed offending food is reassumed after a few weeks of the elimination diet. Many guidelines and expert consensus on cow's milk allergy have recently been published. However, the role of diet is still debated, and recommendations on the appropriateness and duration of allergen elimination in FPIAP are heterogeneous. This review summarizes and compares the different proposed nutritional management of infants suffering from FPIAP, highlighting the pros and cons according to the most recent literature data.

Objective: To preliminarily explore the association of pregnancy factors with cow's milk protein allergy in infants., Methods: This study was based on data from a subcohort of a study called genetic susceptibility to cow's milk allergy in Chinese children, including infants born in Peking University People's Hospital between March 1, 2020, and December 31, 2020. The infants were divided into a cow's milk protein allergy (CMPA) group and a control group according to whether they had developed cow's milk protein allergy at the age of 1 year. We retrospectively collected the clinical data of infants and their mothers before and during pregnancy, and analyzed the association of multiple factors during pregnancy with cow's milk protein allergy in infants., Results: A total of 278 infants were enrolled in this study, including 52 infants with CMPA and 226 infants without CMPA. Among them, there were 143 boys and 135 girls. The proportion of male infants in the CMPA group (69.2%) was higher than that in the control group (47.3%), and the difference was statistically significant ( P =0.004). There were no significant differences in the distribution of birth weight, gestational age at birth, low-birth-weight infants, premature, umbilical cord entangle neck, and neonatal asphyxia between the CMPA group and the control group ( P >0.05). The proportion of mothers complicated with autoimmune diseases, anemia or antibiotics exposure during pregnancy in the CMPA group was higher than that in the control group, and there were statistical differences between the two groups ( P < 0.05). There was no significant difference in the distribution of other pregnancy complications between the two groups ( P >0.05), such as eclampsia/preeclampsia, chronic hypertension/gestational hypertension, diabetes/gestational diabetes, thyroid diseases, and so on. There was no significant difference in the overall distribution of some blood routine indexes during pregnancy between the CMPA group and the control group ( P >0.05). Multivariate Logistic regression analysis showed that male infant, mothers complicated with autoimmune diseases or anemia, antibiotic exposure during pregnancy were independent risk factors for cow's milk protein allergy., Conclusion: Male infant, mothers complicated with autoimmune diseases or anemia, antibiotic exposure during pregnancy were independent risk factors for cow's milk protein allergy.

We have previously reported that the gut microbiota of healthy infants harbors allergy-protective bacteria taxa that are depleted in infants with cow's milk allergy (CMA). Few reports have investigated the role of the gut microbiota in promoting allergic responses. In this study we selected a CMA-associated microbiota with increased abundance of Gram-negative bacteria for analysis of its proinflammatory potential. LPS is the major component of the outer membrane of Gram-negative bacteria. Colonization of mice with a global or conditional mutation of the LPS receptor TLR4 with this CMA microbiota induced expression of serum amyloid A1 (Saa1) and other Th17-, B cell-, and Th2-associated genes in the ileal epithelium in a TLR4-dependent manner. In agreement with the gene expression data, mice colonized with the CMA microbiota have expanded populations of Th17 and regulatory T cells and elevated concentrations of fecal IgA. Importantly, we used both antibiotic-treated specific pathogen-free and germ-free rederived mice with a conditional mutation of TLR4 in the CD11c+ compartment to demonstrate that the induction of proinflammatory genes, fecal IgA, and Th17 cells is dependent on TLR4 signaling. Furthermore, metagenomic sequencing revealed that the CMA microbiota has an increased abundance of LPS biosynthesis genes. Taken together, our results show that a microbiota displaying a higher abundance of LPS genes is associated with TLR4-dependent proinflammatory gene expression and a mixed type 2/type 3 response in mice, which may be characteristic of a subset of infants with CMA., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Objectives: To evaluate outcomes of oral food challenge (OFC) test to assess tolerance in infants with non-IgE-mediated cow's milk allergy (CMA) with gastrointestinal manifestations and explore clinical data predictive of these outcomes., Methods: Single-center retrospective study including infants (age < 12 months) who were referred for CMA between 2000 and 2018 and underwent OFC on follow-up. A univariate logistic regression test was performed to evaluate variables associated with the outcomes of the follow-up OFC test., Results: Eighty-two patients were included, 50% were male. Eighteen patients had a positive OFC test (22%). Most patients had presented with hematochezia (77%). The median age of symptom onset was 30 days. Two-thirds of the patients were on appropriate infant formula (extensively hydrolyzed or amino acid-based formula), exclusively or in association with breastfeeding. The median time on an elimination diet before the OFC test was 8 months (Q1 6 - Q3 11 months). All cases with positive follow-up OFC tests (n = 18) had been exposed to cow's milk-based formula before the first clinical manifestation of CMA. Five out of eight cases with Food Protein-Induced Enterocolitis Syndrome (FPIES) had positive OFC tests. Exposure to cow's milk-based formula before diagnosis, a history of other food allergies, hematochezia and diarrhea were predictors of a positive OFC test., Conclusions: In infants with non-IgE-mediated CMPA with gastrointestinal manifestations, the use of cow's milk-based formula, a history of other food allergies, and hematochezia and diarrhea upon initial presentation were associated factors for the later achievement of tolerance., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Objectives: The Cow's Milk-related Symptom Score (CoMISS) is an awareness tool for evaluating cow's milk-related symptoms in otherwise healthy infants <1 year of age. This study assessed whether replacing the Bristol Stool Form Scale (BSFS) with the Brussels Infants and Toddlers Stool Scale (BITSS) in non-toilet-trained infants would modify the overall CoMiSS and change the clinical approach regarding potential cow's milk allergy., Methods: Non-toilet-trained infants aged <13 months were assessed by CoMiSS using the 7 images from the BSFS (CoMiSS-BSFS) compared to the 4 images of stools from BITSS (CoMiSS-BITSS). The Wilcoxon signed-rank test and Pearson correlation coefficient were calculated. A post hoc analysis using identical tests was performed in subsets of CoMiSS-BSFS scores ≥10, ≥12, ≤5, and ≥6., Results: Eight hundred forty-four pairwise scores were collected. Applying the Wilcoxon test over the complete dataset, the difference between CoMiSS-BSFS and CoMiSS-BITSS was statistically significant ( P < 0.001). However, there was no significant difference in the subsets with CoMiSS-BSFS ≥10, ≥12, and ≥6 ( P = 0.84, P = 0.48, and P = 0.81, respectively). The significant difference remained restricted to the group with CoMiSS-BSFS ≤5, considered at low risk for CM-related symptoms ( P < 0.001)., Conclusion: Replacing BSFS with BITSS does not change the cutoff for awareness of possible CM-related symptoms and will not impact the use of CoMiSS in clinical practice. Changes in CoMiSS remained limited to the subgroup with a low risk for CM-related symptoms., (Copyright © 2023 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Cow milk (CM) allergy is the most prevalent food allergy in young children in the United States and Great Britain. Current diagnostic tests are either unreliable (IgE test and skin prick test) or resource-intensive with risks (food challenges)., Objective: We sought to determine whether allergen-specific T cells in CM-allergic (CMA) patients have a distinct quality and/or quantity that could potentially be used as a diagnostic marker., Methods: Using PBMCs from 147 food-allergic pediatric subjects, we mapped T-cell responses to a set of reactive epitopes in CM that we compiled in a peptide pool. This pool induced cytokine responses in in vitro cultured cells distinguishing subjects with CMA from subjects without CMA. We further used the pool to isolate and characterize antigen-specific CD4 memory T cells using flow cytometry and single-cell RNA/TCR sequencing assays., Results: We detected significant changes in the transcriptional program and clonality of CM antigen-specific (CM+) T cells elicited by the pool in subjects with CMA versus subjects without CMA ex vivo. CM+ T cells from subjects with CMA had increased percentages of FOXP3 + cells over FOXP3 - cells. FOXP3 + cells are often equated with regulatory T cells that have suppressive activity, but CM+ FOXP3 + cells from subjects with CMA showed significant expression of interferon-responsive genes and dysregulated chemokine receptor expression compared with subjects without CMA, suggesting that these are not conventional regulatory T cells. The CM+ FOXP3 + cells were also more clonally expanded than the FOXP3 - population. We were further able to use surface markers (CD25, CD127, and CCR7) in combination with our peptide pool stimulation to quantify these CM+ FOXP3 + cells by a simple flow-cytometry assay. We show increased percentages of CM+ CD127 - CD25 + cells from subjects with CMA in an independent cohort, which could be used for diagnostic purposes. Looking specifically for T H 2 cells normally associated with allergic diseases, we found a small population of clonally expanded CM+ cells that were significantly increased in subjects with CMA and that had high expression of T H 2 cytokines and pathogenic T H 2/T follicular helper markers., Conclusions: Overall, these findings suggest that there are several differences in the phenotypes of CM+ T cells with CM allergy and that the increase in CM+ FOXP3 + cells is a potential diagnostic marker of an allergic state. Such markers have promising applications in monitoring natural disease outgrowth and/or the efficacy of immunotherapy that will need to be validated in future studies., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious diagnoses such as Hirschsprung's disease (HD), meconium ileus due to Cystic Fibrosis, etc. The diagnosis of HD particularly warrants invasive testing to confirm the diagnosis, such as anorectal manometry or rectal suction biopsy. What if there was another etiology of perinatal constipation, that is far lesser known? Cow's milk protein allergy (CMPA) is often diagnosed in infants within the first few weeks of life, however, there are studies that show that the CMPA allergen can be passed from mother to an infant in-utero, therefore allowing symptoms to show as early as day one of life. The presentation is more atypical, with perinatal constipation rather than with bloody stools, diarrhea, and vomiting. The diagnosis and management would be avoidance of cow's milk protein within the diet, with results and symptom improvement in patients immediately. Therefore, we discuss whether an alternative pathway to address perinatal constipation should be further discussed and implemented to potentially avoid invasive techniques in patients. This entails first ruling out CMPA with safe, noninvasive techniques with diet modification, and if unsuccessful, then moving forward with further diagnostic modalities., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

The "Atopy Patch Test" (APT) has been proposed as a diagnostic tool for food allergies (FA), especially in children with FA-related gastrointestinal symptoms. However, its diagnostic accuracy is debated, and its usefulness is controversial. The aim of this systematic review was to evaluate the APT diagnostic accuracy compared with the diagnostic gold standard, i.e., the oral food challenge (OFC), in children affected by non-IgE mediated gastrointestinal food allergies, including the evaluation in milk allergic subgroup. Both classical non-IgE mediated clinical pictures and food induced motility disorders (FPIMD) were considered. The search was conducted in PubMed and Scopus from January 2000 to June 2022 by two independent researchers. The patient, intervention, comparators, outcome, and study design approach (PICOS) format was used for developing key questions, to address the APT diagnostic accuracy compared with the oral food challenge (OFC). The quality of the studies was assessed by the QUADAS-2 system. The meta-analysis was performed to calculate the pooled sensitivity, specificity, DOR (diagnostic odds ratio), PLR (positive likelihood ratio), and NLR (negative likelihood ratio) with their 95% confidence intervals (CI). Out of the 457 citations initially identified via the search (196 on PubMed and 261 on Scopus), 37 advanced to full-text screening, and 16 studies were identified to be included in the systematic review. Reference lists from relevant retrievals were searched, and one additional article was added. Finally, 17 studies were included in the systematic review. The analysis showed that APT has a high specificity of 94% (95%CI: 0.88-0.97) in the group of patients affected by FPIMD. Data showed a high pooled specificity of 96% (95% CI: 0.89-0.98) and the highest accuracy of APT in patients affected by cow's milk allergy (AUC = 0.93).      Conclusion: APT is effective in identifying causative food in children with food-induced motility disorders.  What is Known: • Atopy patch test could be a useful diagnostic test for diagnosing food allergy, especially in children with food allergy-related gastrointestinal symptoms. What is New: • Atopy patch test may be a useful tool in diagnosing non IgE food allergy, especially in children with food-induced gastrointestinal motility disorders and cow's milk allergy., (© 2023. The Author(s).)

The development of early-onset cow's milk protein allergy and atopic dermatitis during the first months of life is multifactorial, including both genetic and nutritional aspects. This study aims to assess the impact of different feeding patterns on the incidence of cow's milk protein allergy, atopic dermatitis, and growth among infants with a family history of allergy. A total of 551 high-risk infants were randomly recruited from 3 European countries in three feeding regimens: exclusive breastfeeding, partially hydrolyzed formula, or standard formula with intact protein either exclusively or supplementary to breastfeeding. During the first 6 months of intervention, amongst infants with a family history of atopic dermatitis, 6.5% of partially hydrolyzed formula-fed infants and 22.7% of exclusively breastfed infants ( p = 0.007) presented with atopic dermatitis respectively. Growth as assessed by weight increase did not differ between the aforementioned groups. Although cow's milk protein allergy was not related to the different milk feeding regimens in the whole cohort, when adjusting for high breast milk intake, the respective incident was significantly lower in the infants consuming partially hydrolyzed formula ( p < 0.001). This data indicates that a specific partially hydrolyzed formula could serve as a more appropriate complement to breast milk compared to a standard intact protein formula in high-risk infants, to reduce the incidence of atopic dermatitis.

Atopic dermatitis (AD) in early childhood often precedes the development of food sensitization and allergy, but the role of treating AD to prevent food allergy remains poorly understood. Our objective was to assess the relationship between facial dermatitis and food sensitization to cow's milk, egg whites, and peanuts in early childhood, as aggressive treatment of facial dermatitis could serve as a potential opportunity for food sensitization prevention. By 3 years of age, food sensitization levels to cow's milk, egg whites, and peanuts were 48% greater in children with facial AD than in children with no facial involvement of their AD. Additional research is needed to determine if facial involvement of AD in infants and young children is associated with increased food allergy., (© 2023 Wiley Periodicals LLC.)

Background: The non-IgE-mediated food allergy (non-IgE-FA) is less prevalent than IgE-mediated food allergy, and their relationship with functional constipation (FC) needs to be clarified., Methods: A total of 305 infants and children with constipation treated in the Department of Pediatric Gastroenterology, Children's Hospital of Nanjing Medical University, from July 2020 to December 2021 were included in this study. Four cases with organic lesions were excluded. Among 301 diagnosed with FC, according to ROME IV criteria, 81 cases with allergy-related indicators were further evaluated for food allergy by food-specific IgG antibody test, allergen- specific IgE antibody detection, skin prick test, and food avoidance and reintroduction., Results: A total of 45 cases with FC were diagnosed with food allergy, and the incidence rate was 15%. Among the 45 patients, 35 cases (77.8%) had FC with non-IgE-FA. The main clinical symptoms or signs included anal fissure, abdominal pain, and pain during defecation. The most prevalent allergic foods were cow's milk, eggs, fish, and shrimp. Ten (22.2%) cases reported FC with mixed food allergy, including both non-IgE-mediated and IgE-mediated food allergy. This study focused on non-IgE-mediated food allergy-related FC., Conclusion: Our results showed that the incidence of food allergy in infants and children with FC was 15%, which was mainly mediated by non-IgE-FA. The main clinical symptoms or signs in these cases included anal fissure, abdominal pain, and pain during defecation, and the main allergens included milk, eggs, fish, and shrimp., Competing Interests: We declare that there are no conflicts of interest relevant to this work. The author for correspondence is in possession of the related documents of this study. All authors read and approved the manuscript.

Background: Protein-losing enteropathy (PLE), a rare condition with excessive gastrointestinal protein loss, presents with hypoalbuminemia, edema, or ascites. Several cases of PLE combined with severe iron deficiency anemia (IDA) have been reported in infants and toddlers that were considered to result from excessive cow's milk consumption, although the mechanism has not been clearly established., Methods: We retrospectively reviewed the clinical, laboratory, endoscopic, and radiologic characteristics of patients diagnosed and treated for PLE with IDA between 2015 and 2021. Long-term outcomes were analyzed according to dietary intervention during the follow-up period., Results: A total of 10 patients aged 7.0-26.7 months were enrolled in the study and the median follow-up duration of them was 9.4 months (range, 1.3-18.0). Six of them were fed powdered formula, while two were fed whole cow's milk, and their median daily intake was 700 mL (range, 300-900). The times to normalization of hemoglobin, albumin, and eosinophil count were shorter in patients with dietary elimination of cow's milk protein immediately after diagnosis compared to those with reduced intake or no dietary change., Conclusion: Early complete elimination of cow's milk protein should be considered, especially if the laboratory parameters are not normalized with adequate iron supplementation even though the clinical symptoms show improvement. We would like to draw attention to the possibility of the cow's milk protein in the pathogenesis of the condition through the non-IgE-mediated immune reactions., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Food allergies have become a global epidemic, affecting more than 10% of the population and 8% of children worldwide. Eliminating or limiting a food group from the diet can adversely impact micronutrient consumption. Milk allergies can impact the amount of calcium consumed in the diet, serving as a barrier to meeting daily calcium needs. Previous research evaluates the nutritional impact food allergies may have on children diagnosed with food allergies; however, there is a marked gap in literature that investigates the impact that children's allergy may have on their parent or caregiver. We hypothesized that milk elimination in a child's diet resulting from a milk allergy is associated with inadequate calcium intake among parents. Study participants (n = 55) lived in the United States and included parents or caregivers of a child with a diagnosed milk allergy (experimental group) and parents of a child without a milk allergy (control group). Calcium intake was estimated by using the validated Calcium Assessment Tool. Results demonstrated that the experimental group consumed significantly less calcium (273 mg/d) than the control group (520 mg/d; P < .01). Notably, both groups consumed inadequate calcium relative to the calcium Recommended Dietary Allowance for adults of 1000 mg/d, although calcium supplementation was not assessed in this study. Key findings from this study indicate widespread inadequate dietary calcium intake and suggest a need for increased calcium consumption in this population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Dietary and environmental factors may influence tolerance acquisition in food protein-induced allergic proctocolitis (FPIAP). This retrospective observational study explored the role of maternal diet during pregnancy and breastfeeding in tolerance acquisition in infantile FPIAP., Methods: Breastfed infants with FPIAP from six diverse regions in Greece were divided into two groups, based on development of tolerance to the trigger food: Group A (n = 43), before, and Group B (n = 53), after, the 6th month of age. Maternal diet during pregnancy and breastfeeding was elicited using the Mediterranean Diet Score Questionnaire and the Mediterranean Oriented Culture Specific Semi-Quantitative Food Frequency Questionnaire., Results: Mean age at diagnosis of FPIAP (1.5 months) and weaning (5.5 months) were the same in both groups. The main trigger was cow's milk. Group A received infant milk formula earlier than Group B. Group B had a higher incidence of asthma/wheeze, siblings with milk allergy, maternal smoking and rural residence. On multivariate analysis, earlier resolution of FPIAP was associated with higher maternal education and with salt intake and consumption of goat/sheep cheese during pregnancy and olive oil during breastfeeding. Consumption of multivitamins during pregnancy and meat, winter fruits, green vegetables, butter, salt, "ready-to-eat" meals and pastries during breastfeeding were correlated with longer duration of symptoms., Conclusions: Mothers of children with FPIAP to cow's milk protein can be advised to eat more yogurt, cheese and olive oil during subsequent pregnancies, and avoid multivitamins, grilled food, "ready-to-eat" meals, pastries, meat and alcohol during breastfeeding, to reduce the duration of FPIAP presenting in future infants.

Background: Food protein-induced allergic proctocolitis (FPIAP) is characterized by bloody stools in well-appearing infants. Zinc is a micronutrient that plays a crucial role in immune modulation and is essential for cellular function during immune response. Although there are studies on the assessment of intracellular zinc levels in allergic diseases, no data is available on erythrocyte zinc levels of patients with FPIAP., Objective: This study aimed to assess the erythrocyte zinc levels of children with allergic proctocolitis and compare zinc levels with clinical and demographic characteristics., Methods: This was a case-control study that prospectively compared 50 patients with FPIAP and 50 healthy children without malnutrition. The erythrocyte zinc levels of children were determined using atomic absorption spectrophotometry., Results: Fifty patients with FPIAP, including 28 (51%) girls, with median age of 7.1 ± 2.9 (3-14) months and 50 healthy children, including 26 (53.1%) girls, with median age of 7.7 ± 2.8 (3-13) months were included in the study. Seventy percent (n = 35) of the patients with FPIAP started to have symptoms while they were exclusively breastfeeding. Offending allergen foods were cow's milk (78%), egg (40%), sesame (10%), hazelnut (8%), almond (6%), beef (6%), and peanuts (6%, n = 3). Intracellular (erythrocyte) zinc levels in patients with FPIAP were lower than in the healthy control group (495.5 ± 134 µg/dL, 567.3 ± 154.4 µg/dL, respectively, P = 0.01). Patients with FPIAP aged younger than 6 months had lower intracellular zinc levels compared with those aged above 6 months (457 ± 137 µg/dL; 548 ± 112 µg/dL, respectively, P = 0.01). There was no relationship between zinc levels and time of symptom onset, presence of concomitant disease, being allergic to multiple foods, and family history of atopy (P > 0.05)., Conclusions: FPIAP is a food allergy with limited information on its pathogenesis. Considering the beneficial effects on gastrointestinal system epithelia, zinc may be involved in the pathogenesis of FPIAP. Future comprehensive prospective research on this subject is of importance., Competing Interests: No conflict of interest was declared by the authors.

Background: Thrombocytopenia absent radius (TAR) syndrome is a rare disease with an estimated prevalence of one in 200,000 live births. TAR is associated with cardiac and renal anomalies as well as gastrointestinal problems such as cow's milk protein allergy (CMPA). Typically neonates with CMPA present with mild intolerance, with few reports in the literature of more severe intolerance resulting in pneumatosis. We present a case of a male infant with TAR syndrome who developed gastric and colonic pneumatosis intestinalis., Case Description: An eight-day-old male infant born at 36 weeks gestation with a diagnosis of TAR, presented with bright red blood in his stool. At this time he was on full formula feeds. Given continued bright red blood within his stool, an abdominal radiograph was obtained which was consistent with colonic and gastric pneumatosis. A complete blood count (CBC) was notable for worsening thrombocytopenia, anemia and eosinophilia. Once enteral feeds were held there was rapid resolution of the radiographic findings and resolution of his bloody stool. He was ultimately diagnosed with a CMPA., Conclusion: Though there are reports of CMPA in patients with TAR, the severity of this patient's presentation with both colonic and gastric pneumatosis is unique. Without the knowledge of the association of CMPA with TAR, this case could have been misdiagnosed and led to reintroduction of cow's milk containing formula, resulting in further complications. This case highlights the importance of a timely diagnosis and severity of CMPA in this population.

Background: The effects of regular soy formula (SF) intake on the development of food sensitization in infancy remain unclear. This study aimed to assess the effects of regular SF intake between 1 and 2 months of age on food sensitization development by 6 months of age., Methods: Using data from a randomized controlled trial of a birth cohort from four Japanese hospitals that assessed cow's milk allergy development, we performed a retrospective cohort study of 235 infants who avoided cow's milk formula and supplemented breastfeeding with SF as required between 1 and 2 months of age. Regular SF intake was defined as SF consumption of ≥14 days per month and ≥1350 ml per month. Food sensitization was defined as positive skin prick test reactions to hen's egg, cow's milk, wheat, and/or soy. Using multivariable logistic regression models that adjusted for parental, perinatal, and environmental factors, we calculated the adjusted odds ratios of regular SF intake for food, hen's egg, and cow's milk sensitization by 6 months of age., Results: From the 235 participants, 114 (48.5%) had regular SF intake. The adjusted odds ratios of regular SF intake for food, hen's egg, and cow's milk sensitization were 0.32 (95% confidence interval: 0.16-0.62, p = .0007), 0.42 (0.20-0.88, p = .02), and 0.33 (0.14-0.81, p = .02), respectively., Conclusion: Regular SF intake between 1 and 2 months of age in infants avoiding cow's milk formula was significantly associated with a reduced risk of food sensitization in infancy., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The 8806H formula is the only renal formula available for pediatric patients with chronic kidney disease in Japan. A 1-month-old female infant could not be administered 8806H because of milk allergy. Administration of low-potassium anti-allergic formula treated with sodium polystyrene sulfonate maintained adequate serum potassium levels, and introduction of peritoneal dialysis could be delayed. The patient had severe renal dysfunction secondary to bilateral hypoplastic and multi-cystic kidneys. Although she received the 8806H formula, this product was switched to hydrolyzed casein formula because she developed allergy to 8806H at 28 days of age, which led to hyperkalemia. We initiated treatment with sodium polystyrene sulfonate at 40 days of age to lower the potassium concentration in milk, which prevented hyperkalemia and maintained the patient's nutritional status to ensure appropriate increase in body weight. We monitored electrolyte levels in milk and confirmed reduction in potassium levels before feeding. Although such condition is rare and there are few reports of potassium reduction in anti-allergic formulas, this strategy may be useful for pediatric patients with renal insufficiency who cannot be treated with renal formulas because of milk allergy., (© 2022. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Background: Cow's milk (CM) is an increasingly common cause of severe allergic reactions, but there is uncertainty with respect to severity of reactions at low-level CM exposure, as well as the reproducibility of reaction thresholds., Objective: We undertook an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges in CM to determine the rate of anaphylaxis to low-level exposures and the reproducibility of reaction thresholds., Methods: We performed a systematic review and IPD meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarification as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodologic checklists., Results: Thirty-four studies were included, representing data from over 1000 participants. The cumulative ED 01 and ED 05 (cumulative doses causing objective symptoms in 1% and 5% of the at-risk allergic population) were 0.3 (95% confidence interval [CI], 0.2-0.5) and 2.9 (95% CI, 1.6-5.4) mg, respectively. At meta-analysis, 4.8% (95% CI, 2.0-10.9) and 4.8% (95% CI, 0.7-27.1) of individuals reacting to ≤5 mg and ≤0.5 mg of CM protein had anaphylaxis (minimal heterogeneity, I 2  = 0%). Then 110 individuals underwent repeat double-blind, placebo-controlled food challenges; the intraindividual variation in reaction threshold was limited to a ½-log change in 80% (95% CI, 65-89) of participants. Two individuals initially tolerated 5 mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis., Conclusions: About 5% of CM-allergic individuals reacting to ED 01 or ED 05 exposure might have anaphylaxis to that dose. This equates to 5 and 24 anaphylaxis events per 10,000 patients exposed to an ED 01 or ED 05 dose, respectively, in the broader CM-allergic population. Most of these anaphylactic reactions would be mild and respond to a single dose of epinephrine., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Infant Gastro-Esophageal Reflux Disease: PHYSIOLOGICAL OR PATHOLOGICAL ? Gastroesophageal reflux (GER) is defined by the rise of gastric contents into the esophagus, with or without externalization. GER is very common in young infants, with a peak around 4 months, and most often physiological due to high milk intakes and inappropriate relaxation of the lower esophageal sphincter. Evoking a GER disease (GERD) is not always obvious due to signs of poor specificity (crying, irritability, regurgitation). On the other hand, one should not miss warning signs evocative of GERD complicated by esophagitis or of recurrent upper respiratory or ENT infections, or even differential diagnoses (cow milk protein allergy, eosinophilic esophagitis, congenital malformations or brain tumours, etc.). The diagnosis of GERD is clinical but investigations can sometimes be discussed like esophagogastroduodenal endoscopy, 24- hour pH-metry, esophagogastroduodenal follow through. The mechanisms of GERD should be clearly explained to parents and physiological GER should be treated with non-drug measures (adaptation of milk intakes/volumes, thickeners). In the absence of improvement, avoidance of cow's milk proteins for 2 to 4 weeks can be proposed, or even treatment with proton pump inhibitors., Competing Interests: Les auteurs déclarent n’avoir aucun lien d’intérêts.

Objectives: To review the evidence pertaining to the association between cow's milk protein allergy and recurrent acute otitis media and otitis media with effusion., Methods: The CENTRAL, Web of Science, EMBASE, MEDLINE, LILACS databases, and gray literature were searched., Results: Four studies were included, identifying the prevalence rates: 0.2% of delayed speech due to chronic otitis media with effusion in 382 children with cow's milk protein allergy, 10.7% of cow's milk protein allergy in 242 children who underwent ENT procedures, 40% of cow's milk protein allergy in 25 children with recurrent otitis media with effusion and higher tendency to otitis media in children with cow's milk protein allergy of 186 children (1.5 + 0.6 vs. 0.4 + 0.1; p < 0.1)., Conclusion: Considering the characteristics and methodological variations of the identified studies, it is not possible to state that there is reliable evidence of an association between cow's milk protein allergy and otitis media., (Copyright © 2021 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Cow's milk protein allergy (CMPA) is the most common food allergy in infants. A previously healthy neonate fed with infant formula presented diarrhoea, vomiting and respiratory distress with cyanosis. Investigations showed thrombocytosis and leucocytosis with lymphocyte predominance. To our surprise blood gas analysis showed metabolic acidosis and a high methaemoglobin level of 33% (normal range <3%). Clinical status, metabolic acidosis and methaemoglobin level returned to normal following fluid resuscitation and methylene blue administration. The neonate was later managed with breast feeding and elemental formula. CMPA was diagnosed based on history and clinical improvement after elemental formula. Although not common in CMPA, methaemoglobinaemia should be recognised as a differential diagnosis in a hypoxic infant with metabolic acidosis and diarrhoea as early recognition and treatment with methylene blue can save a child's life., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Gastro-oesophageal reflux (GOR) and cow's milk protein intolerance (CMPI) are two frequently occurring conditions found in infancy. The aim of this review is to examine the association between the two., Methods: A literature review was conducted via PubMed, Sciencedirect and Google scholar using search terms "gastro-oesophageal reflux" + "cow's milk protein intolerance". The inclusion criteria were studies from 1985 to present, studies involving infants and studies involving both GOR and CMPI. Exclusion criteria were studies not including infants, or studies involving GOR or CMPI independently., Results: This review revealed varying degrees of co-existence of GOR and CMPI. Iacono et al., Farahmand et al., Kamer et al., and Semeniuk and Kaczmarski, displayed co-occurrence of GOR and CMPI in 41.8%, 33.3%, 46.5%, and 44.9% of infants respectively. In two separate studies by Cavataio et al., concomitance was apparent in 41.6% and 30% of infants. Others suggested a less significant link at 16-20%. Nielsen et al. found 18/42 children to have severe GORD, 10 of whom had CMPI in addition., Conclusion: This review highlights an association between GOR and CMPI. CMPI should be considered, particularly in cases of reflux resistant to pharmacological therapy, as a co-existing or causative entity accounting for symptoms., (© 2021. Royal Academy of Medicine in Ireland.)

Background: Suspicion of food protein-induced proctocolitis based on empirical understanding of rectal bleeding can lead to misdiagnosis., Objective: to verify clinical and evaluative characteristics of patients who presented neonatal rectal bleeding and were on a restricted cow's milk diet., Methods: A cross-sectional retrospective study included patients followed up in a tertiary care center, who presented rectal bleeding in the neonatal period. The analyzed data included gender, gestational age, type of delivery, use of antibiotics during the last trimester of pregnancy, use of parenteral nutrition before the first manifestation, use of mechanical ventilation, initial clinical manifestations associated with rectal bleeding, diet before the first manifestation, period of elimination diet, oral food challenge (OFC) results and symptoms presented in cases of positive OFC. Fisher's exact test and Mann-Whitney test were used to analyze the data. The level of significance was set to 5%., Results: Forty-two patients were selected: 30 preterm infants, 34 cesarean deliveries, 10 exclusively breastfed patients before rectal bleeding. Median age at OFC was 6.3 months old. Median of length of the elimination period before OFC was 5.9 months. OFC was negative in 33/42 (79%) patients and positive in 9/42 (21%). There was no association between OFC results and the evaluated data. The main symptom observed in patients with positive OFC was blood in stools., Conclusion: OFC was negative in most cases of suspected cow's milk allergy due to rectal bleeding in neonates, most of them with a history of prematurity.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease. A third of pediatric AD patients have also food allergy. Although food challenge test is gold standard test for the diagnosis of food allergies, they should be administered by experienced physicians, considering that the test is time-consuming and carries some risks. Documentation of the efficacies of specific IgE (sIgE), skin prick test (SPT), and atopy patch test (APT) are important for determining the necessity of oral food challenge tests(OFC)., Methods: Fifty-three AD patients with suspected cow's milk allergy (CMA) were included in our study. Diet-related questions were asked to the patients. Blood samples were taken for measurement of total blood count, total IgE, and milk sIgE. OFC, SPT, and APT were performed using pasteurized cow milk., Results: The mean age of the study population was 1.4±0.8 years, and the male:female ratio was 1.12. Cow milk allergy was detected in 45.3% of the patients after OFC. A comparison between CMA(+) and CMA(-) patients revealed no significant difference in sIgE positivity (P=0.940), but there was a significant difference in SPT (P=0.000) and APT (P=0.001) positivity. When our study group was divided into immediate reaction, delayed onset reaction, and not reactive subgroups after OFC, efficacy of SPT was more prominent in immediate reaction subgroup while APT was more efficient in delayed reaction subgroup., Conclusions: Our study showed that using SPT test with APT test in allergic reactions with IgE and other mechanisms such as AD will increase the diagnostic yield, thereby reducing the need for OFC.

Background: Some cohort studies have suggested that gut microbiota composition is associated with allergic diseases in children. The microbiota of the first-pass meconium, which forms before birth, represents the first gut microbiota that is easily available for research and little is known about any relationship with allergic disease development., Objective: We investigated whether the bacterial composition of the first-pass meconium is associated with the development of allergic diseases before 4 years of age., Methods: Prospective birth cohort study. Bacterial composition of first-pass meconium was analysed using bacterial 16S rRNA gene amplicon sequencing. Atopic and allergic diseases were evaluated via online survey or telephone to age 4 years, based on the International Study of Asthma and Allergies in Childhood questionnaire., Results: During a 6-week period in 2014, 312 children were born at the Central Finland Central Hospital. Meconium was collected from 212 at a mean of 8-hour age. Outcome data at 4 years were available for 177 (83%) children, and 159 of these had sufficient amplification of bacterial DNA in meconium. Meconium microbiota composition, including diversity indices and relative abundances of the main phyla and genera, was not associated with subsequent atopic eczema, wheezing or cow's milk allergy. Principal components analysis did not identify any clustering of the meconium microbiomes of children with respect to wheezing or cow's milk allergy., Conclusions: We found no evidence that gut microbiota composition of first-pass meconium is associated with atopic manifestations to age 4 years. However, larger studies are needed to fully exclude a relationship., (© 2022 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Constipation is a very common disorder, mostly functional in nature, that may persist for years in up to 35-52% of children. Food allergy prevalence, severity and persistence are increasing over time, and cows' milk protein is the commonest food allergen recognised to affect gastrointestinal motility in children. There is mounting evidence of the role of cows' milk (CM) allergy (CMA) in children with constipation. With this narrative review, we aim to provide clinicians with an updated and critical overview of food allergy-associated constipation. We searched Embase, Medline and the Cochrane Library, using keywords related to the topic. Only reviews and studies including children aged 0-17 years that were published in English were considered. Constipation has been reported in 4.6% of infants with CMA; the prevalence of food allergy underlying chronic constipation in children resistant to conventional treatment and presenting to tertiary clinics ranges between 28% and 78%. The identification of predisposing risk factors and of a specific phenotype of food allergy-induced constipation remains elusive. No allergic tests, radiological or motility investigations achieve sufficient sensitivity and specificity to screen children for CMA-related constipation. A 4-week cows' milk protein (CMP) elimination diet may be considered for children with chronic constipation resistant to conventional treatment and who lack alarm sign/symptoms of organic diseases. In subjects with ameliorated symptoms on CMP elimination, the diagnosis of CMA should be confirmed by a food challenge to avoid an unnecessary protracted diet.

Background: Non-IgE-mediated Cow's Milk Allergy (CMA) has a prevalence of less than 1% in children. Guidelines developed to help non-specialists diagnose CMA may lead to misattribution of normal symptoms and contribute to overdiagnosis of CMA. We sought to establish the frequency of symptoms during infancy associated with non-IgE-mediated CMA, using the international Milk Allergy in Primary Care (iMAP) guideline as representative of CMA guidelines more generally., Method: Secondary analysis of the Enquiring About Tolerance (EAT) randomized controlled trial (ISRCTN 14254740; 1303 exclusively breastfed 3-month-old healthy infants). Key outcomes were ≥2 iMAP symptoms associated with 'mild-moderate' and 'severe' non-IgE-mediated CMA., Results: Whilst breastfeeding and parental atopy rates were higher than the general population, participants were otherwise similar to the population of England and Wales. Two or more non-IgE CMA symptoms were reported by 25% families for mild-moderate and 1.4% for severe symptoms each month between ages 3 and 12 months, peaking at 38% with ≥2 mild-moderate and 4.3% ≥2 severe symptoms at three months, when participants were not directly consuming cow's milk. 74% of participants reported ≥2 mild-moderate symptoms and 9% ≥2 severe symptoms in at least one month during this period. At six months there was no evidence of difference in the proportion of children with ≥2 symptoms between those consuming (29.5% mild-moderate, 1.8% severe) and not consuming cow's milk (35.3% mild-moderate, 2.2% severe). Mean monthly reporting of ≥2 symptoms was also no different between those with (15.8% mild-moderate, 1.1% severe) or without eczema at baseline (16.7% mild-moderate, 1.3% severe)., Conclusions: Guideline-defined symptoms of non-IgE-mediated CMA are very common in infants. Guidelines may promote milk allergy overdiagnosis by labelling normal infant symptoms as possible milk allergy., (© 2021 John Wiley & Sons Ltd.)

Children with medical complexities, such as multi-system disorders and/or neurological impairments, often experience feeding difficulties and need enteral nutrition. They frequently have impaired motility and digestive-absorbing functions related to their underlying condition. If a cow's milk allergy (CMA) occurs as a comorbidity, it is often misdiagnosed, due to the symptoms' overlap. Many of the commercialized mixtures intended for enteral nutrition are composed of partially hydrolyzed cow's milk proteins, which are not suitable for the treatment of CMA; thus, the exclusion of a concomitant CMA is mandatory in these patients for obtaining symptoms relief. In this review, we focus on the use of elemental and semi-elemental formulas in children with neurological diseases and in preterm infants as clinical "models" of medical complexity. In children with neurodisabilities, when gastrointestinal symptoms persist despite the use of specific enteral formula, or in cases of respiratory and/or dermatological symptoms, CMA should always be considered. If diagnosis is confirmed, only an extensively hydrolyzed or amino-acid based formula, or, as an alternative, extensively hydrolyzed nutritionally adequate formulas derived from rice or soy, should be used. Currently, enteral formulas tailored to the specific needs of preterm infants and children with neurological impairment presenting concomitant CMA have not been marketed yet. For the proper monitoring of the health status of patients with medical complexity, multidisciplinary evaluation and involvement of the nutritional team should be promoted.

The presence of rectal bleeding in the first months of life is very often diagnosed as food protein-induced allergic proctocolitis (FPIAP). The symptoms typically start in infancy, and most cases resolve by age 12 months. Infants with FPIAP usually present bloody stools mixed with mucus, with or without reduced stool consistency. Most affected infants are generally healthy-appearing. We used the story of an infant with rectal bleeding as a reminder that there is also the possibility of a form of benign non-allergic proctocolitis that is not usually included in the differential diagnosis. In the absence of warning signs and in case of infant well-being, it should be the first clinical entity to suspect. Therefore, we suggest we should wait at least 2 months before starting to eliminate cow milk or other foods from the diet., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Several factors that increase the risk of severe food-induced anaphylaxis have been identified. Objective: We aimed to determine the demographic, etiologic, and clinical features of food-induced anaphylaxis in early childhood and also any other factors associated with severe anaphylaxis. Methods: We carried out a medical chart review of anaphylaxis cases from 16 pediatric allergy and immunology centers in Turkey. Results: The data of 227 patients with 266 food-induced anaphylaxis episodes were included in the study. The median (interquartile range) age of the first anaphylaxis episode was 9 months (6-18 months); 160 of these patients were boys (70.5%). The anaphylaxis episodes were mild in 75 cases (28.2%), moderate in 154 cases (57.9%), and severe in 37 cases (13.9%). The most frequent food allergens involved were cow's milk (47.4%), nuts (16.7%), and hen's egg (15.8%). Epinephrine was administered in only 98 (36.8%) of these anaphylaxis episodes. A logistic regression analysis revealed two statistically significant factors that were independently associated with severe anaphylaxis: the presence of angioedema and hoarseness during the anaphylactic episode. Urticaria was observed less frequently in patients who developed hypotension. In addition, confusion and syncope were associated with 25.9- and 44.6-fold increases, respectively, in the risk of concomitant hypotension. Conclusion: Cow's milk, nuts, and hen's egg caused the majority of mild and moderate-to-severe anaphylaxis episodes. The presence of angioedema and hoarseness in any patient who presents with a history of food-induced anaphylaxis should alert clinicians that the reaction may be severe. In addition, the presence of confusion, syncope, or stridor probably indicates concomitant hypotension.

Objective: To investigate the association between functional constipation, infant feeding in early infancy and eating behavior in preschool children., Methodology: A cross-sectional study was undertaken in public and private schools in the state of Sergipe (Northeast of Brazil). The sample calculation was based on a 25% estimate of constipation prevalence in Brazilian children, resulting in a sample size of 1051 children. Functional constipation was assessed using Rome IV criteria. Eating behavior was assessed using the Children's Eating Behavior Questionnaire. Adjusted odds ratios were estimated using a multivariate model., Results: The prevalence of functional constipation was 23%. After adjusting for water intake, children with food fussiness were >6 times likely to have constipation (odds ratio [OR] = 6.65; 95% confidence interval [CI] 5.19-8.52). Children who were fed with cow's milk in the first 6 months of age were up to 15.2 times more likely to have functional constipation. Bottle feeding at 0-6 months of age increased the risk of functional constipation at preschool age (whole cow's milk: OR = 17.02; 95% CI 7.33-39.51, infant formula: OR = 6.35; 95% CI 3.42-11.79, mixed breastfeeding: OR = 10.83; 95% CI 4.57-25.69)., Conclusion: Food fussiness and the use of cow's milk-based feeding bottles at 0-6 months of age were associated with functional constipation in preschool children., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Children with food allergy are at specific risk for nutritional deficiencies., Objective: To retrospectively determine prevalence of vitamin D and iron deficiencies in children with or without food allergy (FA)., Methods: We compared the markers of vitamin D and iron status of 0 to 17-year-olds with cow's milk allergy (CMA) (n = 77), those with other FAs (n = 70), and those with atopy without FA (n = 87) at an academic pediatric allergy practice. Multiple linear regression analyses were performed to determine the impact of CMA and other FAs on vitamin D levels and iron markers., Results: Vitamin D deficiency was detected in one-fourth and insufficiency in one-third of children with CMA and other FAs and in those with atopic diseases but no FA, respectively. Vitamin D levels were associated with vitamin D supplementation and consumption of breast milk, cow's milk, infant formula, or plant-based milk beverage, but not with CMA or other FAs. Older children with FA who did not consume any cow's milk or alternative milk beverage were at highest risk for vitamin D insufficiency. Children with CMA have a higher rate of iron deficiency anemia (8%) than children with other FAs (1%) or those with no FA (5%, P < .001); however, suboptimal levels of transferrin saturation and iron were detected in up to one-third of children with CMA or other FAs., Conclusion: Vitamin D deficiency and insufficiency is common in children with atopy overall, but children with CMA are at higher risk for iron deficiency anemia. Intensive nutritional counseling and nutrient intake monitoring, specifically for vitamin D and iron in those avoiding cow's milk, are necessary to optimize nutritional status., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Bakground: It is suggested that early intake of cow's milk could be a risk factor for type 1 diabetes (T1DM). Further, the different immunological background, gives a suggestion of an inverse relationship for the occurrence of these diseases. The aim of this study was to explore the association between cow's milk allergy (CMA) and the risk of T1DM in a register-based case-cohort study., Methods: Data were obtained from Finnish nationwide health registers. The study included all children born in Finland between January 01, 1986 and December 31, 2008 and diagnosed with T1DM before the age of 16 years (n = 7754). A 10% random sample from each birth year cohort was selected as a reference cohort (n = 137,798). T1DM, CMA, and asthma were defined based on valid special reimbursements for the costs of drugs/special formulas needed in the treatment of the diseases. Child's sex, birth decade, asthma, maternal diabetes and asthma, smoking during pregnancy, and previous deliveries were considered as confounding factors. Time-dependent, weighted Cox regression was applied for statistical analyses., Results: Children with CMA had an increased risk of developing T1DM in fully adjusted model (HR = 1.17; 95% CI 1.02-1.34), but the association was no longer observed when including the use of special infant formulas in the definition of CMA in the sensitivity analysis (HR = 1.11; 95% CI 0.92-1.32). CMA was associated with an increased risk of T1DM in children without asthma (HR = 1.27; 95%CI 1.10-1.47), but not in children with asthma (HR = 0.80; 95% CI 0.92-1.27)., Conclusion: Children with CMA may have an increased risk of T1DM., (© 2021 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

Introduction and Objectives: The aim of this study was to determine the frequency of food-induced anaphylaxis, analyze the symptoms, and triggering factors in a group of youngest children. Also, the study aims to estimate the frequency of anaphylaxis episodes in children in the Kuyavian-Pomeranian Voivodeship region., Methods: Retrospective analysis of medical records of 29 children aged 0-3 years that presented symptoms of food-induced anaphylaxis. Medical charts were reviewed using a collection of documents with the clinical data., Results: The frequency of anaphylaxis was determined to be 0.3% of all hospitalized children aged 0-3 years and 1.9% of children suspected of food allergy. The mean age of an anaphylactic reaction was 12±9 months. The most common symptom was mild-moderate urticaria. The respiratory symptoms were significantly more prevalent in toddlers than in infants (p = 0.148). Cardiac symptoms occurred only in the infant group, i.e., in two (11%) infants. As a possible cause of the symptoms, in 18 (62%) cases, parents most often indicated the consumption of milk or milk-rice porridge. Anaphylaxis as the first manifestation of food-allergy was significantly more prevalent in infants than in older children (p = 0.0002)., Conclusions: The incidence of anaphylactic reactions rated at 0.3% of all children hospitalized at this age. The most common symptoms of anaphylactic reaction were skin lesions. The primary cause of allergic reactions was cow's milk after the first exposure at home. Anaphylaxis has different patterns of symptoms depending on the age of the child.

Objectives: To compare the impact of different formulas on the occurrence of other atopic manifestations and the time of immune tolerance acquisition., Study Design: In a 36-month prospective cohort study, the occurrence of other atopic manifestations (eczema, urticaria, asthma, and rhinoconjunctivitis) and the time of immune tolerance acquisition were comparatively evaluated in immunoglobulin E-mediated children with cow's milk allergy (CMA) treated with extensively hydrolyzed casein formula containing the probiotic L. rhamnosus GG (EHCF + LGG), rice hydrolyzed formula, soy formula, extensively hydrolyzed whey formula (EHWF), or amino acid-based formula., Results: In total, 365 subjects were enrolled into the study, 73 per formula cohort. The incidence of atopic manifestations was 0.22 (Bonferroni-corrected 95% CI 0.09-0.34) in the EHCF + LGG cohort; 0.52 (0.37-0.67) in the rice hydrolyzed formula cohort; 0.58 (0.43-0.72) in the soy formula cohort; 0.51 (0.36-0.66) in the EHWF cohort; and 0.77 (0.64-0.89) in the amino acid-based formula cohort. The incidence of atopic manifestations in the rice hydrolyzed formula, soy formula, EHWF, and amino acid-based formula cohorts vs the EHCF + LGG cohort was always greater than the prespecified absolute difference of 0.25 at an alpha-level of 0.0125, with corresponding risk ratios of 2.37 (1.46-3.86, P < .001) for rice hydrolyzed formula vs EHCF + LGG; 2.62 (1.63-4.22, P < .001) for soy formula vs EHCF + LGG; 2.31 (1.42-3.77, P < .001) for EHWF vs EHCF + LGG; and 3.50 (2.23-5.49, P < .001) for amino acid-based formula vs EHCF + LGG. The 36-month immune tolerance acquisition rate was greater in the EHCF + LGG cohort., Conclusions: The use of EHCF + LGG for CMA treatment is associated with lower incidence of atopic manifestations and greater rate of immune tolerance acquisition., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Food Protein-Induced Enterocolitis Syndrome (FPIES) is a clinically well-characterised, non-Immunoglobulin E (IgE)-mediated food allergy syndrome, yet its rare atypical presentation remains poorly understood., Objective: Aim of this study was to present the 10-year experience of a referral centre highlighting the atypical FPIES cases and their long-term outcome., Methods: FPIES cases were prospectively evaluated longitudinally in respect of food outgrowth and developing other allergic diseases with or without concomitant IgE sensitisation., Results: One hundred subjects out of a total of 14,188 referrals (0.7%) were identified. At presentation, 15 patients were found sensitised to the offending food. Fish was the most frequent eliciting food, followed by cow's milk and egg. Tolerance acquisition was earlier for cow's milk, followed by egg and fish, while found not to be protracted in atypical cases. Resolution was not achieved in half of the fish subjects during the 10-year follow-up time. Sensitisation to food was not related to infantile eczema or culprit food, but was related to sensitisation to aeroallergens. In the long-term evaluation, persistence of the FPIES or aeroallergen sensitisation was significantly associated with an increased hazard risk of developing early asthma symptoms., Conclusion: Sensitisation to food was related neither to eczema or culprit food nor to tolerance acquisition but rather to the development of allergic asthma through aeroallergen sensitisation. In addition to an IgE profile at an early age, FPIES persistence may also trigger mechanisms switching FPIES cases to a T-helper 2 cells immune response later in life, predisposing to atopic respiratory symptoms; albeit further research is required., Competing Interests: None.

Functional constipation (FC) is one of the most common disorders in childhood and has a negative impact on the quality of life of children. Scientific evidence regarding a causal relationship between FC and cow's milk allergy is controversial, as it is also reported by the latest European Society for Paediatric Gastroenterology, Hepatology and Nutrition-North American Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN-NASPGHAN) recommendations. In the case of FC, routine allergometric tests are not recommended and the cows' milk-free diet is only proposed in the case of laxative-resistant constipation and only following the advice of an expert. Instead, after a careful review of the literature and in view of the many clinical cases encountered in our clinical practice, we believe that it is useful to propose cows' milk-free diet as first line for the treatment of FC at least in pre-school children and in children with a personal or family history of atopy or with a previous diagnosis of cow's milk protein allergy., Competing Interests: The authors declare no conflicts of interest.

Necrotizing enterocolitis is one of the most common and worrying diseases in neonates, commonly shown in premature neonates, and is associated with significant mortality and morbidity. Necrotizing enterocolitis is characterized by intestinal mucosal injury that can progress to transmural bowel necrosis, and radiologically it can present with either pneumatosis intestinalis or portal venous gas. It is postulated to develop in an immunocompromised host in the setting of bacterial colonization, usually after administration of non-breast milk feed. Cow's milk allergy association with necrotizing enterocolitis has not been well determined, and the pathophysiology is still not clear. Necrotizing enterocolitis is very rare following living donor liver transplant. In our case, a 6-year-old boy who was doing well in the postoperative period had sudden worsening of general condition after he was started on milk feed. On evaluation and reexploration, he was diagnosed with necrotizing enterocolitis and later succumbed to death.

Background: The aim of the study was to establish whether the use of a strict milk-free diet in children with cow's milk allergy, resulting in the resolution of clinical symptoms of the disease, also extinguishes the inflammatory reaction induced by the allergy., Methods: We examined 64 children (aged 3-6 years) with a diagnosed cow's milk allergy who had been treated with an elimination diet for at least six months and showed remission of the disease's clinical symptoms as a result of the treatment. The control group consisted of 30 healthy children of the same age following an unrestricted age-appropriate diet. Concentrations of cytokines, calprotectin, and adipokines (leptin, resistin, chemerin, neutrophilic lipocalin associated with gelatinase-NGAL) were determined in the serum samples obtained from the studied children by immunoenzymatic assays., Results: Patients with CMA had significantly higher median values of serum IL-6, TNF-α, resistin, chemerin and NGAL in comparison to the healthy children ( p < 0.05, p < 0.001, p < 0.05, p < 0.01, p < 0.001, respectively). Serum concentrations of IL-10, leptin, calprotectin and CRP as well as in WBC count were in the same range in both studied groups. We observed direct statistically significant correlations between levels of IL-10 and CRP ( p = 0.005), IL-10 and WBC ( p = 0.045), TNF-α and WBC ( p = 0.038), calprotectin and WBC ( p < 0.001), chemerin and CRP ( p < 0.001) as well as between NGAL and WBC ( p = 0.002) in children with CMA., Conclusion: The use of a strict milk-free diet by children with CMA, resulting in the resolution of clinical symptoms of the disease, does not seem to extinguish the inflammation induced by the allergy. The findings of this study-elevated IL-6, TNF-α, resistin, chemerin and NGAL levels in patients with CMA-suggest that these parameters seem to be involved in the generation of a low-grade proinflammatory environment observed in cow's milk allergy and could be used to monitor the effectiveness of treatment.

Background: The association between atopic sensitisation, atopic eczema (AE) and asthma is known, but distinct roles of allergies on long-term health are unestablished., Objective: Evaluation of allergic symptoms and sensitisation in adolescents who in infancy had AE and verified cows' milk allergy (CMA) or AE and a negative CMA challenge, and controls., Methods: Children with AE, with and without CMA, from a randomised controlled study in 1999-2001 examining the effect of probiotics on AE severity at older than 12 months of age, attended a follow-up visit at age 16 to 18, with age-matched controls. Data came from a questionnaire (ISAAC questionnaire), analysis of serum antigen-specific immunoglobulin Es (IgEs), and clinical evaluation. Group comparisons were carried out (χ 2 tests and logistic regression)., Results: Fifty-two patients with AE and CMA (AE/CMA+ group), 52 with AE and suspicion of CMA (AE/CMA- group), and 57 controls attended a study visit. IgE-mediated sensitisation was significantly more prevalent in the AE/CMA+ group vs the controls, for horse, cat, dog, egg white and wheat (P < .024 for all). For birch, timothy and mugwort (P < .008 for all), sensitisation was more prevalent in both the AE/CMA+ group and the AE/CMA- group vs controls. On the basis of questionnaire data the AE/CMA + group reported a significantly higher lifetime prevalence of wheezing (64% vs 35% and 32%; P = .001), noninfectious rhinitis (85% vs 62% and 56%; P = .004), and hay fever (77% vs 52% and 33%; P < .001) vs the AE/CMA- group and the control group, respectively., Conclusion and Clinical Relevance: Patients with AE and CMA in infancy, as opposed to patients with AE only, or controls, report more allergic symptoms and exhibit more allergic sensitisation in adolescence. This indicates that CMA in infancy is an independent risk factor of allergic disease in adolescence., (© 2020 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)