Evidence that eating baked egg or milk influences egg or milk allergy resolution: a systematic review.

BACKGROUND: It has been proposed that the frequent ingestion of baked hen's egg or cow's milk accelerates the resolution of hen's egg or cow's milk allergy. This practice is being introduced into clinical practice. OBJECTIVE: To systematically review the evidence to determine whether the introduction of baked hen's egg or cow's milk into the diet of children with hen's egg or cow's milk allergies respectively leads to a larger proportion of children outgrowing these allergies than expected. METHODS: A systematic review of the literature was conducted in Medline, Embase and CINAHL. The inclusion criteria were as follows: randomized control trials, case-control or cohort studies; children aged 0-18 years with hen's egg or cow's milk allergy; baked hen's egg or cow's milk intervention with or without a comparator; and resolution of the hen's egg or cow's milk allergy as determined by food challenge as the outcome. Studies were critically appraised using the quality assessment tool for quantitative studies. PROSPERO reference CRD42015026029. RESULTS: We identified 851 and 2816 hen's egg and cow's milk articles respectively. Only three hen's egg and three cow's milk studies fulfilled our pre-specified inclusion criteria. The studies concluded that baked products either increased the likelihood of the resolution of allergy or accelerated resolution. However, when critiqued, all studies were classified as weak because they were observational, lacking an appropriate control group; this brings into doubt the study's conclusions. There were a number of examples of severe reactions to baked products. CONCLUSION: There is little evidence to address the hypothesis that the ingestion of baked hen's egg or cow's milk results in more patients outgrowing their hen's egg or cow's milk allergy respectively. Data are required from a trial comparing the resolution rates of baked-tolerant participants who are randomized to ingest or avoid baked products to assess the accuracy of this hypothesis.

A new framework for the documentation and interpretation of oral food challenges in population-based and clinical research.

BACKGROUND: The conduct of oral food challenges as the preferred diagnostic standard for food allergy (FA) was harmonized over the last years. However, documentation and interpretation of challenge results, particularly in research settings, are not sufficiently standardized to allow valid comparisons between studies. Our aim was to develop a diagnostic toolbox to capture and report clinical observations in double-blind placebo-controlled food challenges (DBPCFC). METHODS: A group of experienced allergists, paediatricians, dieticians, epidemiologists and data managers developed generic case report forms and standard operating procedures for DBPCFCs and piloted them in three clinical centres. The follow-up of the EuroPrevall/iFAAM birth cohort and other iFAAM work packages applied these methods. RECOMMENDATIONS: A set of newly developed questionnaire or interview items capture the history of FA. Together with sensitization status, this forms the basis for the decision to perform a DBPCFC, following a standardized decision algorithm. A generic form including details about severity and timing captures signs and symptoms observed during or after the procedures. In contrast to the commonly used dichotomous outcome FA vs no FA, the allergy status is interpreted in multiple categories to reflect the complexity of clinical decision-making. CONCLUSION: The proposed toolbox sets a standard for improved documentation and harmonized interpretation of DBPCFCs. By a detailed documentation and common terminology for communicating outcomes, these tools hope to reduce the influence of subjective judgment of supervising physicians. All forms are publicly available for further evolution and free use in clinical and research settings.

Incidence and natural history of hen's egg allergy in the first 2 years of life-the EuroPrevall birth cohort study.

BACKGROUND: Parents and health staff perceive hen's egg allergy (HEA) as a common food allergy in early childhood, but the true incidence is unclear because population-based studies with gold-standard diagnostic criteria are lacking. OBJECTIVE: To establish the incidence and course of challenge-confirmed HEA in children, from birth until the age of 24 months, in different European regions. METHODS: In the EuroPrevall birth cohort study, children with a suspected HEA and their age-matched controls were evaluated in 9 countries, using a standardized protocol including measurement of HE-specific immunoglobulin E-antibodies in serum, skin prick tests, and double-blind, placebo-controlled food challenges (DBPCFC). RESULTS: Across Europe, 12 049 newborns were enrolled, and 9336 (77.5%) were followed up to 2 years of age. In 298 children, HEA was suspected and DBPCFC was offered. HEA by age two was confirmed in 86 of 172 challenged children (mean raw incidence 0.84%, 95% confidence interval (95% CI) 0.67-1.03). Adjusted mean incidence of HEA was 1.23% (95% CI 0.98-1.51) considering possible cases among eligible children who were not challenged. Centre-specific incidence ranged from United Kingdom (2.18%, 95% CI 1.27-3.47) to Greece (0.07%). Half of the HE-allergic children became tolerant to HE within 1 year after the initial diagnosis. CONCLUSIONS: The largest multinational European birth cohort study on food allergy with gold-standard diagnostic methods showed that the mean adjusted incidence of HEA was considerably lower than previously documented, although differences in incidence rates among countries were noted. Half of the children with documented HEA gained tolerance within 1 year postdiagnosis.

EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy.

Food allergy can have significant effects on morbidity and quality of life and can be costly in terms of medical visits and treatments. There is therefore considerable interest in generating efficient approaches that may reduce the risk of developing food allergy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Prevention and is part of the EAACI Guidelines for Food Allergy and Anaphylaxis. It aims to provide evidence-based recommendations for primary prevention of food allergy. A wide range of antenatal, perinatal, neonatal, and childhood strategies were identified and their effectiveness assessed and synthesized in a systematic review. Based on this evidence, families can be provided with evidence-based advice about preventing food allergy, particularly for infants at high risk for development of allergic disease. The advice for all mothers includes a normal diet without restrictions during pregnancy and lactation. For all infants, exclusive breastfeeding is recommended for at least first 4-6 months of life. If breastfeeding is insufficient or not possible, infants at high-risk can be recommended a hypoallergenic formula with a documented preventive effect for the first 4 months. There is no need to avoid introducing complementary foods beyond 4 months, and currently, the evidence does not justify recommendations about either withholding or encouraging exposure to potentially allergenic foods after 4 months once weaning has commenced, irrespective of atopic heredity. There is no evidence to support the use of prebiotics or probiotics for food allergy prevention.

Dietary habits and supplement use in relation to national pregnancy recommendations: data from the EuroPrevall birth cohort.

Assessing maternal dietary habits across Europe during pregnancy in relation to their national pregnancy recommendations. A collaborative, multi-centre, birth cohort study in nine European countries was conducted as part of European Union funded EuroPrevall project. Standardised baseline questionnaire data included details of food intake, nutritional supplement use, exposure to cigarette smoke during pregnancy and socio-demographic data. Pregnancy recommendations were collected from all nine countries from the appropriate national organisations. The most commonly taken supplement in pregnancy was folic acid (55.6 % Lithuania-97.8 % Spain) and was favoured by older, well-educated mothers. Vitamin D supplementation across the cohort was very poor (0.3 % Spain-5.1 % Lithuania). There were significant differences in foods consumed in different countries during pregnancy e.g. only 2.7 % Dutch mothers avoided eating peanut, while 44.4 % of British mothers avoided it. Some countries have minimal pregnancy recommendations i.e. Lithuania, Poland and Spain while others have similar, very specific recommendations i.e. UK, the Netherlands, Iceland, Greece. Allergy specific recommendations were associated with food avoidance during pregnancy [relative rate (RR) 1.18 95 % CI 0.02-1.37]. Nutritional supplement recommendations were also associated with avoidance (RR 1.08, 1.00-1.16). Maternal dietary habits and the use of dietary supplements during pregnancy vary significantly across Europe and in some instances may be influenced by national recommendations.

Infant feeding and allergy prevention: a review of current knowledge and recommendations. A EuroPrevall state of the art paper.

The relationship between infant feeding patterns and the later development of food allergies has been the focus of much debate and research over the last decade. National recommendations have been made by many countries on how to feed infants to reduce the risk of food allergy but due to the lack of firm evidence the recommendations differ widely. This review has been developed as part of EuroPrevall, a European multicentre research project funded by the European Union, to document the differing feeding recommendations made across Europe, to investigate the current evidence base for any allergy prevention feeding recommendations and to identify areas where further research is needed. This review will also provide information which, when combined with the infant feeding data collected as part of EuroPrevall, will give an indication of compliance to national feeding guidelines which can be utilised to assess the effectiveness of current dissemination and implementation strategies.

Exposure of the fetus and infant to hens' egg ovalbumin via the placenta and breast milk in relation to maternal intake of dietary egg.

BACKGROUND: Maternally derived allergens may be transferred to the developing infant during pregnancy and lactation. However, it is not known how manipulation of environmental allergen levels might impact on this early-life exposure. OBJECTIVE: To measure dietary egg allergen (ovalbumin (OVA)) in gestation-associated environments, in relation to maternal dietary egg intake. METHOD: OVA was measured by allergen-specific ELISA in maternal blood collected throughout pregnancy, infant blood at birth (umbilical cord) and in breast milk at 3 months post-partum. Samples derived from pregnant women undergoing diagnostic amniocentesis at 16-18 weeks gestation who were not subject to any dietary intervention, and from pregnant women, with personal or partner atopy, randomized to complete dietary egg exclusion or an unmodified healthy diet before 20 weeks gestation as a primary allergy prevention strategy. Maternal dietary egg intake was monitored closely throughout the study period by diary record and serial measurement of OVA-specific immunoglobulin G concentration. RESULTS: Circulating OVA was detected throughout pregnancy in 20% of women and correlated with both presence (P<0.001) and concentration (r=0.754, P<0.001) of infant OVA at birth (umbilical cord). At 3 months post-partum OVA was detected in breast milk samples of 35% women, in higher concentrations than measured in blood. Blood and breast milk OVA were not related to maternal dietary intake or atopic pre-disposition. CONCLUSIONS: Rigorous dietary egg exclusion does not eliminate trans-placental and breast milk egg allergen passage. This early-life exposure could modulate developing immune responses.

Does severity of low-dose, double-blind, placebo-controlled food challenges reflect severity of allergic reactions to peanut in the community?

BACKGROUND: The severity of allergic reactions to food appears to be affected by many interacting factors. It is uncertain whether challenge-based reactions reflect the severity of past reactions or can predict future risk. OBJECTIVE: To explore the relationship of a subject's clinical history of past reactions to the severity of reaction elicited by a low-dose, double-blind, placebo-controlled food challenge (DBPCFC) with peanut. METHOD: Cross-sectional questionnaire assessment of community-based allergic reactions and low-dose DBPCFC in self-selected peanut-allergic subjects. Reaction severity was assessed using a novel scoring system, taking account of the dose of allergen ingested. RESULTS: Forty subjects (15 males, 23 children, 23 asthmatics by history) were studied. Only the most recent community reaction predicted the severity of reaction in the DBPCFC, but even this association was weak (r=0.37, P=0.03). Peanut-specific IgE (PsIgE) and skin prick test (SPT) weal size were not associated with community score but PsIgE level correlated well with the challenge score (r=0.6, P=0.001). Asthma did not affect the eliciting dose or challenge score directly but the association of PsIgE and challenge score was stronger in those without asthma (r=0.72, P=0.001) than in those with asthma (r=0.48, P=0.02). CONCLUSIONS: The scoring system developed appears to improve the sensitivity of assessment of reactions induced by DBPCFC. This is the first prospective study showing an association between PsIgE levels and clinical reactivity in DBPCFC, an effect that is more pronounced in non-asthmatics. This finding has important implications for the clinical care of subjects with food allergy. There is a poor correlation between the severity of reported reactions in the community and the severity of reaction elicited during low-dose DBPCFC with peanut.

The promiscuity of immunoglobulin E binding to peanut allergens, as determined by Western blotting, correlates with the severity of clinical symptoms.

BACKGROUND: IgE binding to a specific protein has been shown to be associated with severe anaphylaxis to hazelnuts; however, the relationship between IgE binding to specific peanut allergens and symptom severity is currently unclear. OBJECTIVE: To determine if the pattern of IgE binding to specific peanut allergens is associated with the severity of clinical symptoms. METHODS: Forty peanut allergic patients underwent a double-blind placebo-controlled low-dose peanut challenge, during which the severity of the patients' peanut allergy was scored. Serum peanut-specific IgE (psIgE) was measured and IgE binding patterns to peanut proteins analysed. RESULTS: Seventeen IgE binding bands were identified between 5 and 100 kDa with eight bound by >50% of patients. The total number of bands per patient correlated significantly with challenge score (P=0.001, r=0.505) and psIgE (P<0.001, r=0.820). Cluster analysis failed to reveal any association between a particular protein or pattern of proteins (based on presence/absence) and challenge score. However, two protein bands ( approximately 43 and 41 kDa) had peak intensities that correlated positively with challenge score and a third band ( approximately 48 kDa) that correlated negatively. The bands were identified as subunits of Ara h 3/4 and 1, respectively. CONCLUSIONS: Promiscuity of IgE binding appears more important than the recognition of individual proteins. This may mean that clinically useful specific immunotherapy for peanut allergy will be difficult to achieve if only selected allergenic proteins are used. Further investigation of Ara h 1 and 3/4 subunits and a possible association with symptom severity are also highlighted by this study.

Kiwi fruit is a significant allergen and is associated with differing patterns of reactivity in children and adults.

BACKGROUND: Allergy to kiwi fruit appears increasingly common, but few studies have evaluated its clinical characteristics, or evaluated methods of investigating the allergy. OBJECTIVE: To characterize the clinical characteristics of kiwi fruit allergy and to study the role of double-blind placebo-controlled food challenge (DBPCFC), skin tests and specific IgE in the diagnosis of this food allergy. METHODS: Two-hundred and seventy-three subjects with a history suggestive of allergy to kiwi completed a questionnaire. Forty-five were investigated by DBPCFC, prick-to-prick skin testing with fresh kiwi pulp, and specific IgE measurement. Nineteen subjects were also skin tested using a commercially available solution. RESULTS: The most frequently reported symptoms were localized to the oral mucosa (65%), but severe symptoms (wheeze, cyanosis or collapse) were reported by 18% of subjects. Young children were significantly more likely than adults to react on their first known exposure (P<0.001), and to report severe symptoms (P=0.008). Twenty-four of 45 subjects (53%) had allergy confirmed by DBPCFC. Prick-to-prick skin test with fresh kiwi was positive in 93% of subjects who had allergy confirmed by DBPCFC, and also in 55% of subjects with a negative food challenge. The commercial extract was significantly less sensitive, but with fewer false-positive reactions. CAP sIgE was only positive in 54% of subjects who had a positive challenge. CONCLUSIONS: Kiwi fruit should be considered a significant food allergen, capable of causing severe reactions, particularly in young children. DBPCFC confirmed allergy to kiwi fruit in 53% of the subjects tested, who had a previous history suggestive of kiwi allergy. Skin testing with fresh fruit has good sensitivity (93%), but poor specificity (45%) in this population. CAP sIgE and a commercially available skin test solution were both much less sensitive (54%; 75%) but had better specificity (90%; 67%).

Serum ovalbumin-specific immunoglobulin G responses during pregnancy reflect maternal intake of dietary egg and relate to the development of allergy in early infancy.

BACKGROUND: The value of allergen elimination diets during pregnancy for primary prevention of infant allergy has been questioned. However, dietary compliance may influence effectiveness. OBJECTIVES: To monitor egg intake during a randomized controlled trial of egg avoidance throughout pregnancy and lactation by serial measurements of serum ovalbumin (OVA) IgG concentration in conjunction with dietary diary record and also, to analyse specific IgG concentrations at birth in relation to infant allergic outcome. METHODS: Pregnant women, with personal or partner atopy, were randomized to complete dietary egg exclusion or an unmodified healthy diet before 20 weeks gestation. The infants were evaluated for atopy at 6 months of age. Serum food-specific IgG concentrations were determined by ELISA in maternal samples collected at study recruitment and during labour, and in infant samples at birth (umbilical cord). RESULTS: Serum-specific IgG to OVA, but not the unrelated allergen, cow's milk beta-lactoglobulin, decreased over pregnancy in egg-avoiding women only (P<0.001). Cord OVA IgG concentration correlated with maternal IgG at delivery (r=0.944; P<0.001), and for infants born to atopic women, cord concentration was higher than that of their mother's (P<0.001). Infants with the lowest and highest cord IgG concentrations were the least likely, and those with mid-range concentrations were the most likely, to be atopic by 6 months of age (P=0.008). CONCLUSION: Serum OVA IgG concentration reflects egg consumption, thereby indicating dietary allergen doses to which the developing immune system might be exposed. Trans-placental maternal IgG must be considered among early life factors that regulate infant atopic programming.

Presentation of allergen in different food preparations affects the nature of the allergic reaction--a case series.

BACKGROUND: Characterization of fatal and non-fatal reactions to food indicates that the majority of reactions are due to the ingestion of prepared foods rather than the non-processed allergen. In an ongoing study that used a double-blind placebo-controlled food challenge to investigate peanut allergy and clinical symptoms, the observed reaction severity in four of the first six subjects was greater than anticipated. We hypothesized that this was due to differences in the composition of the challenge vehicle. OBJECTIVE: The aim was to investigate whether the severity of observed challenge reactions would be repeated on re-challenge with a lower fat challenge vehicle. METHODS: Peanut-allergic subjects were re-challenged with a lower fat recipe after reacting more severely than was anticipated to an initial peanut challenge. Similar challenge vehicle recipes were used, the only difference being the lower fat content (22.9% compared with 31.5%). The peanut content of the two recipes was analysed using RAST inhibition studies and ELISA tests. RESULTS: Three of four subjects reacted to much smaller doses of peanut protein on re-challenge (mean dose equivalence - 23 times less peanut) with the lower fat recipe. RAST inhibition showed that neither recipe altered epitope recognition. The higher fat recipe required twice as much peanut to cause 50% inhibition. ELISA detected far lower levels of peanut in the higher fat recipe (220 000 parts per million (p.p.m.)) than in the lower fat recipe (990 000 p.p.m.). CONCLUSION: The fat content of a challenge vehicle has a profound effect on the reaction experienced after allergen ingestion. This is another factor to be considered in assessing the risk of certain foods to food-allergic consumers and adds another dimension to clinical, research and regulatory practice.