Early-life gut microbiome and egg allergy.

BACKGROUND: Gut microbiota may play a role in egg allergy. We sought to examine the association between early-life gut microbiota and egg allergy. METHODS: We studied 141 children with egg allergy and controls from the multicenter Consortium of Food Allergy Research study. At enrollment (age 3 to 16 months), fecal samples were collected, and clinical evaluation, egg-specific IgE measurement, and egg skin prick test were performed. Gut microbiome was profiled by 16S rRNA sequencing. Analyses for the primary outcome of egg allergy at enrollment, and the secondary outcomes of egg sensitization at enrollment and resolution of egg allergy by age 8 years, were performed using Quantitative Insights into Microbial Ecology, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States, and Statistical Analysis of Metagenomic Profiles. RESULTS: Compared to controls, increased alpha diversity and distinct taxa (PERMANOVA P = 5.0 × 10-4 ) characterized the early-life gut microbiome of children with egg allergy. Genera from the Lachnospiraceae, Streptococcaceae, and Leuconostocaceae families were differentially abundant in children with egg allergy. Predicted metagenome functional analyses showed differential purine metabolism by the gut microbiota of egg-allergic subjects (Kruskal-Wallis Padj  = 0.021). Greater gut microbiome diversity and genera from Lachnospiraceae and Ruminococcaceae were associated with egg sensitization (PERMANOVA P = 5.0 × 10-4 ). Among those with egg allergy, there was no association between early-life gut microbiota and egg allergy resolution by age 8 years. CONCLUSION: The distinct early-life gut microbiota in egg-allergic and egg-sensitized children identified by our study may point to targets for preventive or therapeutic intervention.

Integrative transcriptomic analysis reveals key drivers of acute peanut allergic reactions.

Mechanisms driving acute food allergic reactions have not been fully characterized. We profile the dynamic transcriptome of acute peanut allergic reactions using serial peripheral blood samples obtained from 19 children before, during, and after randomized, double-blind, placebo-controlled oral challenges to peanut. We identify genes with changes in expression triggered by peanut, but not placebo, during acute peanut allergic reactions. Network analysis reveals that these genes comprise coexpression networks for acute-phase response and pro-inflammatory processes. Key driver analysis identifies six genes (LTB4R, PADI4, IL1R2, PPP1R3D, KLHL2, and ECHDC3) predicted to causally modulate the state of coregulated networks in response to peanut. Leukocyte deconvolution analysis identifies changes in neutrophil, naive CD4+ T cell, and macrophage populations during peanut challenge. Analyses in 21 additional peanut allergic subjects replicate major findings. These results highlight key genes, biological processes, and cell types that can be targeted for mechanistic study and therapeutic targeting of peanut allergy.

Component-resolved analysis of IgA, IgE, and IgG4 during egg OIT identifies markers associated with sustained unresponsiveness.

BACKGROUND: In a previously reported CoFAR study, 55 subjects with egg allergy underwent randomized, placebo-controlled egg oral immunotherapy (eOIT). Active treatment induced desensitization in most and sustained unresponsiveness (SU) in a smaller subset. We hypothesized that component-resolved analysis of IgE, IgG4, IgA, IgA1, and IgA2 may identify potential biomarkers of SU in OIT subjects. METHODS: Longitudinal samples for 51 egg-allergic subjects (37 active and 14 placebo) were available. Egg white (EW)-, ovalbumin (OVA)-, and ovomucoid (OVM)-specific levels of IgA, IgA1, and IgA2 were quantified by ELISA. IgE and IgG4 to these antigens were quantified using ImmunoCAP® . Clinical responders achieved SU to egg; all others were considered nonresponders. Between-group comparisons were made among active and placebo, as well as responders and nonresponders. RESULTS: No placebo subjects achieved responder status. Through month 48, among the 37 active subjects, baseline IgE-OVM was lower in responders (median 3.97 kU/l, n = 19) than in nonresponders (10.9 kU/l, n = 18, P = 0.010). Logistic regression analysis revealed that lower baseline IgE-EW (P = 0.038), IgE-OVM (P = 0.032), and a higher IgG4/IgE-OVM ratio (P = 0.013) were associated with clinical response. Relative increases in IgG4-EW, IgA-EW, and IgA2-EW were observed in responders (P = 0.024, 0.024, and 0.029, respectively). IgG4/IgE, IgA/IgE, and IgA2/IgE ratios for EW and IgA/IgE ratio for OVA were found to be significantly elevated among responders (P = 0.004, 0.009, 0.028, and 0.008, respectively). CONCLUSIONS: Increased IgG4-EW, IgA-EW, and IgA2-EW during eOIT are associated with clinical response to eOIT. Lower pretreatment IgE-EW and IgE-OVM are also associated with SU. Future studies are needed to evaluate and validate these potential biomarkers.

A phase 1 study of heat/phenol-killed, E. coli-encapsulated, recombinant modified peanut proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the treatment of peanut allergy.

BACKGROUND: Immunotherapy for peanut allergy may be limited by the risk of adverse reactions. OBJECTIVE: To investigate the safety and immunologic effects of a vaccine containing modified peanut proteins. METHODS: This was a phase 1 trial of EMP-123, a rectally administered suspension of recombinant Ara h 1, Ara h 2, and Ara h 3, modified by amino acid substitutions at major IgE-binding epitopes, encapsulated in heat/phenol-killed E. coli. Five healthy adults were treated with 4 weekly escalating doses after which 10 peanut-allergic adults received weekly dose escalations over 10 weeks from 10 mcg to 3063 mcg, followed by three biweekly doses of 3063 mcg. RESULTS: There were no significant adverse effects in the healthy volunteers. Of the 10 peanut-allergic subjects [4 with intermittent asthma, median peanut IgE 33.3 kUA /l (7.2-120.2), and median peanut skin prick test wheal 11.3 mm (6.5-18)]; four experienced no symptoms; one had mild rectal symptoms; and the remaining five experienced adverse reactions preventing completion of dosing. Two were categorized as mild, but the remaining three were more severe, including one moderate reaction and two anaphylactic reactions. Baseline peanut IgE was significantly higher in the five reactive subjects (median 82.4 vs 17.2 kUA /l, P = 0.032), as was baseline anti-Ara h 2 IgE (43.3 versus 8.3, P = 0.036). Peanut skin test titration and basophil activation (at a single dilution) were significantly reduced after treatment, but no significant changes were detected for total IgE, peanut IgE, or peanut IgG4. CONCLUSIONS: Rectal administration of EMP-123 resulted in frequent adverse reactions, including severe allergic reactions in 20%.

Mental health and quality-of-life concerns related to the burden of food allergy.

As food allergy increases, more research is devoted to its influence on patient and family mental health and quality of life (QoL). This article discusses the effects on parent and child QoL, as well as distress, while appraising the limitations of knowledge given the methods used. Topics include whether QoL and distress are affected compared with other illnesses, assessment of distress and QoL in parents compared with children, concerns about food allergy-related bullying, and the necessity for evidence-based interventions. Suggestions are offered for how to improve QoL and reduce distress on the way to better coping with food allergy.

Clinical implications of cross-reactive food allergens.

As a consequence of the general increase in allergic sensitization, the prevalence of hypersensitivity reactions to multiple foods that share homologous proteins has become a significant clinical problem. A variety of these allergens conserved among plants (eg, profilin and lipid transfer proteins) and animals (eg, tropomyosin and caseins) have been characterized. Although studies with molecular biologic techniques have elucidated the nature of these ubiquitous allergens, clinical studies have lagged behind. The physician is called on to determine the risk of reaction to related foods among legumes, tree nuts, fish, shellfish, cereal grains, mammalian and avian food products, and a variety of other plant-derived foods that may share proteins with pollens, latex, and each other. Clinical evaluations require a careful history, laboratory evaluation, and in some cases oral food challenges. The pitfalls in the evaluation of food allergy-unreliable histories and limitations in laboratory assessment primarily caused by false-positive skin prick test responses/RAST results are magnified when dealing with cross-reactive proteins. This review focuses on the clinical data regarding cross-reacting food allergens with the goal of providing a background for improved risk assessment and a framework on which to approach these difficult clinical questions.

Peanut and tree nut allergic reactions in restaurants and other food establishments.

BACKGROUND: The clinical features of food-allergic reactions in restaurants and other food establishments have not been studied. Of the registrants in the United States Peanut and Tree Nut Allergy Registry (PAR), 13.7% have reported reactions associated with such establishments. OBJECTIVE: The purpose of this study was to determine the features of allergic reactions to peanut and tree nut in restaurant foods and foods purchased at other private establishments (eg, ice cream shops and bakeries). METHODS: Telephone interviews were conducted through use of a structured questionnaire. Subjects/parental surrogates were randomly selected from among the 706 PAR registrants who reported a reaction in a restaurant or other food establishment. RESULTS: Details were obtained for 156 episodes (29 first-time reactions) from 129 subjects/parental surrogates. Most reactions were caused by peanut (67%) or tree nut (24%); for some reactions (9%), the cause was a combination of peanut and another nut or was unknown. Symptoms began at a median of 5 minutes after exposure and were severe in 27% of reactions. Overall, 86% of reactions were treated (antihistamines, 86%; epinephrine, 40%). Establishments commonly cited were Asian food restaurants (19%), ice cream shops (14%), and bakeries/doughnut shops (13%). Among meal courses, desserts were a common cause (43%). Of 106 registrants with previously diagnosed allergy who ordered food specifically for ingestion by the allergic individual, only 45% gave prior notification about the allergy to the establishment. For 83 (78%) of these 106 reactions, someone in the establishment knew that the food contained peanut or tree nut as an ingredient; in 50% of these incidents, the food item was "hidden" (in sauces, dressings, egg rolls, etc), visual identification being prevented. In 23 (22%) of the 106 cases, exposures were reported from contamination caused primarily by shared cooking/serving supplies. In the remaining 21 subjects with previously diagnosed allergy, reactions resulted from ingestion of food not intended for them, ingestion of food selected from buffet/food bars, or skin contact/inhalation (residual food on tables, 2; peanut shells covering floors, 2; being within 2 feet of the cooking of the food, 1). CONCLUSIONS: Restaurants and other food establishments pose a number of dangers for peanut- and tree nut-allergic individuals, particularly with respect to cross-contamination and unexpected ingredients in desserts and Asian food. Failure to establish a clear line of communication between patron and establishment is a frequent cause of errors.

A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants.

BACKGROUND: A voluntary registry of individuals with peanut and/or tree nut allergy was established in 1997 to learn more about these food allergies. OBJECTIVE: The purpose of this study was to elucidate a variety of features of peanut and tree nut allergy among the first 5149 registry participants. METHODS: The registry was established through use of a structured questionnaire distributed to all members of the Food Allergy and Anaphylaxis Network and to patients by allergists. Parental surrogates completed the forms for children under the age of 18 years. RESULTS: Registrants were primarily children (89% of registrants were younger than 18 years of age; the median age was 5 years), reflecting the membership of the Network. Isolated peanut allergy was reported by 3482 registrants (68%), isolated tree nut allergy by 464 (9%), and allergy to both foods by 1203 (23%). Registrants were more likely to have been born in October, November, or December (odds ratio, 1.2; 95% CI, 1.18-1.23; P <.0001). The median age of reaction to peanut was 14 months, and the median age of reaction to tree nuts was 36 months; these represented the first known exposure for 74% and 68% of registrants, respectively. One half of the reactions involved more than 1 organ system, and more than 75% required treatment, frequently from medical personnel. Registrants with asthma were more likely than those without asthma to have severe reactions (33% vs 21%; P <.0001). In comparison with initial reactions, subsequent reactions due to accidental ingestion were more severe, more common outside the home, and more likely to be treated with epinephrine. CONCLUSIONS: Allergic reactions to peanut and tree nut are frequently severe, often occur on the first known exposure, and can become more severe over time.

Hypoallergenicity and efficacy of an amino acid-based formula in children with cow's milk and multiple food hypersensitivities.

OBJECTIVE: To determine the hypoallergenicity and efficacy of a pediatric amino acid-based formula (AAF), EleCare, for children with cow's milk allergy (CMA) and multiple food allergies (MFA). STUDY DESIGN: Hypoallergenicity was determined by performing blinded oral food challenges in 31 consecutive children with documented CMA. Growth, tolerance, and biochemical response were evaluated during a nonrandomized feeding study with each child serving as his or her own control. RESULTS: Thirty-one children (median age, 23.3 months; range, 6 months to 17.5 years) were recruited; 29 had MFA, 17 had acute reactions and cow's milk-specific IgE antibody, and 14 had allergic eosinophilic gastroenteritis. At study entry, 23 were receiving another AAF; 13 had not tolerated extensively hydrolyzed formula. Eighteen subjects with allergic eosinophilic gastroenteritis and/or MFA were followed up while receiving AAF for a median of 21 months (range, 7 to 40 months), with biochemical analysis performed at 4 months. No statistically significant differences were observed in the change in weight or height National Center for Health Statistics z scores from entry; the percent of expected growth exceeded 90%. There was a small decline in percent eosinophils and increase in hemoglobin, hematocrit, and serum ferritin level (P < .05). Except for small increases in plasma leucine and valine levels (P < or = .006), the remaining biochemical markers were unchanged. CONCLUSIONS: The AAF was hypoallergenic and effective in maintaining normal growth for children with CMA and MFA.

The US Peanut and Tree Nut Allergy Registry: characteristics of reactions in schools and day care.

OBJECTIVE: Severe food-allergic reactions occur in schools, but the features have not been described. STUDY DESIGN: Participants in the US Peanut and Tree Nut Allergy Registry (PAR) who indicated that their child experienced an allergic reaction in school or day care were randomly selected for a telephone interview conducted with a structured questionnaire. RESULTS: Of 4586 participants in the PAR, 750 (16%) indicated a reaction in school or day care, and 100 subjects or parental surrogates described 124 reactions to peanut (115) or tree nuts (9); 64% of the reactions occurred in day care or preschool, and the remainder in elementary school or higher grades. Reactions were reported from ingestion (60%), skin contact/possible ingestion (24%), and inhalation/possible skin contact or ingestion (16%). In the majority of reactions caused by inhalation, concomitant ingestion/skin contact could not be ruled out. Various foods caused reactions by ingestion, but peanut butter craft projects were commonly responsible for the skin contact (44%) or inhalation (41%) reactions. For 90% of reactions, medications were given (86% antihistamines, 28% epinephrine). Epinephrine was given in school by teachers in 4 cases, nurses in 7, and parents or others in the remainder. Treatment delays were attributed to delayed recognition of reactions, calling parents, not following emergency plans, and an unsuccessful attempt to administer epinephrine. CONCLUSIONS: School personnel must be educated to recognize and treat food-allergic reactions. Awareness must be increased to avoid accidental exposures, including exposure from peanut butter craft projects.

Diagnosis and management of childhood food allergy.

The pediatrician plays a pivotal role in the initial diagnosis of food allergy. Alternative diagnoses are considered as a careful history, physical examination, and directed laboratory tests determine the type of adverse reaction and the responsible food. Through elimination diets in infants, appropriately selected tests for specific IgE, and, in some cases, supervised oral food challenges, a diagnosis is secured. Treatment consists of strict dietary elimination with provisions for emergency management of accidental ingestions. Referral to an allergist and dietitian is made as warranted by the severity and type of allergy and for follow-up for possible resolution of the allergy. The pediatrician also provides information to the family for the prevention of allergy in at-risk newborns. Future diagnostic tests and treatment modalities are likely to simplify the management of the food allergic child.

The impact of childhood food allergy on quality of life.

BACKGROUND: Food allergy affects >6% of children, but the impact of this disease on health-related quality of life has not been well studied. METHODS: Parental perceptions of physical and psychosocial functioning were measured with the Children's Health Questionnaire (CHQ-PF50). This tool and an additional allergy-related questionnaire were sent to 400 members of the Food Allergy and Anaphylaxis Network with children aged 5 to 18, an age group on which the tool has been validated. RESULTS: Surveys were completed by 253 parents (63%). The mean age of the food-allergic children was 10.8 years (range, 5 to 18 yrs); 59% were male. Sixty-eight percent were allergic to one or two foods, the remainder to more than two foods. Concomitant chronic atopic diseases included: asthma with atopic dermatitis (33%), atopic dermatitis alone (13%), asthma alone (33%), and 21% had neither asthma nor atopic dermatitis. In comparison to previously established norms, the families scored significantly lower (more than 10 scale score points lower and P < 0.0001) for general health perception (GH), emotional impact on the parent (PE), and limitation on family activities (FA). Associated atopic disease, influenced primarily by those with both asthma and atopic dermatitis, accounted for a significant reduction in the GH scale (analysis of variance, P = 0.0001), but not for measures of PE and FA. Within the study group, food-allergic individuals with several (more than two) food allergies had significantly lower (P < 0.05) scores for 7 of 12 scales compared with individuals with few (one or two) food allergies. However, those with one or two food allergies scored significantly lower (P < 0.0001) than established norms on scales for GH, PE, and FA. CONCLUSIONS: Childhood food allergy has a significant impact on GH, PE, and FA. Factors that influence reductions in these scales include associated atopic disease and the number of foods being avoided.

Peanut and tree nut allergy.

Among foods causing allergic reactions in children, peanut (a legume) and tree nuts (ie, walnut, hazel nut, Brazil nut, pecan) have attracted considerable attention for several reasons. Allergies to these foods are common, frequently have an onset in the first few years of life, generally persist, and account for severe and potentially fatal allergic reactions. Furthermore, the ubiquity of these foods in the diet makes avoidance difficult and accidental ingestions, with reactions, common. This review discusses recent and emerging information on the prevalence, clinical characteristics, natural history, genetic basis, and current treatment of these allergies. In addition, recent advances in the molecular and immunologic characteristics of these allergens, and novel therapeutic options under investigation in animal models, are reviewed.