Tolerance development in cow's milk-allergic children receiving amino acid-based formula with synbiotics: 36-Months follow-up of a randomized controlled trial (PRESTO Study).

The objective of the present study is to assess the rates of acquired tolerance to cow's milk (CM) after 36 months in subjects who consumed amino acid-based formula with synbiotics (AAF-S) or amino acid-based formula without synbiotics (AAF) during a 1-year intervention period in early life as part of the PRESTO study (Netherlands Trial Register number NTR3725). Differences in CM tolerance development between groups were analysed using a logistic regression model. Results show that the proportion of subjects (mean [±SD] age, 3.8 ± 0.27 years) who developed CM tolerance after 36 months was similar in the group receiving AAF-S (47/60 [78%]) and in the group receiving AAF (49/66 [74%]) (p = 0.253), that is, figures comparable to natural outgrowth of CM allergy. Our data suggest that the consumption of AAF and absence of exposure to CM peptides do not slow down CM tolerance acquisition.

Tolerance development in cow's milk-allergic infants receiving amino acid-based formula: A randomized controlled trial.

BACKGROUND: Tolerance development is an important clinical outcome for infants with cow's milk allergy. OBJECTIVE: This multicenter, prospective, randomized, double-blind, controlled clinical study (NTR3725) evaluated tolerance development to cow's milk (CM) and safety of an amino acid-based formula (AAF) including synbiotics (AAF-S) comprising prebiotic oligosaccharides (oligofructose, inulin) and probiotic Bifidobacterium breve M-16V in infants with confirmed IgE-mediated CM allergy. METHODS: Subjects aged ≤13 months with IgE-mediated CM allergy were randomized to receive AAF-S (n = 80) or AAF (n = 89) for 12 months. Stratification was based on CM skin prick test wheal size and study site. After 12 and 24 months, CM tolerance was evaluated by double-blind, placebo-controlled food challenge. A logistic regression model used the all-subjects randomized data set. RESULTS: At baseline, mean ± SD age was 9.36 ± 2.53 months. At 12 and 24 months, respectively, 49% and 62% of subjects were CM tolerant (AAF-S 45% and 64%; AAF 52% and 59%), and not differ significantly between groups. During the 12-month intervention, the number of subjects reporting at least 1 adverse event did not significantly differ between groups; however, fewer subjects required hospitalization due to serious adverse events categorized as infections in the AAF-S versus AAF group (9% vs 20%; P = .036). CONCLUSIONS: After 12 and 24 months, CM tolerance was not different between groups and was in line with natural outgrowth. Results suggest that during the intervention, fewer subjects receiving AAF-S required hospitalization due to infections.

International Consensus Recommendations for Eosinophilic Gastrointestinal Disease Nomenclature.

BACKGROUND & AIMS: Substantial heterogeneity in terminology used for eosinophilic gastrointestinal diseases (EGIDs), particularly the catchall term "eosinophilic gastroenteritis," limits clinical and research advances. We aimed to achieve an international consensus for standardized EGID nomenclature. METHODS: This consensus process utilized Delphi methodology. An initial naming framework was proposed and refined in iterative fashion, then assessed in a first round of Delphi voting. Results were discussed in 2 consensus meetings, and the framework was updated and reassessed in a second Delphi vote, with a 70% threshold set for agreement. RESULTS: Of 91 experts participating, 85 (93%) completed the first and 82 (90%) completed the second Delphi surveys. Consensus was reached on all but 2 statements. "EGID" was the preferred umbrella term for disorders of gastrointestinal (GI) tract eosinophilic inflammation in the absence of secondary causes (100% agreement). Involved GI tract segments will be named specifically and use an "Eo" abbreviation convention: eosinophilic gastritis (now abbreviated EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). The term "eosinophilic gastroenteritis" is no longer preferred as the overall name (96% agreement). When >2 GI tract areas are involved, the name should reflect all of the involved areas. CONCLUSIONS: This international process resulted in consensus for updated EGID nomenclature for both clinical and research use. EGID will be the umbrella term, rather than "eosinophilic gastroenteritis," and specific naming conventions by location of GI tract involvement are recommended. As more data are developed, this framework can be updated to reflect best practices and the underlying science.

Identifying key priorities for research to protect the consumer with food hypersensitivity: A UK Food Standards Agency Priority Setting Exercise.

INTRODUCTION: Food hypersensitivity (FHS), including food allergy, coeliac disease and food intolerance, is a major public health issue. The Food Standards Agency (FSA), an independent UK Government department working to protect public health and consumers' wider interests in food, sought to identify research priorities in the area of FHS. METHODS: A priority setting exercise was undertaken, using a methodology adapted from the James Lind Alliance-the first such exercise with respect to food hypersensitivity. A UK-wide public consultation was held to identify unanswered research questions. After excluding diagnostics, desensitization treatment and other questions which were out of scope for FSA or where FSA was already commissioning research, 15 indicative questions were identified and prioritized by a range of stakeholders, representing food businesses, patient groups, health care and academia, local authorities and the FSA. RESULTS: 295 responses were received during the public consultation, which were categorized into 70 sub-questions and used to define 15 key evidence uncertainties ('indicative questions') for prioritization. Using the JLA prioritization framework, this resulted in 10 priority uncertainties in evidence, from which 16 research questions were developed. These could be summarized under the following 5 themes: communication of allergens both within the food supply chain and then to the end consumer (ensuring trust in allergen communication); the impact of socio-economic factors on consumers with FHS; drivers of severe reactions; mechanism(s) underlying loss of tolerance in FHS; and the risks posed by novel allergens/processing. DISCUSSION: In this first research prioritization exercise for food allergy and FHS, key priorities identified to protect the food-allergic public were strategies to help allergic consumers to make confident food choices, prevention of FHS and increasing understanding of socio-economic impacts. Diagnosis and treatment of FHS was not considered in this prioritization.

Personalized medicine for allergy treatment: Allergen immunotherapy still a unique and unmatched model.

The introduction of personalized medicine (PM) has been a milestone in the history of medical therapy, because it has revolutionized the previous approach of treating the disease with that of treating the patient. It is known today that diseases can occur in different genetic variants, making specific treatments of proven efficacy necessary for a given endotype. Allergic diseases are particularly suitable for PM, because they meet the therapeutic success requirements, including a known molecular mechanism of the disease, a diagnostic tool for such disease, and a treatment blocking the mechanism. The stakes of PM in allergic patients are molecular diagnostics, to detect specific IgE to single-allergen molecules and to distinguish the causative molecules from those merely cross-reactive, pursuit of patient's treatable traits addressing genetic, phenotypic, and psychosocial features, and omics, such as proteomics, epi-genomics, metabolomics, and breathomics, to forecast patient's responsiveness to therapies, to detect biomarker and mediators, and to verify the disease control. This new approach has already improved the precision of allergy diagnosis and is likely to significantly increase, through the higher performance achieved with the personalized treatment, the effectiveness of allergen immunotherapy by enhancing its already known and unique characteristics of treatment that acts on the causes.

Upskilling healthcare professionals to manage clinical allergy.

It has long been recognised that given the high prevalence and considerable impact of allergic disease globally, there needs to be a focus on appropriate training for clinical professionals. The health-economic consequences of allergic disease are significant, with both direct healthcare costs (doctor, nurse and dietitian consultations, hospital admissions and prescribed medications) and indirect costs (lost school and work time, reduced productivity and over-the-counter medications). There is also a well-recognised impairment of quality of life, with less tangible costs including anxiety, distress, discomfort, disability and, occasionally, death. To help to mitigate these effects, there is a need to upskill the professional workforce at all levels, and also to equip those trained with the skills to become future healthare professional trainers. Upskilling the workforce from the grass-roots of undergraduate study in Medical, Nursing and Allied Health Professionals (AHP) through the entirety of training to senior consultant levels could have a major beneficial impact on the patient and their families, lead to a reduction in emergency use of clinical service, and help increase economic productivity.

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.

A synbiotic-containing amino-acid-based formula improves gut microbiota in non-IgE-mediated allergic infants.

BackgroundPrebiotics and probiotics (synbiotics) can modify gut microbiota and have potential in allergy management when combined with amino-acid-based formula (AAF) for infants with cow's milk allergy (CMA).MethodsThis multicenter, double-blind, randomized controlled trial investigated the effects of an AAF-including synbiotic blend on percentages of bifidobacteria and Eubacterium rectale/Clostridium coccoides group (ER/CC) in feces from infants with suspected non-IgE-mediated CMA. Feces from age-matched healthy breastfed infants were used as reference (healthy breastfed reference (HBR)) for primary outcomes. The CMA subjects were randomized and received test or control formula for 8 weeks. Test formula was a hypoallergenic, nutritionally complete AAF including a prebiotic blend of fructo-oligosaccharides and the probiotic strain Bifidobacterium breve M-16V. Control formula was AAF without synbiotics.ResultsA total of 35 (test) and 36 (control) subjects were randomized; HBR included 51 infants. At week 8, the median percentage of bifidobacteria was higher in the test group than in the control group (35.4% vs. 9.7%, respectively; P<0.001), whereas ER/CC was lower (9.5% vs. 24.2%, respectively; P<0.001). HBR levels of bifidobacteria and ER/CC were 55% and 6.5%, respectively.ConclusionAAF including specific synbiotics, which results in levels of bifidobacteria and ER/CC approximating levels in the HBR group, improves the fecal microbiota of infants with suspected non-IgE-mediated CMA.

Palatability of hypoallergenic formulas for cow's milk allergy and healthcare professional recommendation.

BACKGROUND: Cows 'milk protein allergy (CMPA) is the most common food allergy in infants in the United Kingdom. Infants with CMPA who are not exclusively breastfed require a substitute hypoallergenic formula, which are perceived as having a poor palatability. This study compares the palatability of different extensively hydrolysed formulas (EHFs) and explores healthcare professional (HCP) expectations of how palatability impacts infants and their families. METHODS: Healthcare professional with experience of CMPA were recruited to take part in a home palatability test of four EHFs [Aptamil Pepti 1, Nutricia Ltd. (EHF W1); Althera, Nestle Health Science (EHF W2); Similac Alimentum, Abbott (EHF C1); Nutramigen LGG 1, Mead Johnson (EHF C2)] using a blind taste procedure. A randomised, complete block design was used to minimise order and carry-over biases. Participants completed a questionnaire about the impact of formula palatability on infants and their families. RESULTS: A total of 100 HCPs took part (51 dietitians and 49 general practitioners). Overall, whey-based lactose-containing EHFs were ranked the most palatable: EHF W1 by 77% of participants and EHF W2 by 20%. EHF W1 was liked significantly more (P < 0.0001) than the other formulas. The vast majority of participants agreed that better palatability would result in an increased chance of non-rejection (96%), more content families (92%) and decreased healthcare costs (90%). CONCLUSION: Amongst HCPs who manage infants with CMPA, whey-based lactose-containing EHFs were ranked the most palatable. HCPs expected that good palatability would result in better acceptance, more content infants and families, alongside decreased wastage and healthcare costs.

Severity and threshold of peanut reactivity during hospital-based open oral food challenges: An international multicenter survey.

BACKGROUND: Peanut allergy is classically managed by food avoidance. Immunotherapy programs are available at some academic centers for selected patients reacting to small amounts of peanut during food challenge. We aimed to determine and compare reaction thresholds and prevalence of anaphylaxis during peanut oral challenges at multiple specialist allergy centers. METHODS: A retrospective, international survey of anonymized case records from seven specialist pediatric allergy centers from the UK and Ireland, as well as the Australian HealthNuts study. Demographic information, allergy test results, reaction severity and threshold during open oral peanut challenges were collated and analyzed. RESULTS: Of the 1634 children aged 1-18 years old included, 525 (32%) failed their peanut challenge. Twenty-eight percent reacted to 25 mg, while 38% only reacted after consuming 1 g or more of whole peanut. Anaphylaxis (55 [11%]) was 3 times more common in teenagers than younger children and the likelihood increased at all ages as children consuming more peanut at the challenge. Children who developed anaphylaxis to 25-200 mg of whole peanut were significantly older. Previous history of reaction did not predict reaction threshold or severity. CONCLUSIONS: More than a third of the children in this large international cohort tolerated the equivalent of one peanut in an oral challenge. Anaphylaxis, particularly to small amounts of peanut, was more common in older children. Tailored immunotherapy programs might be considered not only for children with low, but also higher reaction thresholds. Whether these programs could prevent heightened sensitivity and anaphylaxis to peanut with age also deserves further study.

How many paediatric referrals to an allergist could be managed by a general practitioner with special interest?

BACKGROUND: The concept of a general practitioner with special interest (GPwSI) was first proposed in the 2000 National Health Service Plan, as a way of providing specialized treatment closer to the patient's home and reducing hospital waiting times. Given the patchy and inadequate provision of paediatric allergy services in the UK, the introduction of GPwSIs might reduce pressure on existing specialist services. METHODS: A total of 100 consecutive referrals to a specialist paediatric allergy clinic were reviewed to assess what proportion could be managed by a GPwSI allergy service with a predefined range of facilities and expertise (accurate diagnosis and management of allergy; skin prick testing; provision of allergen avoidance advice; ability to assess suitability for desensitization). Each referral was reviewed independently by three allergy specialists. Cases were initially judged on the referral letter and then, to determine whether appropriate triage decisions could be made prospectively, cases were re-assessed with information summarized in the clinic letter. The proportion of referrals suitable for a GPwSI was calculated and their characteristics identified. RESULTS: At least 42% and up to 75% were suitable for management by a GPwSI in allergy based on unanimous and majority agreement, respectively. The appropriateness of 79% referrals could be identified based on the information in the referral letter. A total of 19% referrals were unsuitable for a GPwSI service because of complex or multisystem disease, need for specialist knowledge or facilities or patient's young age. CONCLUSIONS: At least two-fifths of paediatric allergy referrals to our hospital-based service could be dealt with in a GPwSI clinic, thereby diversifying the patient pathway, allowing specialist services to focus on complex cases and reducing waiting times for appointments.

Pollen food syndrome amongst children with seasonal allergic rhinitis attending allergy clinic.

BACKGROUND: There is limited information regarding the onset and sensitization patterns of pollen food syndrome (PFS) in children. The aim was to explore this within children referred to a specialist allergy clinic at a London Tertiary Hospital. METHODS: A total of 54 patients with seasonal allergic rhinitis (SAR) were enrolled in equal numbers in three age groups; 0-5, 6-10, 11-15 years. Families completed a questionnaire on rhinitis, food symptoms and quality of life. Children underwent skin prick testing (SPT) to fresh fruits, nuts and a blood test for microarray analysis. RESULTS: Clinical diagnosis of PFS was made in 26/54 (48%), increasing with age (group 1 = 3 (17%), group 2 = 9 (50%), group 3 = 14 (78%) (p = 0.03)). Microarray demonstrates children aged 2.8 years sensitized to pan-allergens and 4.5 years symptomatic to pan-allergens. Peach, cherry, carrot and strawberry SPT had the highest sensitivity and NPV at 100%. The sensitivity of PR10 molecules on microarray was 92%, PPV 62% and NPV 87%. Microarray confirmed 69% of allergens on clinical history compared to 61% by SPT. Microarray and SPT had a 19% false-negative rate. The quality-of-life data showed moderate impact across all domains, and patients with PFS were significantly more likely to have increased anxiety over time spent preparing food (p = 0.029). CONCLUSIONS: We demonstrate that SAR occurs in children from 1.4 years and PFS from 4.5 years with a changing pattern of pan-allergen sensitization. Microarray and SPT have moderate concordance in confirming allergens. PFS impacts negatively on quality of life and should be assessed in all paediatric allergy patients.

Efficacy of MP-AzeFlu in children with seasonal allergic rhinitis: Importance of paediatric symptom assessment.

BACKGROUND: This study aimed to assess the efficacy of MP-AzeFlu (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in a single spray) in children with seasonal allergic rhinitis (SAR) and explore the importance of child symptom severity assessment in paediatric allergic rhinitis (AR) trials. METHODS: A total of 348 children (4-11 years) with moderate/severe SAR were randomized into a double-blind, placebo-controlled, 14-day, parallel-group trial. Efficacy was assessed by changes from baseline in reflective total nasal symptom score (rTNSS), reflective total ocular symptom score (rTOSS) and individual symptom scores over 14 days (children 6-11 years; n = 304), recorded by either children or caregivers. To determine whether a by-proxy effect existed, efficacy outcomes were assessed according to degree of child/caregiver rating. Moreover, total Paediatric Rhinitis Quality of Life Questionnaire (PRQLQ) score was compared between the groups. RESULTS: A statistically superior, clinically relevant efficacy signal of MP-AzeFlu versus placebo was apparent for PRQLQ overall score (diff: -0.29, 95% CI -0.55, -0.03; p = 0.027), but not for rTNSS (diff: -0.80; 95% CI: -1.75; 0.15; p = 0.099). However, as the extent of children's self-rating increased, so too did the treatment difference between MP-AzeFlu and placebo; MP-AzeFlu provided significantly better relief than placebo for rTNSS (p = 0.002), rTOSS (p = 0.009) and each individual nasal and ocular symptom assessed (except rhinorrhoea; p = 0.064) when children mostly rated their own symptoms. CONCLUSIONS: MP-AzeFlu is an effective treatment for AR in childhood. Caregivers are less able than children to accurately assess response to treatment with available tools. A simple paediatric-specific tool to assess efficacy in AR trials in children is needed.

Cow's Milk Allergy Prescribing Is Influenced by Regional and National Guidance.

OBJECTIVES: Cow's milk allergy (CMA) is the most common food allergy in children with many clinical manifestations, leading to misdiagnoses such as gastro-oesophageal reflux, infantile colic, and lactose intolerance with inappropriate prescribing. We aimed to determine the impact of infant feeding guidelines on CMA prescribing in UK primary care using a simple and inexpensive training package. METHODS: Prospectively collected data of infant feeding prescriptions in Northern Ireland from June 2012 to March 2014 were analysed with the intervention period between November 2012 and March 2013. A comparison was made between hypoallergenic formulae, appropriate for CMA, versus alternative prescriptions including antiregurgitation and colic products, lactose-free and partially hydrolysed milks, or infant Gaviscon. RESULTS: Comparing pre- and postintervention period, the total quantity of hypoallergenic formulae increased by 63.2% and alternative prescriptions decreased by 44.6% (P < 0.001). The total amount of all prescribed products decreased by 41.0% (P < 0.001). During the study period, the proportion of recommended CMA treatment increased from 3.4% before training to 9.8% in the short- and long-term follow-up (P < 0.001). The overall increase was £33,508 per year or £95.5 per general practitioner's surgery. CONCLUSIONS: We present the first study evaluating the impact of infant feeding guidelines on CMA prescribing in UK primary care. Practical advice and teaching of health professionals allowed for effective implementation of regional and national guidelines, with a significant impact on prescription patterns. This study shows promising results for prospective research on a national scale, including socioeconomical impact and cost-effectiveness.