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Cow's milk allergy (CMA) is one of the most common presentations of food allergy in early childhood. Management of CMA involves individualized avoidance of cow's milk and other mammalian milk and foods containing these. Optimal elimination of cow's milk avoidance includes: label reading; information about safe and nutritious substitute foods; appropriate choice of infant formula or a plant-based food; establishing tolerance to baked milk and monitoring nutritional intake and growth. Substitute formulas are divided into soy formula (not hydrolyzed), milk-based extensively hydrolyzed formulas, rice based extensive, and partially hydrolyzed formulas and amino acid-based formulas. The use of other mammalian milks is not recommended for the management of cow's milk allergy due to a high level of cross-reactivity and nutritional concerns. For toddlers who are eating well, children, and adults, a suitable plant-based beverage may be a suitable alternative to a specialized formula, following careful nutritional considerations. Families need to be instructed on finding suitable nutritious foods and how to prepare suitable meals at home. Individuals with CMA also need to know how to identify and treat acute severe reactions.

Background: Cow's milk allergy (CMA) is the most common food allergy in infants. The replacement with specialized formulas is an established clinical approach to ensure adequate growth and minimize the risk of severe allergic reactions when breastfeeding is not possible. Still, given the availability of multiple options, such as extensively hydrolyzed cow's milk protein formula (eHF-CM), amino acid formula (AAF), hydrolyzed rice formula (HRF) and soy formulas (SF), there is some uncertainty as to the most suitable choice with respect to health outcomes. Furthermore, the addition of probiotics to a formula has been proposed as a potential approach to maximize benefit. Objective: These evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of milk specialized formulas, with and without probiotics, for individuals with CMA. Methods: WAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to review by stakeholders. Results: After reviewing the summarized evidence and thoroughly discussing the different management options, the WAO guideline panel suggests: a) using an extensively hydrolyzed (cow's milk) formula or a hydrolyzed rice formula as the first option for managing infants with immunoglobulin E (IgE) and non-IgE-mediated CMA who are not being breastfed. An amino-acid formula or a soy formula could be regarded as second and third options respectively; b) using either a formula without a probiotic or a casein-based extensively hydrolyzed formula containing Lacticaseibacillus rhamnosus GG (LGG) for infants with either IgE or non-IgE-mediated CMA.The issued recommendations are labeled as “conditional” following the GRADE approach due to the very low certainty about the health effects based on the available evidence. Conclusions: If breastfeeding is not available, clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable consequences of each formula in infants with CMA, integrating them with the patients' and caregivers’ values and preferences, local availability, and cost, before deciding on a treatment option. We also suggest what research is needed to determine with greater certainty which formulas are likely to be the most beneficial, cost-effective, and equitable.

In many parts of the world, goat milk has been part of the human diet for millennia. Allergy to goat’s milk, not associated with allergy to cow’s milk, is a rare disorder, although some cases have been described. Goat milk proteins have substantial homology with cow’s milk proteins and even show cross-reactivity; therefore, they are not advised as an alternative to cow’s milk for infants with IgE-mediated cow’s milk allergies. However, there are indications that, due to the composition of the goat milk proteins, goat milk proteins show lower allergenicity than cow’s milk due to a lower αS1-casein content. For this reason, goat milk might be a better choice over cow’s milk as a first source of protein when breastfeeding is not possible or after the breastfeeding period. Additionally, some studies show that goat milk could play a role in specific types of non-IgE-mediated cow milk allergy or even in the prevention of sensitization to cow’s milk proteins. This review discusses a possible role of goat milk in non-IgE mediated allergy and the prevention or oral tolerance induction of milk allergy.

Cow's milk allergy is rare in exclusively breastfed infants. To support the continuation of breastfeeding an infant after diagnosis with a cow's milk allergy, it is critical to examine the evidence for and against any form of cow's milk elimination diet for lactating mothers. In this narrative review, we highlight the lack of high-quality evidence, hence subsequent controversy, regarding whether the minuscule quantities of cow's milk proteins detectable in human milk cause infant cow's milk allergy symptoms. Current clinical practice recommendations advise a 2–4 week trial of maternal cow's milk dietary elimination for: a) IgE-mediated cow's milk allergy only if the infant is symptomatic on breastfeeding alone; b) non-IgE-mediated associated symptoms only if the history and examination strongly suggest cow's milk allergy; and c) infants with moderate to severe eczema/atopic dermatitis, unresponsive to topical steroids and sensitized to cow's milk protein. There should be a clear plan for home reintroduction of cow's milk into the maternal diet for a period of 1 week to determine that the cow's milk elimination is responsible for resolution of symptoms, and then subsequent reoccurrence of infant symptoms upon maternal cow's milk reintroduction. The evidence base to support the use of maternal cow's milk avoidance for the treatment of a breastfed infant with cow's milk allergy is of limited strength due to a lack of high-quality, adequately powered, randomised controlled trials. It is important to consider the consequences of maternal cow's milk avoidance on reducing immune enhancing factors in breast milk, as well as the potential nutritional and quality of life impacts on the mother. Referral to a dietitian is advised for dietary education, along with calcium and vitamin D supplementation according to local recommendations, and a maternal substitute milk should be advised. However, for most breastfed infants with cow's milk allergy maternal cow's milk dietary elimination will not be required, and active support of the mother to continue breastfeeding is essential.

Background: Allergic diseases are increasing globally and are a significant public health challenge, especially in children. Cow's milk allergy (CMA) is one of the most common food allergies in early childhood. When CMA is diagnosed and exclusive breastfeeding is not possible, current guidelines recommend extensively hydrolyzed formulas (eHF) or amino acid-based formulas (AAF), depending on the diagnosis and severity of symptoms. Hydrolyzed rice formulas (HRF) are considered an alternative to eHF and AAF where available. Objectives & methods: We aimed to understand how HRF are being used and their position in the management of CMA, and to generate consensus on indications for use. Two virtual roundtables of international healthcare experts in pediatric food allergy focused on HRF were convened in May and October 2021. Experts provided multiple perspectives due to different specialties, locations, healthcare settings, and availability of HRF. Following discussion of international CMA guidelines and HRF use, identification of challenges along the diagnosis and treatment pathway, and translation of guidelines into clinical practice, an expert consensus on the use of HRF for CMA was developed. This involved repeated voting followed by statement amendment to reach 100% agreement. This publication summarizes insights from these meetings. Results: There was 100% agreement on all 8 statements: (1) While breastmilk is the best source of nutrition for infants with CMA, when breastfeeding is not possible, a hypoallergenic formula can be used; (2) Per definition, a HRF is cow's milk protein-free; (3) A minority of infants with immunoglobulin (Ig)E-mediated CMA react to eHF due to residual cow's milk protein; (4) More infants with non-IgE-mediated CMA than IgE-mediated CMA react to eHF likely due to residual cow's milk protein; (5) When a diagnostic elimination diet is indicated, HRF can be used; (6) A HRF can be recommended as a first-line option for CMA, where available, as outlined in the Diagnosis and Rationale for Action against Cow's Milk Allergy guidelines; (7) HRFs have proven hypoallergenicity and are suitable for the dietary management of CMA; (8) HRFs have been shown to support growth in infants with CMA, similar to other hypoallergenic formulas. Participants recommend healthcare professionals take these statements as guidance to use HRF in clinical practice. Based on efficacy and growth evidence, the experts found HRF a suitable option for the dietary management of CMA. Conclusion: HRF can be recommended as a first-line alternative to cow's milk-based eHF or AAF, where available, in the dietary management of CMA.

Background: Allergy to cow's milk is the most common food allergy in infants and it is usually outgrown by 5 years of age. In some individuals it persists beyond early childhood. Oral immunotherapy (OIT, oral desensitization, specific oral tolerance induction) has been proposed as a promising therapeutic strategy for persistent IgE-mediated cow's milk allergy. We previously published the systematic review of OIT for cow's milk allergy (CMA) in 2010 as part of the World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. Objective: To systematically synthesize the currently available evidence about OIT for IgE-mediated CMA and to inform the updated 2022 WAO guidelines. Methods: We searched the electronic databases including PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations. We included all studies irrespective of the language of the original publication. The last search was conducted in February 2021. We registered the protocol on Open Science Framework (10.17605/OSF.IO/AH2DT). Results: We identified 2147 unique records published between 2010 and 2021, including 13 randomized trials and 109 observational studies addressing cow's milk OIT. We found low-certainty evidence that OIT with unheated cow's milk, compared to elimination diet alone, increased the likelihood of being able to consume ≥150 ml of cow's milk in controlled settings (risk ratio (RR): 12.3, 95% CI: 5.9 to 26.0; risk difference (RD): 25 more per 100, 95% CI 11 to 56) as well as accidently ingest a small amount (≥5 ml) of cow's milk (RR: 8.7, 95% CI: 4.7 to 16.1; RD: 25 more per 100, 95% CI 12 to 50). However, 2–8 weeks after discontinuation of a successful OIT, tolerance of cow's milk persisted in only 36% (range: 20%–91%) of patients. OIT increased the frequency of anaphylaxis (rate ratio: 60.0, 95% CI 15 to 244; rate difference 5 more anaphylactic reactions per 1 person per year, 95% CI: 4 to 6; moderate evidence) and the frequency of epinephrine use (rate ratio: 35.2, 95% CI: 9 to 136.5; rate difference 268 more events per 100 person-years, 95% CI: 203 to 333; high certainty). OIT also increased the risk of gastrointestinal symptoms (RR 6.9, 95% CI 1.6–30.9; RD 28 more per 100, CI 3 to 100) and respiratory symptoms (RR 49.0, 95% CI 3.12–770.6; RD 77 more per 100, CI 62 to 92), compared with avoidance diet alone. Single-arm observational studies showed that on average 6.9% of OIT patients (95% CI: 3.8%–10%) developed eosinophilic esophagitis (very low certainty evidence). We found 1 trial and 2 small case series of OIT with baked milk. Conclusions: Moderate certainty evidence shows that OIT with unheated cow's milk in patients with IgE-mediated CMA is associated with an increased probability of being able to drink milk and, at the same time, an increased risk of serious adverse effects.

Background: The prevalence of cow's milk allergy (CMA) is approximately 2–4.5% in infants and less than 0.5% in adults. Most children outgrow cow's milk allergy in early childhood, particularly that to the baked milk products. Immunotherapy with unheated cow's milk has been used as a treatment option for those who have not yet outgrown CMA, but the benefits must be balanced with the adverse effects. Objective: These evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of oral and epicutaneous immunotherapy for the treatment of IgE-mediated CMA. Methods: WAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to public comment. Results: After a careful review of the summarized evidence and thorough discussions the WAO guideline panel suggests: a) using oral immunotherapy with unheated cow's milk in those individuals with confirmed IgE-mediated CMA who value the ability to consume controlled quantities of milk more than avoiding the large adverse effects of therapy, b) not using oral immunotherapy with unheated cow's milk in those who value avoiding large adverse effects of therapy more than the ability to consume controlled quantities of milk, c) using omalizumab in those starting oral immunotherapy with unheated cow's milk, d) not using oral immunotherapy with baked cow's milk in those who do not tolerate both unheated and baked milk, and e) not using epicutaneous immunotherapy outside of a research setting. The recommendations are labeled “conditional” due to the low certainty about the health effects based on the available evidence. Conclusions: Clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable effects of oral immunotherapy for IgE-mediated CMA and integrate them with the patients' values and preferences before deciding on a treatment option. More robust research is needed to determine with greater certainty which interventions are likely to be the most beneficial with the least harms, and to develop safer, low-cost, and equitable treatments.

Since the World Allergy Organization (WAO) Diagnosis and Rationale against Cow's Milk Allergy (DRACMA) Guidelines were published 10 years ago, new evidence has accumulated about the diagnosis, therapy, and specific immunotherapy for cow's milk allergy (CMA). For this reason, WAO has felt the need to update the guidelines.We introduce here this update. The new DRACMA guidelines aim to comprehensively address the guidance on diagnosis and therapy of both IgE non-IgE-mediated forms of cow's milk allergy in children and adults. They will be divided into 18 chapters, each of which will be dedicated to an aspect. The focus will be on the meta-analyzes and recommendations that will be expressed for the 3 most relevant clinical aspects: (a) the diagnostic identification of the condition; (b) the choice of the replacement formula in case of CMA in infancy when the mother is not able to breastfeed, and (c) the use of specific immunotherapy for cow's milk protein allergy.

CoMiSS® was developed 7 years ago to increase the awareness of health care professionals towards the possibility that symptoms presented by infants could be related to cow’s milk. While CoMiSS was conceived mostly on theoretical concepts, data is now available from 25 clinical trials. Based on this extensive research using the tool since 2015, we aim to propose an updated CoMiSS. The evidence was reviewed, debated and discussed by 10 experts, of whom seven were part of the original group. The panel concluded that the cut-off previously proposed to indicate the likelihood that symptoms may be cow’s milk related should be lowered from ≥12 to ≥10. Data in healthy infants > 6 months are missing. Since the Brussels Infant and Toddlers Stool Scale (BITSS) was recently developed for non-toilet trained children, the Bristol Stool Scale was changed to the BITSS without changing the impact of stool characteristics on CoMiSS. Overall, CoMiSS raises awareness that symptoms might be cow’s milk related. New studies are needed to determine if the change in cut-off and other small adaptions improve its sensitivity and specificity. Data for CoMiSS is still needed in presumed healthy infants between 6 and 12 months old. There may also be regional differences in CoMiSS, in healthy infants as well as in those with cow’s milk allergy. Finally, we emphasize that CoMiSS is an awareness tool and not a diagnostic test.

The Cow’s Milk-related Symptom Score (CoMiSS™) was developed as a clinical tool aimed at increasing the awareness of health care professionals for the presence and intensity of clinical manifestations possibly related to cow’s milk (CM) intake. This review summarizes current evidence on CoMiSS. We found twenty-five original studies, one pooled analysis of three studies, and two reviews on CoMiSS. Infants exhibiting symptoms possibly related to CM, present with a higher median CoMiSS (6 to 13; 16 studies) than apparently healthy infants (median from 3 to 4; and mean 3.6–4.7; 5 studies). In children with cow’s milk allergy (CMA), 11 studies found that a CoMiSS of ≥12 predicted a favorable response to a CM-free diet; however, sensitivity (20% to 77%) and specificity (54% to 92%) varied. The decrease of CoMiSS during a CM elimination diet was also predictive of a reaction to an oral food challenge to diagnose CMA. A low CoMiSS (p < 0.001) in repeated assessments. This review found that CoMiSS cannot be considered as a stand-alone CMA diagnostic tool, but that it is a useful awareness tool for CMA as well as for monitoring symptom improvement.

Symptoms related cow’s milk proteins allergy (CMPA) usually improve between two to four weeks following an elimination diet, firstly with extensively hydrolyzed formulas (eHF). The aim of the EVA study was to observe the evolution of CMPA-related symptoms in real life after initiation of a whey-based extensively hydrolyzed formula (w-eHF, Althéra®, Nestlé Health Science, Switzerland). This cross-sectional prospective non-interventional study was carried out alongside paediatricians in private practice in France between June 2019 and June 2020. Infants aged 0–3 years presenting with confirmed diagnosis or clinical symptoms suggesting CMPA were enrolled. Data were collected at enrolment (baseline visit) and three to five weeks later (follow-up visit). Symptoms were assessed using the Cow’s Milk-related Symptom Score (CoMiSS®). The per protocol population included 135 infants. The average number of symptoms per infant significantly decreased under the study formula (from 2.81 to 1.36, p < 0.001) and the proportions of infants with any CMPA related symptoms decreased. Daily crying and regurgitation showed the largest decline, respectively −44.4% and −31.85% (p < 0.001). These results describe the early management of symptoms suspected to be related to CMPA in routine practice that was rarely described in the literature. The number and severity of symptoms decreased most of the cases after commencing the study formula.

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

Cow’s milk allergy (CMA) is the most common food allergy in early childhood, and its prevalence continues to rise. Exclusive breastfeeding is recommended for infants in the first 6 months of life, but this recommendation is poorly adhered to in many parts of the world, including the Middle East, North Africa, and Pakistan (MENAP) region. If the infant is affected by CMA, current guidelines recommend extensively hydrolyzed formulas (eHFs) or amino acid-based formulas (AAFs) in the case of severe symptoms, and hydrolyzed rice formulas (HRFs) where available. In recent years, HRFs have been proposed as a plant-based alternative to cow’s milk protein-based eHFs, and updates to current guidelines have been recommended. In 2014, a consensus statement and guidelines were published for the Middle East region on the prevention, diagnosis, and management of CMA. As new advances have been made in the extensively hydrolyzed hypoallergenic infant formula space, along with updated scientific evidence, a workshop of experts from the MENAP region focused on HRF was convened in 2021. This publication summarizes the insights from this meeting. During the consensus part of the meeting, a new approach was discussed and approved by all participants, and agreement was reached that HRF can be recommended as a first-line alternative to cow’s milk-based eHF in the dietary management of CMA.

Background: Epicutaneous immunotherapy (EPIT®), currently investigated in the treatment of food allergy, needs the integrity of the skin to warrant safety and efficacy. Mutations in the gene encoding the key epidermal protein filaggrin (FLG) are risk factors for peanut allergy and disrupt the skin intergrity. We investigated the association between FLG deficiency and peanut EPIT® efficacy in a murine model. Methods: FLG mutant mice deficient in filaggrin (FLG-/-) or wild-type (WT) mice were sensitized with peanut protein extract (peanut protein) and cholera toxin. Sensitized mice received a patch per week during 8 weeks for EPIT®, using Viaskin®, and were then submitted to sustained peanut oral exposure. We assessed blood humoral and cellular responses and evaluated eosinophil infiltration in the gut mucosa. The different steps of allergen capture and transportation following deposition on the skin was also analyzed in sensitized mice. Results: Sensitization of mice was confirmed by a significant increase of specific Th2 biaised immunological responses. In sensitized mice, EPIT® significantly reduced IgE levels, splenocytes secretion of Th2 cytokines and recruitment of eosinophils in esophagus, compared to sensitized mice without epicutaneous immunotherapy. The allergen applied onto the skin of FLG-/- mice did not undergo passive skin passage or systemic delivery. Instead, the allergen was captured by skin CD205high DCs, which migrated to afferent lymph nodes, as already described in WT mice. Conclusions: EPIT® was efficient and safe in FLG-/- mice, suggesting that in Humans EPIT® keeps efficacy and safety in the presence of loss of function of FLG.

Abstract Background In 2010, the diagnosis and treatment of IgE-mediated CMA were systematized in a GRADE guideline. Objectives & methods After 6 years, the state of the knowledge in diagnosis and treatment of CMA has largely evolved. We summarize here the main advances, and exemplify indicating some specific points: studies aimed at better knowledge of the effects of breastfeeding and the production of new special formulae intended for the treatment of CMA. The literature (PubMed/MEDLINE) was searched using the following algorithms: (1) [milk allergy] AND diagnosis; (2) [milk allergy] AND [formul*] OR [breast*], setting the search engine [6-years] time and [human] limits. The authors drew on their collective clinical experience to restrict retrieved studies to those of relevance to a pediatric allergy practice. Results Several clinical studies did address the possibility to diagnose CMA using new tools in vitro and in vivo, or to diagnose it without any evaluation of sensitization. Some studies also addressed the clinical role of formulae based on milk hydrolysates, soy, or rice hydrolysates in the treatment of CMA. Many studies have elucidated the effects of selective nutrients in breastfed infants on their immunologic and neurologic characteristics. Conclusions Evidence-based diagnostic criteria should be identified for non-IgE-mediated CMA. Debate is ongoing about the best substitute for infants with CMA. In particular, Hydrolyzed Rice Formulae have been widely assessed in the last six years. In the substitute choice, clinicians should be aware of recent studies that can modify the interpretation of the current recommendations. New systematic reviews and metanalyses are needed to confirm or modify the current DRACMA recommendations.

Formulas adapted to infant feeding, although most of the time made from cow’s milk proteins, can be made from hydrolyzed rice protein but they must be classified as “formulas for specific medical needs”, according to European regulations. The nutritional quality of rice proteins is thus suitable to be used in infant formulas giving that it is supplemented by certain amino acids which can be lacking. Besides, hydrolysis is required to facilitate their water solubility and digestibility. Owing to a low allergenicity of rice and to the absence of the cross-allergy between milk proteins and rice proteins, these formulas are adapted to the diet of children with cow’s milk protein allergy (CMPA), which explains their growing use in some countries. However, CMPA, an expanding disorder, has consequences for growth, bone mineralization, and often has an association with allergy to other foods, including cow’s milk extensive hydrolysate, so that a surveillance of the adaption of hydrolyzed rice protein formulas (HRPF) to CMPA, the absence of unexpected side effects, and the appropriate response to its various health hazards seems mandatory. This paper analyses the health problem deriving from CMPA, the industrial development of hydrolyzed rice protein formulas, and the limited number of clinical studies, which confirms, at the moment, a good allergic tolerance and safety. The goal is to better advise heath care professionals on their use of HRPFs during CMPA.

Functional constipation (FC) is a chronic constipation for which no physiological, anatomical or iatrogenic origin can be evidenced. This condition has a high impact on a patient’s quality of life and healthcare costs. Since FC is frequently associated with low physical activity and a diet low in fiber and/or water, first-line recommendations focus on sufficient activity, and sufficient fiber and water intake. In case of inefficacy of these measures, numerous drug treatments are available, either over the counter or on prescription. Magnesium sulfate has a long history in the treatment of FC, and magnesium sulfate-rich mineral waters have been used for centuries for their laxative properties. The laxative effect of magnesium and sulfate has since been widely demonstrated. Nevertheless, it appears that no clinical studies aiming at demonstrating their efficacy in FC had been conducted before the 21st century. In this paper, we reviewed the clinical data reporting the efficacy of magnesium sulfate-rich natural mineral waters. In view of their reported efficacy and safety, magnesium sulfate-rich natural mineral waters may represent a natural treatment for FC.

The skin is a major immunologic organ that may induce protection, sensitization or tolerance. Epicutaneous immunotherapy (EPIT) has been proposed as an attractive strategy to actively treat food allergy and has been shown to induce tolerance in sensitized mice through the induction of Foxp3+ regulatory T cells (Tregs), especially CD62L+ Tregs. Among immune cells in the skin, dendritic cells are key players in antigen-specific immune activation or regulation. The role of different populations of skin DCs in tolerance induction remains to be elucidated. Using OVA-sensitized BALB/c mice, we demonstrated that the application of a patch containing OVA-A647 to the skin resulted in allergen uptake by Langerhans cells (LCs) and CD11b+ dermal cDC2 and subsequent migration into skin draining lymph nodes. These 2 populations induced Foxp3 expression in CD4+ cells in vitro. Only LCs induced LAP+ cells and CD62L+ Tregs. Using Langerin-eGFP-DTR mice, we analyzed the role of LCs in the mechanisms of tolerance induction by EPIT in vivo. Following complete depletion of LCs, a dramatic decrease in the number of OVA+ DCs and OVA+ CD11b+ dermal cDC2 was observed in skin draining lymph nodes 48 h after epicutaneous application. Likewise, 2 weeks of EPIT in non-depleted mice induced Foxp3+ Tregs, especially CD62L+, and LAP+ Tregs in skin draining lymph nodes and spleen, whereas no induction of Tregs was observed in LC-depleted mice. Following 8 weeks of treatment, EPIT-treated mice showed significant protection against anaphylaxis accompanied by a significant increase of Foxp3+ Tregs, especially CD62L+ Tregs, which was not seen in the absence of LCs. In summary, although both LCs and CD11b+ dermal cDC2s could induce regulatory T cells, the absence of LCs during EPIT impaired treatment efficacy, indicating their crucial role in skin-induced tolerance.

During the nutritional vulnerable period of 1−3 years of age, nutrient intake is often inadequate due to an unbalanced diet. Young child formula (YCF) has been proposed as a means of improving nutrition in this age group. We compared the food consumption and nutrient intake of 241 YCF consumers (YCF-C) to those of 206 non-consumers (YCF-NC), selected from among the children enrolled in the Nutri-Bébé survey, an observational cross-sectional survey, conducted from 3 January to 21 April 2013. Food consumption and nutrient intake were analyzed from a three-day dietary record. The YCF-C < 2 years group had a protein (−8 g/d; p < 0.0001) and sodium (−18%; p = 0.0003) intake that was lower than that of YCF-NC, but still above the respective EFSA (European Food Safety Authority) Average Requirement (AR) or Adequate Intake (AI). At all ages, the YCF-C group had higher intakes of essential fatty acids (p < 0.0001), vitamins C (p < 0.0001), A, D, and E (p < 0.0001), all B vitamins (p < 0.001) except B12, iron (9 vs. 5 mg/d, p < 0.0001), reaching the Dietary Reference Values (DRVs, AR or AI), but similar DHA and ARA intakes. Getting closer to the reference values proposed by EFSA required at least 360 mL/d of YCF. The consumption of YCF may help infants and children at risk of nutrient deficiencies to meet their nutritional requirements. However, protein, sodium, and vitamin A intakes remained above the EFSA DRVs, and DHA, ARA, and vitamin D remained below.

BackgroundFood allergy may affect the gastrointestinal tract and eosinophilia is often associated with allergic gastrointestinal disorders. Allergy to peanuts is a life-threatening condition and effective and safe treatments still need to be developed. The present study aimed to evaluate the effects of sustained oral exposure to peanuts on the esophageal and jejunal mucosa in sensitized mice. We also evaluated the effects of desensitization with epicutaneous immunotherapy (EPIT) on these processes.MethodsMice were sensitized by gavages with whole peanut protein extract (PPE) given with cholera toxin. Sensitized mice were subsequently exposed to peanuts via a specific regimen and were then analysed for eosinophilia in the esophagus and gut. We also assessed mRNA expression in the esophagus, antibody levels, and peripheral T-cell response. The effects of EPIT were tested when intercalated with sensitization and sustained oral peanut exposure.ResultsSustained oral exposure to peanuts in sensitized mice led to severe esophageal eosinophilia and intestinal villus sub-atrophia, i.e. significantly increased influx of eosinophils into the esophageal mucosa (136 eosinophils/mm(2)) and reduced villus/crypt ratios (1.6±0.15). In the sera, specific IgE levels significantly increased as did secretion of Th2 cytokines by peanut-reactivated splenocytes. EPIT of sensitized mice significantly reduced Th2 immunological response (IgE response and splenocyte secretion of Th2 cytokines) as well as esophageal eosinophilia (50 eosinophils/mm(2), pConclusionsGastro-intestinal lesions induced by sustained oral exposure in sensitized mice are efficaciously treated by allergen specific EPIT.

BACKGROUND: Analysis of the evolutionary dynamics of Helicobacter pylori allowed tracing the spread of infection through populations on different continents but transmission pathways between individual humans have not been clearly described. MATERIALS AND METHODS: To investigate person-to-person transmission, we studied three families each including one child with persistence of symptoms after antibiotic treatment. Ten isolates from the antrum and corpus of stomach of each family member were analyzed both by sequencing of two housekeeping genes and macroarray tests. RESULTS: A total of 134 (8.4%) out of the 1590 coding sequences (CDSs) tested, including cag PAI and insertion sequences, were present in some but not all isolates (and are therefore defined as variable CDSs). Most of the variable CDSs encoded proteins of unknown function (76/134) or were selfish DNA including that encoding restriction/modification enzymes (13/134). Isolates colonizing the stomach of one individual can vary by point mutations, as seen in hspA, or by the gain or loss of one to five CDSs. They were considered as (genetic) variants. The phylogenetic clustering of gene profiles obtained on macro-arrays allowed identifying the different strains infecting families. Two to five strains circulated within a family. Identical strains were present in at least two members of all three families supporting the accepted model of intrafamilial transmission. Surprisingly, the mother was not implicated in the transmission of H. pylori in the two French families. Sibling-to-sibling transmission and acquisition of H. pylori from outside the family appeared to be probable in the transmission pathways. CONCLUSION: Macroarray analysis based on previously selected CDSs gives a comprehensive view of the genome diversity of a pathogen. This approach combined with information on the origin of the hspA and glmM alleles revealed that Helicobacter pylori infection may be acquired by more diverse routes than previously expected.