Probiotics in Infancy and Childhood for Food Allergy Prevention and Treatment.

Food allergy represents a failure of oral tolerance mechanisms to dietary antigens. Over the past few years, food allergies have become a growing public health problem worldwide. Gut microbiota is believed to have a significant impact on oral tolerance to food antigens and in initiation and maintenance of food allergies. Therefore, probiotics have also been proposed in this field as a possible strategy for modulating both the gut microbiota and the immune system. In recent years, results from preclinical and clinical studies suggest a promising role for probiotics in food allergy prevention and treatment. However, future studies are needed to better understand the mechanisms of action of probiotics in food allergies and to design comparable study protocols using specific probiotic strains, defined doses and exposure times, and longer follow-up periods.

Antibiotic Prophylaxis for the Prevention of Urinary Tract Infections in Children: Guideline and Recommendations from the Emilia-Romagna Pediatric Urinary Tract Infections (UTI-Ped-ER) Study Group.

Background: Urinary tract infection (UTI) represents one of the most common infectious diseases and a major cause of antibiotic prescription in children. To prevent recurrent infections and long-term complications, low-dose continuous antibiotic prophylaxis (CAP) has been used. However, the efficacy of CAP is controversial. The aim of this document was to develop updated guidelines on the efficacy and safety of CAP to prevent pediatric UTIs. Methods: A panel of experts on pediatric infectious diseases, pediatric nephrology, pediatric urology, and primary care was asked clinical questions concerning the role of CAP in preventing UTIs in children. Overall, 15 clinical questions were addressed, and the search strategy included accessing electronic databases and a manual search of gray literature published in the last 25 years. After data extraction and narrative synthesis of results, recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Results: The use of CAP is not recommended in children with a previous UTI, with recurrent UTIs, with vesicoureteral reflux (VUR) of any grade, with isolated hydronephrosis, and with neurogenic bladder. CAP is suggested in children with significant obstructive uropathies until surgical correction. Close surveillance based on early diagnosis of UTI episodes and prompt antibiotic therapy is proposed for conditions in which CAP is not recommended. Conclusions: Our systematic review shows that CAP plays a limited role in preventing recurrences of UTI in children and has no effect on its complications. On the other hand, the emergence of new antimicrobial resistances is a proven risk.

Are Phe-Free Protein Substitutes Available in Italy for Infants with PKU All the Same?

Breastfeeding or standard infant formulas, alongside phenylalanine (Phe)-free protein substitutes, constitute the dietary management for infants with PKU to guarantee protein requirements are met in compliance with metabolic tolerance. This work aims to analyse the nutritional composition of Phe-free infant protein substitutes, in terms of macronutrients, micronutrients and functional components, available for PKU dietary management in Italy. A total of seven infant Phe-free protein substitutes were included in this review, six powder and one liquid. A second analysis was conducted to compare them to the composition of formulas intended for healthy infants, taking into consideration the Commission Delegated Regulation (EU) 2016/127 and Commission Delegated Regulation (EU) 2016/128 for micronutrients. The analysis revealed heterogeneity among protein substitutes suitable for infants with PKU. The energy and protein equivalents (P.Eq.) content are different; all of the substitutes contain docosahexaenoic acid (DHA) and arachidonic acid (ARA), while eicosapentaenoic acid (EPA), fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), human milk oligosaccharides (HMOs) and nucleotides are not present in all the substitutes. More attention should be paid to these infant products to ensure metabolic control of PKU, and also promote proper growth, cognitive neurodevelopment, favourable gut microbiota composition, and immune system health, while reducing the risk for non-communicable diseases (NCDs).

Nutrition during Pregnancy and Lactation: Epigenetic Effects on Infants' Immune System in Food Allergy.

Food allergies are an increasing health problem worldwide. They are multifactorial diseases, in which the genome alone does not explain the development of the disease, but a genetic predisposition and various environmental factors contribute to their onset. Environmental factors, in particular nutritional factors, in the early stages of life are recognized as key elements in the etiology of food allergies. There is growing evidence advising that nutrition can affect the risk of developing food allergies through epigenetic mechanisms elicited by the nutritional factors themselves or by modulating the gut microbiota and its functional products. Gut microbiota and postbiotics can in turn influence the risk of food allergy development through epigenetic mechanisms. Epigenetic programming accounts not only for the short-term effects on the individual's health status, but also for those observed in adulthood. The first thousand days of life represent an important window of susceptibility in which environmental factors, including nutritional ones, can influence the risk of developing allergies through epigenetic mechanisms. From this point of view, it represents an interesting window of opportunity and intervention. This review reports the main nutritional factors that in the early stages of life can influence immune oral tolerance through the modulation of epigenetic mechanisms.

Fish Roe-Induced Anaphylaxis in Italy: A Pediatric Case Report.

Fish roe are not yet described as triggers of allergic reactions in Italy, especially during the pediatric age; they are more frequently involved in anaphylaxis in Eastern countries, such as Japan. For this report, we reported a case of anaphylaxis in a 2-year-old boy admitted to our Hospital Pediatric Emergency Room with a suspected allergic reaction. 15 min after the meal, he presented generalized urticaria, angioedema, wheezing, sneezing, and two vomiting episodes. The meal was smoked salmon, butter, mayonnaise, anchovies, and fish roe (salmon and lumpfish roe). Tryptase serum levels presented as elevated in the acute phase and normal after 24 h. Serum food-specific IgE tested negative for salmon and other fish, such as skin prick tests. Serum food-specific IgE showed that the patient was sensitized to cow's milk and eggs, but he doesn't have a food allergy. He had regularly consumed milk and eggs before and after the allergic reaction without clinical problems. A prick-by-prick test resulted positive for fish roe (salmon and lumpfish roe). Based on patient's history, allergy test results in vivo, and tryptase serum levels, the diagnosis of anaphylaxis induced by fish roe was confirmed. In conclusion, to the best of our knowledge, this is the first pediatric case of fish roe-induced anaphylaxis reported in Italy.

Clinical Outcome of Discordant Empirical Therapy and Risk Factors Associated to Treatment Failure in Children Hospitalized for Urinary Tract Infections.

With the spread of antibiotic resistance in pediatric urinary tract infections (UTIs), more patients are likely to be started empirically on antibiotics to which pathogens are later found to be resistant (discordant therapy). However, in-vivo effectiveness may be different from in-vitro susceptibility. Aims of this study were to describe clinical outcomes of discordant empirical treatments in pediatric UTIs and to investigate risk factors associated to treatment failure. This observational, retrospective study was conducted on children hospitalized for febrile UTIs with positive urine culture and started on discordant empirical therapy. Failure rates of discordant treatments and associated risk factors were investigated. A total of 142/1600 (8.9%) patients were treated with inadequate empirical antibiotics. Clinical failure was observed in 67/142 (47.2%) patients, with no fatal events. Higher failure rates were observed for combinations of penicillin and beta-lactamase inhibitors (57.1%). Significant risk factors for failure of discordant treatment were history of recurrent UTIs (95% CI: 1.13-9.98, OR: 3.23, p < 0.05), recent use of antibiotics (95% CI: 1.46-21.82, OR: 5.02, p < 0.01), infections caused by Pseudomonas aeruginosa (95% CI: 1.85-62.10, OR: 7.30, p < 0.05), and empirical treatment with combinations of penicillin and beta-lactamase inhibitors (95% CI: 0.94-4.03, OR: 1.94, p = 0.05). This study showed that discordant empirical treatments may still be effective in more than half of pediatric UTIs. Clinical effectiveness varies between different discordant antibiotics in pediatric UTIs, and patients presenting risk factors for treatment failure may need a differentiated empirical approach.

Retrospective 8-Year Study on the Antibiotic Resistance of Uropathogens in Children Hospitalised for Urinary Tract Infection in the Emilia-Romagna Region, Italy.

The development and spread of antibiotic resistance is an increasingly important global public health problem, even in paediatric urinary tract infection (UTI). In light of the variability in the data, it is necessary to conduct surveillance studies to determine the prevalence of antibiotic resistance in specific geographical areas to optimize therapeutic management. In this observational, retrospective, multicentre study, the medical records of 1801 paediatric patients who were hospitalised for UTI between 1 January 2012, and 30 June 2020, in Emilia-Romagna, Italy, were analysed. Escherichia coli was the most frequently detected pathogen (75.6%), followed by Klebsiella pneumoniae (6.9%) and Pseudomonas aeruginosa (2.5%). Overall, 840 cases (46.7%) were due to antimicrobial-resistant uropathogens: 83 (4.7%) extended spectrum beta-lactamase (ESBL)-producing, 119 (6.7%) multidrug resistant (MDR) and 4 (0.2%) extensively drug resistant (XDR) bacteria. Empirical antibiotic therapy failed in 172 cases (9.6%). Having ESBL or MDR/XDR uropathogens, a history of recurrent UTI, antibiotic therapy in the preceding 30 days, and empirical treatment with amoxicillin or amoxicillin/clavulanate were significantly associated with treatment failure, whereas first-line therapy with third-generation cephalosporins was associated with protection against negative outcomes. In conclusion, the increase in the resistance of uropathogens to commonly used antibiotics requires continuous monitoring, and recommendations for antibiotic choice need updating. In our epidemiological context, amoxicillin/clavulanate no longer seems to be the appropriate first-line therapy for children hospitalised for UTI, whereas third-generation cephalosporins continue to be useful. To further limit the emergence of resistance, every effort to reduce and rationalise antibiotic consumption must be implemented.

Lactose Intolerance in Pediatric Patients and Common Misunderstandings About Cow's Milk Allergy.

Lactose intolerance is a common gastrointestinal condition caused by the inability to digest and absorb dietary lactose. Primary lactose intolerance is the most common type of lactose intolerance. It is one of the most common forms of food intolerance and occurs when lactase activity is reduced in the brush border of the small bowel mucosa. People may be lactose intolerant to varying degrees, depending on the severity of these symptoms. When lactose is not digested, it is fermented by gut microbiota, leading to abdominal pain, bloating, flatulence, and diarrhea with a considerable intraindividual and interindividual variability in the severity of clinical manifestations. These gastrointestinal symptoms are similar to cow's milk allergy and could be wrongly labeled as symptoms of "milk allergy." There are important differences between lactose intolerance and cow's milk allergy. Therefore, a better knowledge of these differences could limit misunderstandings in the diagnostic approach and in the management of these conditions. [Pediatr Ann. 2021;50(4):e178-e185.].

Anaphylaxis caused by artisanal honey in a child: a case report.

BACKGROUND: Honey is a rare cause of food allergy, especially in children, but it can cause severe systemic allergic reactions. In the pediatric age group, only a few cases have been reported in the literature. Honey allergy may be caused by pollen content or bee-derived proteins. A role for Compositae has been suggested among pollen allergens. Allergology workup of a patient with suspected honey allergy is not well defined. Here we describe a rare case of anaphylaxis in a 5-year-old boy, sensitized to Compositae pollen (ragweed and mugwort), after the ingestion of artisanal honey. CASE PRESENTATION: The Slavic patient was referred to our hospital emergency department for generalized urticaria and breathing impairment. All the symptoms occurred approximately 30 minutes after the ingestion of a meal containing salmon and artisanal honey. The allergology workup revealed that a skin prick-by-prick test with the implicated artisanal honey was positive, while a variety of different commercial honey and salmon products yielded negative results. Skin prick test and serum-specific immunoglobulin E (IgE) results were also positive for Compositae pollen (ragweed and mugwort). Patients sensitized to weed pollens who ingest bee products may experience an immediate allergic reaction because of the cross-reaction between weed pollens and Compositae bee product pollen. In this case, primary sensitization may be due to airborne Compositae pollen. Commercial honey is heavily processed due to pasteurization and filtration, which removes most of the pollen. These observations highlight the role of Compositae pollen in the observed allergic reaction and suggest that the different pollen content in the artisanal honey relative to commercial honey was responsible for the allergic reaction in our patient. CONCLUSIONS: This is the first reported pediatric case of honey-induced anaphylaxis in a child under 6 years of age sensitized to Compositae pollen. Pediatricians should be aware of the potential risk of severe allergic reactions upon ingestion of honey and bee products, especially in patients sensitized to weed pollens. To diagnose honey allergy, obtaining a proper clinical history is essential. In addition, skin prick-by-prick tests are helpful, and may represent a simple method to screen for honey allergy in patients sensitized to Compositae pollen, in light of the potential risk.

Butyrate: A Link between Early Life Nutrition and Gut Microbiome in the Development of Food Allergy.

Increased prevalence of food allergies in the last thirty years has been attributed to lifestyle changes in Westernized countries. Among the environmental factors, nutritional factors and their interaction with the gut microbiome in early life are thought to have an important role in the observed epidemiological change. The gut microbiome synthesizes bacterial metabolites, which represent a link among gut microbiome, nutrition, and immune system. The main metabolites produced by gut microbiome are short-chain fatty acids (SCFAs). SCFAs have multiple beneficial effects on human health including protective effects in autoimmune and inflammatory diseases. Among SCFAs, butyrate is essential for maintaining gut immune homeostasis and exerts a pivotal role in immune tolerance with strong anti-inflammatory effects in allergic diseases. Recent findings suggest that butyrate takes part in the development of immunological tolerance to food, especially in the first 1000 days of life. Herein, we provide a critical review of the scientific literature on the role of butyrate for prevention and treatment of food allergies with focus on the complex interplay among early life nutrition, gut microbiome, and immune system.

Butyrate as a bioactive human milk protective component against food allergy.

BACKGROUND: Food allergy (FA) is a growing health problem worldwide. Effective strategies are advocated to limit the disease burden. Human milk (HM) could be considered as a protective factor against FA, but its mechanisms remain unclear. Butyrate is a gut microbiota-derived metabolite able to exert several immunomodulatory functions. We aimed to define the butyrate concentration in HM, and to see whether the butyrate concentration detected in HM is able to modulate the mechanisms of immune tolerance. METHODS: HM butyrate concentration from 109 healthy women was assessed by GS-MS. The effect of HM butyrate on tolerogenic mechanisms was assessed in in vivo and in vitro models. RESULTS: The median butyrate concentration in mature HM was 0.75 mM. This butyrate concentration was responsible for the maximum modulatory effects observed in all experimental models evaluated in this study. Data from mouse model show that in basal condition, butyrate up-regulated the expression of several biomarkers of gut barrier integrity, and of tolerogenic cytokines. Pretreatment with butyrate significantly reduced allergic response in three animal models of FA, with a stimulation of tolerogenic cytokines, inhibition of Th2 cytokines production and a modulation of oxidative stress. Data from human cell models show that butyrate stimulated human beta defensin-3, mucus components and tight junctions expression in human enterocytes, and IL-10, IFN-γ and FoxP3 expression through epigenetic mechanisms in PBMCs from FA children. Furthermore, it promoted the precursors of M2 macrophages, DCs and regulatory T cells. CONCLUSION: The study's findings suggest the importance of butyrate as a pivotal HM compound able to protect against FA.

Gut Microbiome Modulation for Preventing and Treating Pediatric Food Allergies.

The increasing prevalence and severity of pediatric food allergies (FA) demands innovative preventive and therapeutic strategies. Emerging evidence suggests a pivotal role for the gut microbiome in modulating susceptibility to FA. Studies have demonstrated that alteration of gut microbiome could precede FA, and that particular microbial community structures early in life could influence also the disease course. The identification of gut microbiome features in pediatric FA patients is driving new prevention and treatment approaches. This review is focused on the potential role of the gut microbiome as a target for FA prevention and treatment.

Dietary Treatment with Extensively Hydrolyzed Casein Formula Containing the Probiotic Lactobacillus rhamnosus GG Prevents the Occurrence of Functional Gastrointestinal Disorders in Children with Cow's Milk Allergy.

OBJECTIVE: To investigate whether the addition of the probiotic Lactobacillus rhamnosus GG (LGG) to the extensively hydrolyzed casein formula (EHCF) for cow's milk allergy (CMA) treatment could reduce the occurrence of functional gastrointestinal disorders (FGIDs). STUDY DESIGN: This cohort study included children with a positive history for CMA in the first year of life who were treated with EHCF alone or in combination with LGG and had evidence of immune tolerance acquisition to cow's milk for at least 12 months. FGID was diagnosed according to the Rome III diagnostic criteria by investigators unaware of previous treatment. A cohort of consecutive healthy children was also evaluated as a control population. RESULTS: A total of 330 subjects were included, 110 per cohort (EHCF, EHCF+LGG, and healthy controls). The rate of subjects with ≥1 FGID was significantly lower in the EHCF+LGG cohort compared with the EHCF cohort (40% vs 16.4%; P < .05). In the EHCF+LGG cohort, a lower incidence was observed for all components of the main study outcome. The prevalence of FGIDs in the healthy cohort was lower than that in the EHCF cohort and similar to that in the EHCF+LGG cohort. The incidence rate ratio of FGIDs for the EHCF+LGG cohort vs the EHCF cohort (0.40; 95% CI, 0.25-0.65; P < .001) was unmodified after correction for age at CMA diagnosis, breastfeeding, weaning time, and presence of a first-degree relative with an FGID. CONCLUSIONS: These results confirm the increased risk for developing FGIDs in children with CMA and suggest that EHCF+LGG could reduce this risk.

Publisher Correction: Randomized controlled trial on the influence of dietary intervention on epigenetic mechanisms in children with cow's milk allergy: the EPICMA study.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Randomized controlled trial on the influence of dietary intervention on epigenetic mechanisms in children with cow's milk allergy: the EPICMA study.

Epigenetic mechanisms could drive the disease course of cow's milk allergy (CMA) and formula choice could modulate these pathways. We compared the effect of two different dietary approaches on epigenetic mechanisms in CMA children. Randomized controlled trial on IgE-mediated CMA children receiving a 12-month treatment with extensively hydrolyzed casein formula containing the probiotic L.rhamnosus GG (EHCF + LGG) or with soy formula (SF). At the baseline, after 6 and 12 months of treatment FoxP3 methylation rate and its expression in CD4+ T cells were assessed. At same study points IL-4, IL-5, IL-10, and IFN-γ methylation rate, expression and serum concentration, miRNAs expression were also investigated. 20 children (10/group) were evaluated. Baseline demographic, clinical and epigenetic features were similar in the two study groups. At 6 and 12 months, EHCF + LGG group showed a significant increase in FoxP3 demethylation rate compared to SF group. At the same study points, EHCF + LGG group presented a higher increase in IL-4 and IL-5 and a higher reduction in IL-10 and IFN-γ DNA methylation rate compared to SF group. A different modulation of miR-155, -146a, -128 and -193a expression was observed in EHCF + LGG vs. SF. Dietary intervention could exert a different epigenetic modulation on the immune system in CMA children.

Targeting Food Allergy with Probiotics.

The dramatic increase in food allergy prevalence and severity globally is demanding effective strategies. Food allergy derives from a defect in immune tolerance mechanisms. Immune tolerance is modulated by gut microbiota composition and function, and gut microbiota dysbiosis has been associated with the development of food allergy. Selected probiotic strains could act on immune tolerance mechanisms. The mechanisms are multiple and still not completely defined. Increasing evidence is providing useful information on the choice of optimal bacterial species/strains, dosage, and timing for intervention. The increased knowledge on the crucial role played by gut microbiota-derived metabolites, such as butyrate, is also opening the way to a post-biotic approach in the stimulation of immune tolerance.

Lactose Intolerance: Common Misunderstandings.

Lactose intolerance primarily refers to a syndrome having different symptoms upon the consumption of foods containing lactose. It is one of the most common form of food intolerance and occurs when lactase activity is reduced in the brush border of the small bowel mucosa. Individuals may be lactose intolerant to varying degrees, depending on the severity of these symptoms. When lactose is not digested, it can be fermented by gut microbiota leading to symptoms of lactose intolerance that include abdominal pain, bloating, flatulence, and diarrhea with a considerable intraindividual and interindividual variability in the severity of clinical manifestations. These gastrointestinal symptoms could be similar to cow's milk allergy and could be wrongly labeled as symptoms of "milk allergy." There are important differences between lactose intolerance and cow's milk allergy; therefore, a better knowledge of these differences could limit misunderstandings in the diagnostic approach and in the management of these conditions.

Gut Microbiota as a Target for Preventive and Therapeutic Intervention against Food Allergy.

The gut microbiota plays a pivotal role in immune system development and function. Modification in the gut microbiota composition (dysbiosis) early in life is a critical factor affecting the development of food allergy. Many environmental factors including caesarean delivery, lack of breast milk, drugs, antiseptic agents, and a low-fiber/high-fat diet can induce gut microbiota dysbiosis, and have been associated with the occurrence of food allergy. New technologies and experimental tools have provided information regarding the importance of select bacteria on immune tolerance mechanisms. Short-chain fatty acids are crucial metabolic products of gut microbiota responsible for many protective effects against food allergy. These compounds are involved in epigenetic regulation of the immune system. These evidences provide a foundation for developing innovative strategies to prevent and treat food allergy. Here, we present an overview on the potential role of gut microbiota as the target of intervention against food allergy.

Extensively hydrolyzed casein formula containing Lactobacillus rhamnosus GG reduces the occurrence of other allergic manifestations in children with cow's milk allergy: 3-year randomized controlled trial.

BACKGROUND: Children with cow's milk allergy (CMA) have an increased risk of other allergic manifestations (AMs). OBJECTIVE: We performed a parallel-arm randomized controlled trial to test whether administration of an extensively hydrolyzed casein formula (EHCF) containing the probiotic Lactobacillus rhamnosus GG (LGG) can reduce the occurrence of other AMs in children with CMA. METHODS: Children with IgE-mediated CMA were randomly allocated to the EHCF or EHCF+LGG groups and followed for 36 months. The main outcome was occurrence of at least 1 AM (eczema, urticaria, asthma, and rhinoconjunctivitis). The secondary outcome was tolerance acquisition, which was defined as the negativization of a double-blind food challenge results at 12, 24, and 36 months. AMs were diagnosed according to standardized criteria. Tolerance acquisition was evaluated every 12 months. RESULTS: A total of 220 children (147 boys [67%]) with a median age of 5.0 months (interquartile range, 3.0-8.0 months) were randomized; 110 children were placed in the EHCF group, and 110 children were placed in the EHCF+LGG group. In the complete case analysis the absolute risk difference for the occurrence of at least 1 AM over 36 months was -0.23 (95% CI, -0.36 to -0.10; P < .001), and the absolute risk difference for the acquisition of cow's milk tolerance was 0.20 (95% CI, 0.05-0.35; P < .01) at 12 months, 0.24 (95% CI, 0.08-0.41; P < .01) at 24 months, and 0.27 (95% CI, 0.11-0.43; P < .001) at 36 months. In the sensitivity analysis the effect size of the main outcome was virtually unchanged when the occurrence of AMs was assigned to all 27 missing children. CONCLUSIONS: EHCF+LGG reduces the incidence of other AMs and hastens the development of oral tolerance in children with IgE-mediated CMA.