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.

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%.

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.

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.

Food protein-induced enterocolitis syndrome: clinical perspectives.

Food Protein-Induced Enterocolitis Syndrome (FPIES) is a symptom complex of severe vomiting and diarrhea caused by non-IgE-mediated allergy to cow's milk and/or soy in infants. Symptoms typically begin in the first month of life in association with failure to thrive and may progress to acidemia and methemoglobinemia. Symptoms resolve after the causal protein (usually sensitivity to both cow's milk and soy) is removed from the diet. Symptoms recur approximately 2 hours after reintroduction of the protein along with a coincident elevation of the peripheral blood polymorphonuclear leukocyte count. The sensitivity is usually outgrown by 3 years of age. The purpose of this review is to delineate the characteristic clinical features, diagnosis and management of FPIES. Furthermore, infantile FPIES will be discussed in relation to clinical syndromes that share features with it ("atypical FPIES") and other food-allergic disorders affecting the gastrointestinal tract.

Manifestations of food allergy: evaluation and management.

The term "food allergy" refers to adverse immunologic reactions to food. Food allergy is usually mediated by IgE antibody directed to specific food proteins, but other immunologic mechanisms can also play a role. The primary target organs for food allergic reactions are the skin, the gastrointestinal tract and the respiratory system. Both acute reactions (hives and anaphylaxis) and chronic disease (asthma, atopic dermatitis and gastrointestinal disorders) may be caused or exacerbated by food allergy. The foods most commonly causing these reactions in children are milk, egg, peanuts, soy, wheat, tree nuts, fish and shellfish; in adults, they are peanuts, tree nuts, shellfish and fish. The diagnosis of food allergy requires a careful search for possible causes, confirmation of the cause(s) with supporting tests, including specific tests for IgE (i.e., prick skin tests, radioallergosorbent tests) and, in some cases, oral food challenges. Treatment consists of elimination of the causal food(s) along with medical treatment, including the prompt self-administration of epinephrine in the event of a serious reaction.

Food allergy: when and how to perform oral food challenges.

In many situations, the diagnosis of food allergy rests simply upon a history of an acute onset of typical symptoms, such as hives and wheezing, following the isolated ingestion of a suspected food, with confirmatory laboratory studies of positive prick skin tests or Radioallergosorbent tests. However, the diagnosis is more complicated when multiple foods are implicated or when chronic diseases, such as asthma or atopic dermatitis, are evaluated. The diagnosis of food allergy and identification of the particular foods responsible is also more difficult when reactions are not mediated by IgE antibody, as is the case with a number of gastrointestinal food allergies. In these latter circumstances, well-devised elimination diets followed by physician-supervised oral food challenges are critical in the identification and proper treatment of these disorders. Because childhood food allergies to common allergenic foods such as milk, egg, wheat and soy are usually outgrown, oral food challenges are also an integral part of the long-term management of these children.

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.

Determinants of systemic manifestations of food allergy.

The myriad of systemic manifestations induced by food hypersensitivity responses is testament to the ability of localized exposure to foods in the gastrointestinal tract to result in symptoms in distal target organs. Cow's milk protein, for example, may induce hives (urticaria), atopic dermatitis, isolated gastrointestinal symptoms, or severe generalized anaphylaxis in different individuals or in the same person at different times. These diverse manifestations are the result of complex interactions among the causal food protein, gut, immune system, and target organs. The dynamic state of these interactions is demonstrated by the development of food tolerance in most subjects and by the ability to experience the development of new allergies in some subjects. This review explores the variety of clinical manifestations of food hypersensitivity disorders in the context of the question: What determines the local or systemic expression of food allergy in a given individual at a particular time? Evidence is provided for both systemic and local immune activation. The role of food-protein chemistry, absorption and processing of ingested allergen, immune responses (type, degree, and specificity), and target organ hyperreactivity are considered as determinants in the expression of food allergic disorders.

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 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.

EMLA cream for pain reduction in diagnostic allergy skin testing: effects on wheal and flare responses.

BACKGROUND: The use of a topical anesthetic cream containing prilocaine and lidocaine (EMLA) has been considered to reduce the pain of diagnostic allergy skin testing, but the effects of the cream on interpretation of skin tests is unclear. OBJECTIVE: To determine the effects of the cream for pain reduction using prick and ID skin tests and for possible alteration of wheal and flare responses to allergen, saline, and histamine. METHODS: In a randomized, double-masked, placebo-controlled design, 20 adult volunteers with a history of positive allergen tests had EMLA and placebo cream placed according to the manufacturer's recommendations on the volar aspect of the arms. Paired skin tests were placed and subjects rated the tests on a pain scale from 0 to 5 and average wheal and flare diameters were determined. RESULTS: Mean pain scores (+/-SEM) were significantly reduced from 2.5 +/- 0.7 to 1.1 +/- 0.6 for prick tests (n = 20, P < .001) and from 3.2 +/- 0.9 to 1.13 +/- 0.9 for intradermal (ID) tests (n = 58, P < .001). The wheal sizes for allergen prick tests, allergen ID tests, and histamine ID tests were identical in comparing placebo to EMLA-treated skin. Flare responses were reduced on the actively treated skin, on average, as follows: allergen skin tests- 52% (P < .001), and histamine- 40% (P < .001). In nine tests there was complete suppression of the flare response, all on the EMLA treated skin. CONCLUSIONS: EMLA significantly reduced the pain associated with diagnostic allergy skin testing and with no effect on the size of the wheal response. It reduces the flare response, in some cases inhibiting it completely, which must be taken into consideration in interpreting results.

Food hypersensitivity and atopic dermatitis: pathophysiology, epidemiology, diagnosis, and management.

Laboratory and clinical investigations over the past two decades have demonstrated that food allergy plays a pathogenic role in a subset of patients, primarily infants and children, with atopic dermatitis (AD). Approximately 40% of infants and young children with moderate to severe AD have food allergy, but identifying this subset of patients and isolating the relevant food allergens requires a high index of suspicion, the use of appropriate laboratory tests, and, in some cases, physician-supervised oral food challenges. Removal of the causal food protein(s) leads to clinical improvement but requires a great deal of education because most of the common causal foods (egg, milk, wheat, soy, peanut, and so forth) are ubiquitous in the food supply, and food elimination diets risk causing nutritional deficits. Fortunately, most food allergies resolve in early childhood, and food allergy is not a common cause for AD in older children and adults.

Cow's milk protein-specific IgE concentrations in two age groups of milk-allergic children and in children achieving clinical tolerance.

BACKGROUND: IgE-mediated cow's milk protein allergy (CMPA) is usually outgrown in children by the age of 3 years. The immunological responses to cow's milk proteins in children who achieve tolerance, in comparison with those who remain allergic, however, are not well described. OBJECTIVE: To compare the level of cow's milk protein-specific IgE among children with documented CMPA under the age of 3 years, another group over the age of 9 years (persistent allergy), and in another group of children in whom clinical tolerance developed. METHODS: Stored sera from children with CMPA were analysed for IgE antibodies specific for whole cow's milk, casein, whey, alpha-lactalbumin (ALA), beta-lactoglobulin (BLG), and bovine serum albumin (BSA) using the Pharmacia CAP System FEIA. RESULTS: Within each group of CMPA children, the concentration of specific IgE antibody to casein proteins was not significantly different from that to whey proteins. However, children in the group with CMPA over 9 years of age had significantly greater concentrations of whole milk (P = 0.02) and casein-specific (P = 0. 04) IgE antibodies compared with the group of children with CMPA under age 3 years. Children under the age of 3 years had a higher median concentration of casein-specific IgE (20.2 vs. 5.5, P = 0.04) than another group of 11 children (mean age 3.5 years), who later lost their milk allergy. Out of 16 children who lost sensitivity to milk, 75% had milk-specific IgE levels below 14.3 kUA/L (median, 1.3 kUA/L). CONCLUSIONS: Although a dominant allergenic milk protein fraction was not identified within either of the two age groups, those with persistent CMPA over age 9 years had significantly elevated levels of milk and casein-specific IgE compared with younger children with CMPA.

Determinants of airway responses to cat allergen: comparison of environmental challenge to quantitative nasal and bronchial allergen challenge.

BACKGROUND: Why allergic subjects may have asthma or rhinitis off allergen exposure remains unclear. OBJECTIVE: This study was carried out to compare airway responses during environmental allergen challenge (EAC) with quantitative allergen provocation challenges of the upper and lower airways. METHODS: Thirteen subjects with allergy to cats underwent EAC to cats. Lower airway responses during EAC were compared with bronchoprovocation with allergen. Nasal mucosal challenge with allergen-soaked disks were compared with EAC nasal responses. Nonspecific bronchial reactivity was assessed with methacholine; allergen sensitivity was assessed by skin prick tests, RAST, and end-point skin titration. RESULTS: During EAC, the maximal fall in FEV1 ranged from 6% to 57% (median, 18%) and correlated closely with allergen bronchoprovocation PD20 (Spearman's correlation coefficient [Rs] = -0.85, p < 0.0002). EAC asthmatic responses and allergen bronchoprovocation correlated with methacholine PD20 (Rs = -0.85, p = 0.0002 and Rs = 0.83, p = 0.0004, respectively). Nasal provocation and EAC nasal responses correlated with each other but not with lower airway responses. On the basis of EAC and allergen bronchoprovocation responses, seven participants with asthma were identified. This group was significantly more sensitive to inhaled methacholine but was similar to the nonasthmatic group in IgE-mediated sensitivity and nasal responses. CONCLUSIONS: The lower respiratory tract is less responsive to allergic and nonallergic stimuli in persons with allergic rhinitis. In persons with asthma during EAC, the response to nebulized cat allergen is also abnormal and correlates closely with their abnormal responsiveness to nonimmunologic stimuli.