Assessing Feeding Difficulties in Children Presenting with Non-IgE-Mediated Gastrointestinal Food Allergies-A Commonly Reported Problem.

Many guidelines have been published to help diagnose food allergies, which have included feeding difficulties as a presenting symptom (particularly for non-IgE-mediated gastrointestinal allergies). This study aimed to investigate the prevalence of feeding difficulties in children with non-IgE-mediated gastrointestinal allergies and the association of such difficulties with symptoms and food elimination. An observational study was performed at Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Children aged 4 weeks to 16 years without non-allergic co-morbidities who improved on an elimination diet using a previously published Likert scale symptom score were included. This study recruited 131 children, and 114 (87%) parents completed the questionnaire on feeding difficulties. Feeding difficulties were present in 61 (53.5%) of the 114 children. The most common feeding difficulties were regular meal refusals (26.9%), extended mealtimes (26.7%), and problems with gagging on textured foods (26.5%). Most children (40/61) had ≥2 reported feeding difficulties, and eight had ≥4. Children with feeding difficulties had higher rates of constipation and vomiting: 60.7% (37/61) vs. 35.8% (19/53), p = 0.008 and 63.9% (39/61) vs. 41.5% (22/53), p = 0.017, respectively. Logistic regression analysis demonstrated an association between having feeding difficulties, the age of the child, and the initial symptom score. Gender and the number of foods excluded in the elimination diet were not significantly associated with feeding difficulties. This study found that feeding difficulties are common in children with non-IgE-mediated gastrointestinal allergies, but there is a paucity of food allergy specific tools for establishing feeding difficulties, which requires further research in the long-term and consensus in the short term amongst healthcare professions as to which tool is the best for food allergic children.

Association of Reaction Symptoms and Eliciting Dose With Health-Related Quality of Life in Children With Peanut Allergy.

BACKGROUND: Food allergy adversely affects the health-related quality of life (HRQoL) of patients. It is unclear whether factors such as the reaction eliciting dose (ED) and the nature of allergic reaction symptoms affect HRQoL. OBJECTIVE: To explore associations between reaction ED or the nature of allergic symptoms and HRQoL among children with peanut allergy. METHODS: This study was a secondary analysis of baseline data from the PPOIT-003 randomized trial in 212 children aged 1 to 10 years with challenge-confirmed peanut allergy. Children's past reaction symptoms were collected by clinicians during screening. Associations between variables of interest and parent-reported child-proxy HRQoL were examined by univariable and multivariable linear regression. RESULTS: Mean age of study participants was 5.9 years; 63.2% were male. Children with a low reaction ED of 80 mg peanut protein had significantly poorer HRQoL (ß = -0.81; 95% CI, -1.61 to -0.00; P = .049) compared with children with a high ED of 2,500 mg peanut protein. Gastrointestinal symptoms (ß = 0.45; 95% CI, 0.03-0.87; P = .037), lower airway symptoms (ß = 0.46; 95% CI, 0.05-0.87; P = .030), multisystem involvement (ß = 0.71; 95% CI, 0.25-1.16; P = .003), or anaphylaxis (ß = 0.46; 95% CI, 0.04-0.87; P = .031) during a previous reaction were associated with worse HRQoL. CONCLUSIONS: Peanut-allergic children with a lower allergen reaction threshold experienced a greater negative HRQoL impact compared with children with higher reaction thresholds. In addition, specific past allergic reaction symptoms were associated with comparatively worse HRQoL. Children experiencing these symptoms and those with lower reaction ED require increased clinical support to manage the food allergy and are likely to benefit from interventions that can improve HRQoL.

The role of online symptom questionnaires to support the diagnosis of cow's milk allergy in children for healthcare professionals - A Delphi consensus study.

BACKGROUND: Cow's milk allergy (CMA) is one of the most common food allergies world-wide. The emergence of online CMA symptom questionnaires, aimed at parents and/or healthcare professionals (HCP), may raise awareness about the possible diagnosis of CMA, but also increases the risk for overdiagnosis leading to unnecessary dietary restriction impacting on growth and nutrition. This publication sets out to establish the availability of these CMA symptom questionnaires and critically assesses the development and validity. METHODS: Thirteen HCP working in the field of CMA, from different countries, were recruited to participate. A combination of a Pubmed and CINAHL literature and online review using the Google search engine in English language was used. Symptoms in the questionnaires were assessed, using the European Academy for Allergy and Clinical Immunology guidelines for food allergy. Following the assessment of both the questionnaires and literature, the authors followed the modified Delphi approach to generate consensus statements. RESULTS: Six hundred and fifty-one publications were identified, of which 29 were suitable for inclusion, with 26 being associated with the Cow's Milk-Related Symptoms Score. The online search yielded 10 available questionnaires: 7/10 were sponsored by formula milk companies and 7/10 were aimed at parents and three at HCP. Following the assessment of data, 19 statements were generated in two rounds of anonymous voting reaching 100% agreement. CONCLUSIONS: Online CMA questionnaires, available to parents and HCP's, are varied in symptoms, and most were not validated. The overarching consensus generated from authors is that these questionnaires should not be used without the involvement of HCP.

Study protocol of a phase 2, dual-centre, randomised, controlled trial evaluating the effectiveness of probiotic and egg oral immunotherapy at inducing desensitisation or sustained unresponsiveness (remission) in participants with egg allergy compared with placebo (Probiotic Egg Allergen Oral Immunotherapy for Treatment of Egg Allergy: PEAT study).

INTRODUCTION: Egg allergy is the most common food allergy in children but recent studies have shown persistence or delayed resolution into adolescence. As there is currently no effective long-term treatment, definitive treatments that improve quality of life and prevent fatalities for food allergies are required. We have previously shown that a novel treatment comprising a combination of the probiotic Lactobacillus rhamnosus CGMCC 1.3724 with peanut oral immunotherapy (OIT) is highly effective at inducing sustained unresponsiveness, with benefit persisting to 4 years after treatment cessation in the majority of initial treatment responders. In this study, we plan to extend the probiotic food OIT platform to another allergen, namely egg. We describe the protocol for a phase 2, dual-centre, randomised, controlled trial evaluating the effectiveness of probiotic and egg OIT at inducing desensitisation or sustained unresponsiveness (remission) in participants with egg allergy compared with placebo. METHODS AND ANALYSIS: 80 participants aged 5-30 years of age with current egg allergy confirmed by double-blind placebo-controlled food challenge at study screening will be recruited from Australia and Singapore. There are two intervention arms-probiotic and egg OIT (active) or placebo. Interventions are administered once daily for 18 months. The primary outcome is the proportion of participants who attain 8-week sustained unresponsiveness in the active group versus placebo group. ETHICS AND DISSEMINATION: This study has been approved by the Human Research Ethics Committees at the Royal Children's Hospital (HREC 2019.082) and the National Healthcare Group Domain Specific Review Board (2019/00029). Results will be published in peer-reviewed journals and disseminated via presentations at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12619000480189.

The Challenge of Home Allergen Re-introductions Using the Ladder Approach in Children With Non-IgE Mediated Gastrointestinal Food Allergy.

Background: Oral food challenges remain the most reliable method for allergy confirmation. Although consensus guidelines have been published to unify Immunoglobulin E (IgE)-mediated challenges, this does not exist for non-IgE mediated gastrointestinal allergies outside of Food Protein Induced Enterocolitis Syndrome. We therefore set out to establish the use of home introduction protocols (HIP) for confirmation of food allergy for milk, soya, egg and wheat using a ladder approach in children with non-IgE mediated allergy. Materials and Methods: Patients with suspected non-IgE mediated gastrointestinal allergies (0-16 years) were recruited following symptom improvement on an elimination diet. All children had skin prick or specific IgE tests to rule out IgE-mediated allergies prior to suggestion the HIP. Number of trials and outcome was documented. HIPs were developed using a published ladder approach for cow's milk as baseline and final dose was calculated based on guidelines for food protein induced enterocolitis syndrome and portions for age from the National Diet and Nutrition Survey. First foods were baked/highly processed and every 4th day patients moved to a more unprocessed/unheated food. Results: From 131 recruited patients, 117 (89.3%) followed the HIP for food allergens. No adverse events were documented. In more than 50% of cases one attempt at the HIP was sufficient to establish allergy status, but many required 2-5 attempts before the outcome was clear. About half of the children were fully tolerant to foods they initially eliminated: 36, 26 and 30% were partially tolerant to milk, soya, and egg and only 15% achieved partial tolerance to wheat. Wheat was the allergen introduced earliest, followed by soya, cow's milk and egg. Conclusions: This study indicates that home HIPs are safe in non-IgE mediated gastrointestinal food allergy and that the ladder approach may be useful in re-introducing allergens in children at home with non-IgE mediated gastrointestinal allergies. From this study we can also conclude that tolerance to processed/baked allergens was observed in many children. Further studies should be performed on the HIP and ideally reintroduction should occur pre-defined time intervals.

Study protocol of a multicentre, randomised, controlled trial evaluating the effectiveness of probiotic and peanut oral immunotherapy (PPOIT) in inducing desensitisation or tolerance in children with peanut allergy compared with oral immunotherapy (OIT) alone and with placebo (the PPOIT-003 study).

INTRODUCTION: Peanut allergy is the the most common cause of life-threatening food-induced anaphylaxis. There is currently no effective long-term treatment. There is a pressing need for definitive treatments that improve the quality of life and prevent fatalities. Allergen oral immunotherapy (OIT) is a promising approach, which is effective at inducing desensitisation; however, OIT has a limited ability to induce sustained unresponsiveness (SU). We have previously shown that a novel treatment comprising a combination of the probiotic Lactobacillus rhamnosus CGMCC 1.3724 with peanut OIT (Probiotic Peanut Oral ImmunoTherapy (PPOIT)) is highly effective at inducing SU, with benefit persisting to 4 years after treatment cessation in the majority of initial treatment responders. Here we describe the protocol for a Phase IIb multicentre, double-blind, randomised, controlled trial (PPOIT-003) with dual primary objectives to evaluate the effectiveness of PPOIT at inducing SU (assessed at 8 weeks after treatment cessation) compared with placebo treatment and peanut OIT alone, in children with peanut allergy. METHODS AND ANALYSIS: 200 children 1 to 10 years of age with current peanut allergy confirmed by failed double-blind placebo-controlled food challenge (DBPCFC) at study screening will be recruited from three tertiary paediatric hospitals in Australia. There are three intervention arms-PPOIT, peanut OIT alone or placebo. Interventions are administered once daily for 18 months. The dual primary outcomes are: (1) the proportion of children who attain 8-week SU in the PPOIT group versus placebo group and (2) the proportion of children who attain 8-week SU in the PPOIT group versus OIT group. ETHICS AND DISSEMINATION: This study has been approved by the Human Research Ethics Committees at the Royal Children's Hospital (HREC 35246) and the Child and Adolescent Health Service (RGS 2543). Results will be published in peer-reviewed journals and disseminated via presentations at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12616000322437.

Diagnosis and management of Non-IgE gastrointestinal allergies in breastfed infants-An EAACI Position Paper.

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

Postnatal probiotics and allergic disease in very preterm infants: Sub-study to the ProPrems randomized trial.

BACKGROUND: Probiotic supplementation to mothers and/or their term-born infants has been suggested to prevent allergic disease, in particular eczema; however, no studies have investigated probiotics for prevention of allergic diseases in very preterm infants. We evaluated the effect of a postnatal probiotic combination on development of allergic diseases in very preterm infants. METHODS: This sub-study was an a priori secondary outcome of the ProPrems multi-center, double-blind, placebo-controlled randomized trial (ANZCTR:12607000144415). ProPrems randomized 1099 very preterm infants to receive a probiotic combination or placebo from soon after birth until discharge from hospital or term corrected age (CA), whichever was earlier. Allergic disease (eczema, atopic eczema, food allergy, wheeze, atopic sensitization) was assessed in a subgroup of ProPrems infants (n = 281) as close to 12 months CA as possible by questionnaire, clinical examination, and skin prick tests to common allergens. RESULTS: There was no difference in eczema incidence between the probiotic and placebo groups (35[30%] of 118 infants vs 37[27%] of 137 infants, respectively, absolute difference 2.65%, 95% CI -8.45 to 13.75). Similarly, the incidence of atopic eczema (6[5%] of 118 vs 3[2%] of 137), food allergy (4[3%] of 124 vs 2[1%] of 154), wheeze (39[31%] of 127 vs 45[29%] of 154), and atopic sensitization (14[13%] of 106 vs 13[11%] of 123) were similar between the probiotic and placebo groups. CONCLUSION: This study found no effect of postnatal administration of a probiotic combination on the incidence of allergic diseases or atopic sensitization in the first 2 years of life in children born very preterm. Evidence that probiotics are effective for prevention of allergic disease in premature infants remains lacking; adequately powered randomized controlled trials evaluating probiotic supplementation for allergy prevention in very preterm infants are needed.

Non-IgE-mediated gastrointestinal allergies-Do they have a place in a new model of the Allergic March.

The rise in food allergy has been described as the "second wave" of the allergy epidemic, with some developed countries reporting a prevalence of 10% of challenge-proven food allergies. Recognition of the Allergic March has played a crucial role in identifying causality in allergic conditions, linking atopic dermatitis to food allergy and food allergy to other atopic disorders, thereby highlighting opportunities in prevention and the importance of early intervention. This publication will establish the value of weaving the less well-understood, non-IgE-mediated food allergy into the Allergic March and mapping its progression through childhood and its associated co-morbidities. The proposed non-IgE-mediated Allergic March highlights the concomitant presentation of gastrointestinal symptoms and atopic dermatitis as early presenting symptoms in confirmed non-IgE-mediated allergies and the later development of atopic co-morbidities, including asthma and allergic rhinitis, similar to the IgE-mediated Allergic March. This publication highlights recent observations of a link between non-IgE-mediated food allergy in early childhood and functional gastrointestinal disorders in later life and also the reported occurrence of extra-intestinal manifestations at later ages. Although significant limitations exist in regard to the proposed evolution of the Allergic March model, the authors hope that this publication will influence the management of non-IgE-mediated gastrointestinal allergies and inform future research and interventions.

The impact of the elimination diet on growth and nutrient intake in children with food protein induced gastrointestinal allergies.

BACKGROUND: Non immunoglobulin E (IgE) mediated allergies affecting the gastrointestinal tract require an elimination diet to aid diagnosis. The elimination diet may entail multiple food eliminations that contribute significantly to macro- and micro-nutrient intake which are essential for normal growth and development. Previous studies have indicated growth faltering in children with IgE-mediated allergy, but limited data is available on those with delayed type allergies. We therefore performed a study to establish the impact on growth before and after commencing an elimination diets in children with food protein induced non-IgE mediated gastrointestinal allergies. METHODS: A prospective, observational study was performed at the tertiary gastroenterology department. Children aged 4 weeks-16 years without non-allergic co-morbidities who were required to follow an elimination diet for suspected food protein induced gastrointestinal allergies were included. Growth parameters pre-elimination were taken from clinical notes and post-elimination measurements (weight and height) were taken a minimum of 4 weeks after the elimination diet. A 3-day estimated food diary was recorded a minimum of 4 weeks after initiating the elimination diet, including also any hypoallergenic formulas or over the counter milk alternatives that were consumed. RESULTS: We recruited 130 children: 89 (68.5 %) boys and a median age of 23.3 months [IQR 9.4-69.2]. Almost all children (94.8 %) in this study eliminated CM from their diet and average contribution of energy in the form of protein was 13.8 % (SD 3.9), 51.2 % (SD 7.5) from carbohydrates and 35 % (SD 7.5) from fat. In our cohort 9 and 2.8 % were stunted and wasted respectively. There was a statistically significant improvement in weight-for-age (Wtage) after the 4 week elimination diet. The elimination diet itself did not improve any of the growth parameters, but achieving energy and protein intake improved Wtage and WtHt respectively, vitamin and/or mineral supplements and hypoallergenic formulas were positively associated with WtHt and Wtage. CONCLUSION: With appropriate dietary advice, including optimal energy and protein intake, hypoallergenic formulas and vitamins and mineral supplementation, growth parameters increased from before to after dietary elimination. These factors were positively associated with growth, irrespective of the type of elimination diet and the numbers of foods eliminated.

A practical approach to vitamin and mineral supplementation in food allergic children.

BACKGROUND: The management of food allergy in children requires elimination of the offending allergens, which significantly contribute to micronutrient intake. Vitamin and mineral supplementation are commonly suggested as part of dietary management. However a targeted supplementation regime requires a complete nutritional assessment, which includes food diaries. Ideally these should be analysed using a computerised program, but are very time consuming. We therefore set out to evaluate current practice of vitamin and mineral supplementation in a cohort of children with non-Immunoglobulin E (IgE) mediated food allergies. METHODS: This prospective, observational study recruited children aged 4 weeks - 16 years, who required to follow an elimination diet for non-IgE mediated allergies. Only children that improved according to a symptom score and were on a vitamin and/or mineral supplement were included. A 3-day food diary including vitamin and mineral supplementation was recorded and analysed using Dietplan computer program. We assessed dietary adequacy with/without the supplement using the Dietary Reference Values. RESULTS: One hundred-and-ten children had completed food diaries and of these 29% (32/110) were taking vitamin and/or mineral supplements. Children on hypoallergenic formulas were significantly (p = 0.007) less likely to be on supplements than those on alternative over-the-counter milks. Seventy-one percent had prescribable supplements, suggested by a dietitian/physician. Sixty percent of those without a vitamin supplement had a low vitamin D intake, but low zinc, calcium and selenium was also common. Of the supplemented cohort many continued to be either under or over-supplemented. CONCLUSION: This study has raised the question for the first time, whether clinicians dealing with paediatric food allergies should consider routine vitamin and/or mineral supplements in the light of deficient intake being so common in addition to being so difficult to predict.