Food allergy; soy; component testing; skin prick testing; IgE; oral food challenge; receiver operating characteristic curve; sensitivity; specificity
Egg allergy is one of the most common food allergies of childhood. There is a lack of information on the immunologic basis of egg allergy beyond the role of IgE.
To use transcriptional profiling as a novel approach to uncover immunologic processes associated with different phenotypes of egg allergy.
Peripheral blood mononuclear cells (PBMCs) were obtained from egg-allergic children who were defined as reactive (BER) or tolerant (BET) to baked egg, and from food allergic controls (AC) who were egg non-allergic. PBMCs were stimulated with egg white protein. Gene transcription was measured by microarray after 24 h, and cytokine secretion by multiplex assay after 5 days.
The transcriptional response of PBMCs to egg protein differed between BER and BET versus AC subjects. Compared to the AC group, the BER group displayed increased expression of genes associated with allergic inflammation as well as corresponding increased secretion of IL-5, IL-9 and TNF-α. A similar pattern was observed for the BET group. Further similarities in gene expression patterns between BER and BET groups, as well as some important differences, were revealed using a novel Immune Annotation resource developed for this project. This approach identified several novel processes not previously associated with egg allergy, including positive associations with TLR4-stimulated myeloid cells and activated NK cells, and negative associations with an induced Treg signature. Further pathway analysis of differentially expressed genes comparing BER to BET subjects showed significant enrichment of IFN-α and IFN-γ response genes, as well as genes associated with virally-infected DCs.
Transcriptional profiling identified several novel pathways and processes that differed when comparing the response to egg allergen in BET, BER, and AC groups. We conclude that this approach is a useful hypothesis-generating mechanism to identify novel immune processes associated with allergy and tolerance to forms of egg.
Peanut allergy is an IgE‐mediated adverse reaction to a subset of proteins found in peanuts. Immunotherapy aims to desensitize allergic patients through repeated and escalating exposures for several months to years using extracts or flours. The complex mix of proteins and variability between preparations complicates immunotherapy studies. Moreover, peanut immunotherapy is associated with frequent negative side effects and patients are often at risk of allergic reactions once immunotherapy is discontinued. Allergen‐specific approaches using recombinant proteins are an attractive alternative because they allow more precise dosing and the opportunity to engineer proteins with improved safety profiles. We tested whether Ara h 1 and Ara h 2, two major peanut allergens, could be produced using chloroplast of the unicellular eukaryotic alga, Chlamydomonas reinhardtii. C. reinhardtii is novel host for producing allergens that is genetically tractable, inexpensive and easy to grow, and is able to produce more complex proteins than bacterial hosts. Compared to the native proteins, algal‐produced Ara h 1 core domain and Ara h 2 have a reduced affinity for IgE from peanut‐allergic patients. We further found that immunotherapy using algal‐produced Ara h 1 core domain confers protection from peanut‐induced anaphylaxis in a murine model of peanut allergy.
algae; peanut; allergy; immunotherapy; biotechnology; recombinant protein; Chlamydomonas reinhardtii
FAHF-2 is a 9-herb formula based on Traditional Chinese Medicine that blocks
peanut anaphylaxis in a murine model. In Phase I studies, FAHF-2 was found to be safe,
and well tolerated.
To evaluate the safety and effectiveness of FAHF-2 as a treatment for food
In this double-blind, randomized, placebo-controlled study, 68 subjects, 12-45
years of age, with allergies to peanut, tree nut, sesame, fish, and/or shellfish,
confirmed by baseline double-blind, placebo controlled food challenge (DBPCFC), received
FAHF-2 (n=46) or placebo (n=22). After 6 months of therapy, subjects
underwent DBPCFC. For those who demonstrated increases in eliciting dose, a repeat
DBPCFC was performed 3 months after stopping therapy.
Treatment was well-tolerated with no serious adverse events. By intent-to-treat
analysis, the placebo group had a higher eliciting dose and cumulative dose
(p=0.05) at the end of treatment DBPCFC. There was no difference in the
requirement for epinephrine to treat reactions (p=0.55). There were no
significant differences in allergen-specific IgE and IgG4, cytokine
production by PBMCs or basophil activation between active and placebo groups. In
vitro immunological studies performed on subject baseline PBMCs incubated
with FAHF-2 and food allergen produced significantly less IL-5, greater IL-10 and
increased numbers of Tregs than untreated cells. Notably, 44% of subjects had
poor drug adherence for at least one-third of the study period.
FAHF-2 is a safe herbal medication for food allergic individuals and shows
favorable in vitro immunomodulatory effects; however, efficacy for improving tolerance
to food allergens is not demonstrated at the dose and duration used.
food allergy; FAHF-2; Chinese herbal therapy; peanut allergy
The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated food allergy. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in IgE-mediated food allergy.
We will undertake a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence. Studies will be independently screened against pre-defined eligibility criteria and critically appraised using established instruments. Data will be descriptively and, if possible and appropriate, quantitatively synthesised.
The findings from this review will be used to inform the development of recommendations for EAACI’s Guidelines on AIT.
Electronic supplementary material
The online version of this article (doi:10.1186/s13601-016-0113-z) contains supplementary material, which is available to authorized users.
Allergy; Allergen immunotherapy; Food allergy; Therapy; Sensitisation
The prevalence of allergic diseases is approximately 10 % in infants whose parents and siblings do not have allergic diseases and 20–30 % in those with an allergic first-degree relative. Vitamin D is involved in the regulation of the immune system and it may play a role in the development, severity and course of asthma and other allergic diseases.
The World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations addressing the use of vitamin D in primary prevention of allergic diseases.
Our WAO guideline panel identified the most relevant clinical questions and performed a systematic review of randomized controlled trials and non-randomized studies (NRS), specifically cohort and case-control studies, of vitamin D supplementation for the prevention of allergic diseases. We also reviewed the evidence about values and preferences, and resource requirements (up to January 2015, with an update on January 30, 2016). We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations.
Having reviewed the currently available evidence, the WAO guideline panel found no support for the hypothesis that vitamin D supplementation reduces the risk of developing allergic diseases in children. The WAO guideline panel suggest not using vitamin D in pregnant women, breastfeeding mothers, or healthy term infants as a means of preventing the development of allergic diseases. This recommendation does not apply to those mothers and infants who have other indications for prophylactic or therapeutic use of vitamin D. The panel’s recommendations are conditional and supported by very low certainty evidence.
WAO recommendations about vitamin D supplementation for the prevention of allergic diseases support parents, clinicians and other health care professionals in their decisions whether or not to use vitamin D in preventing allergic diseases in healthy, term infants.
Electronic supplementary material
The online version of this article (doi:10.1186/s40413-016-0108-1) contains supplementary material, which is available to authorized users.
Allergic Diseases; Prevention; Vitamin D; Practice guidelines; GRADE
Breastfeeding; breast milk; human milk; cow’s milk; infants; allergy; gut mucosa; cytokine; chemokine; growth factor; tolerance
We previously reported initial results of the first multi-center randomized, double blind, placebo controlled clinical trial of peanut sublingual immunotherapy (SLIT), observing a favorable safety profile associated with modest clinical and immunologic effects in the first year.
To provide long-term (3-year) clinical and immunologic outcomes for our peanut SLIT trial. Key endpoints: (1) percentage of responders at 2 years (could consume 5g of peanut powder or a 10-fold increase from baseline), 2) percentage reaching desensitization at 3 years, (3) percentage attaining sustained unresponsiveness after 3 years, (4) immunologic endpoints and (5) assessment of safety parameters.
Response to treatment was evaluated in 40 subjects aged 12-40 years by performing a 10g peanut powder oral food challenge (OFC) following 2 and 3 years of daily peanut SLIT therapy. At 3 years, SLIT was discontinued for 8 weeks followed by another 10g OFC, and an open feeding of peanut butter to assess sustained unresponsiveness.
Approximately 98% of the 18,165 doses were tolerated without adverse reactions beyond the oropharynx, with no severe symptoms or uses of epinephrine. A high rate (>50%) discontinued therapy. By study end, 4/37 (10.8%) of SLIT treated participants were fully desensitized to 10g of peanut powder, and all 4 achieved sustained unresponsiveness. Responders at 2 years showed a significant decrease in peanut-specific basophil activation and skin prick test titration compared to non-responders.
Peanut SLIT induced a modest level of desensitization, decreased immunologic activity over 3 years in responders, and had an excellent long-term safety profile. However, most patients discontinued therapy by the end of year 3, and only 10.8% of subjects achieved sustained unresponsiveness.
Peanut allergy; sublingual immunotherapy; desensitization; food allergy; follow-up
Previous studies report epinephrine use for positive oral food challenges (OFCs) to be 9–11% when generally performed to determine outgrowth of food allergies. Epinephrine use for positive OFCs performed as screening criteria for enrollment in therapeutic trials for food allergy has not been reported.
To assess the characteristics and treatment for positive OFCs performed for screening subjects for food therapeutic trials.
Retrospective review of positive screening OFCs from two treatment trials, Food Allergy Herbal Formula-2 (FAHF-2) (n=45) and Milk Oral Immunotherapy (MOIT) (n=29) conducted at the Icahn School of Medicine at Mount Sinai was performed.
The most common initial symptom elicited was oral pruritus, reported for 81% (n=60) of subjects. Overall, subjective gastrointestinal symptoms (oral pruritus, throat pruritus, nausea, abdominal pain) were most common (97.3% subjects), followed by cutaneous symptoms (48.7%). Of the 74 positive DBPCFCs, 29 (39.2%) were treated with epinephrine; 2 of these subjects received 2 doses of epinephrine (6.9% of the reactions treated with epinephrine or 2.7% of all reactions). Biphasic reactions were infrequent, occurring in 3 subjects (4%).
Screening OFCs to confirm food allergies can be performed safely, but there was a higher rate of epinephrine use compared to OFCs used for assessing food allergy outgrowth. Therefore, personnel skilled and experienced in the recognition of early signs and symptoms of anaphylaxis who can promptly initiate treatment are required.
Epinephrine; positive oral food challenge; anaphylaxis; food allergy
Asthma causes significant morbidity in children, and studies have demonstrated that environmental allergies contribute to increased asthma morbidity.
We investigated the differences between allergen skin tests and specific IgE and the role of IgG in regards to allergen exposure levels, and asthma morbidity in inner-city children.
Five hundred and six serum samples from the National Cooperative Inner City Asthma Study (NCICAS) were evaluated for specific IgE to cockroach (Blattella germanica), dust mite (Dermatophagoides farinae) and Alternaria as well as specific IgG and IgG4 to cockroach (B. germanica) and total IgE levels. Associations between sensitization to these allergens, exposures, and asthma morbidity were determined.
Sensitization to environmental allergens and total IgE correlated with increased healthcare and medication use, but not with wheeze symptoms. Sensitization with exposure to cockroach was associated with increased asthma morbidity, whereas dust mite sensitization was correlated with asthma morbidity independent of exposure. There was also a strong correlation between specific IgE levels and skin test results, but the tests did not always agree. The relationship between specific IgE and asthma morbidity is linear with no obvious cutoff value. Increased Bla g 1 in the home was a good predictor for sensitization; however this relationship was not demonstrated for Der f 1. Cockroach-specific IgG correlated with increased healthcare use, however, there was no modifying effect of specific IgG or IgG4 on the association between cockroach-specific IgE and asthma morbidity.
Specific IgE levels and prick skin test results to environmental allergens can serve as markers of severe asthma for inner-city children. Asthma morbidity increased in a linear manner with specific IgE levels. Cockroach-specific IgG was not an important predictor or modifier of asthma morbidity.
Alternaria; asthma; cockroach; dust mite; sensitization
The prevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10 % and reaches 20–30 % in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Prebiotics – non-digestible oligosaccharides that stimulate growth of probiotic bacteria – have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention.
The World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of prebiotics in the prevention of allergy.
The WAO guideline panel identified the most relevant clinical questions about the use of prebiotics for the prevention of allergy. We performed a systematic review of randomized controlled trials of prebiotics, and reviewed the evidence about patient values and preferences, and resource requirements (up to January 2015, with an update on July 29, 2015). We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations.
Based on GRADE evidence to decision frameworks, the WAO guideline panel suggests using prebiotic supplementation in not-exclusively breastfed infants and not using prebiotic supplementation in exclusively breastfed infants. Both recommendations are conditional and based on very low certainty of the evidence. We found no experimental or observational study of prebiotic supplementation in pregnant women or in breastfeeding mothers. Thus, the WAO guideline panel chose not to provide a recommendation about prebiotic supplementation in pregnancy or during breastfeeding, at this time.
WAO recommendations about prebiotic supplementation for the prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether or not to use prebiotics for the purpose of preventing allergies in healthy, term infants.
Electronic supplementary material
The online version of this article (doi:10.1186/s40413-016-0102-7) contains supplementary material, which is available to authorized users.
Food allergy; hazelnut; birch; component testing; skin prick testing; IgE; oral food challenge; sensitivity; specificity
cow's milk; food allergy; partially hydrolyzed whey formula; casein; alpha-lactalbumin; beta-lactoglobulin; protein
The impact of maternal ingestion of peanut during pregnancy and lactation on an offspring’s risk for peanut allergy is under debate.
To investigate the influence of maternal dietary peanut exposure and breast milk on an offspring’s allergy risk.
Preconceptionally peanut-exposed C3H/HeJ females were either fed or not fed peanut during pregnancy and lactation. The offsprings’ responses to peanut sensitization or oral tolerance induction by feeding antigen prior to immunization were assessed. We also assessed the impact of immune murine milk on tolerance induction pre- or post-weaning. For antigen uptake studies, mice were gavaged with fluorescent peanut in the presence or absence of immune murine milk; Peyer’s patches were harvested for immunostaining.
Preconceptional peanut exposure resulted in the production of varying levels of maternal antibodies in serum (and breast milk), which were transferred to the offspring. Despite this, maternal peanut exposure either preconceptionally or during pregnancy and lactation, when compared to no maternal exposure, had no impact on peanut allergy. When offspring were fed peanut directly, dose-dependent tolerance induction, unaltered by maternal feeding of peanut, was seen. Although peanut uptake into the gut-associated lymphoid tissues was enhanced by immune milk as compared to naïve milk, tolerance induction was not affected by the co-administration of immune milk either pre- or post-weaning.
Maternal peanut exposure during pregnancy and lactation has no impact on the development of peanut allergy in the offspring. Tolerance to peanut can be induced early, even pre-weaning, by giving moderate amounts of peanut directly to the infant, and this is neither enhanced nor impaired by concurrent exposure to immune milk.
Food protein-induced enterocolitis syndrome (FPIES) is a gastrointestinal hypersensitivity disorder with a poorly understood pathophysiology and no biomarkers to aid in diagnosis.
To investigate humoral and cellular responses to casein in children with milk-FPIES, including the role of casein-specific (cs) IgA and T-cell mediated TGF-β responses.
Patients and methods
Thirty-one children previously diagnosed with milk-FPIES were challenged with milk. Twelve age-matched children with FPIES to other foods and 6 milk-tolerant children without a history of FPIES were used as controls. Casein-specific IgE, IgG, IgG4 and IgA were measured in serum and TGF-β levels in supernatants of casein-stimulated PBMCs.
Twenty-six children with milk-FPIES reacted (active milk-FPIES) and five tolerated milk (milk-FPIES-resolved) during food challenge. All of them had significantly lower levels of csIgG, csIgG4 and csIgA than control children (p-value<0.001). There were no TGF-β responses in supernatants of active milk-FPIES children.
Children with milk-FPIES have low levels of csIgG, csIgG4 and csIgA. In particular, children with active FPIES to cow’s milk have deficient T-cell mediated TGF-β responses to casein, rendering TGF-β a promising biomarker in identifying children who are likely to experience FPIES reactions to this allergen. Prospective studies are needed to validate these findings, elucidate their role in FPIES pathophysiology and establish the diagnostic utility of TGF-β in milk-induced FPIES.
milk allergy; casein; immunoglobulin A; IgA; IgG4; transforming growth factor β; TGF-β; peripheral blood mononuclear cell; PBMCs; food challenge
Kiwifruit allergy has been described mostly in the adult population, but immunoglobulin (Ig)E-mediated allergic reactions to kiwifruit appear to be occurring more frequently in children. To date, 13 allergens from kiwifruit have been identified. Our aim was to identify kiwifruit allergens in a kiwifruit allergic-pediatric population, describing clinical manifestations and patterns of recognition. Twenty-four children were included. Diagnosis of kiwifruit allergy was based on compatible clinical manifestations and demonstration of specific IgE by skin prick test (SPT) and/or serum-specific IgE determination. SDS-PAGE and immunoblotting were performed with kiwifruit extract, and proteins of interest were further analyzed by mass spectrometry/mass spectrometry. For component-resolved in vitro diagnosis, sera of kiwifruit-allergic patients were analyzed by an allergen microarray assay. Act d 1 and Act d 2 were bound by IgE from 15 of 24 children. Two children with systemic manifestations recognized a protein of 15 kDa, homologous to Act d 5. Act d 1 was the allergen with the highest frequency of recognition on microarray chip, followed by Act d 2 and Act d 8. Kiwifruit allergic children develop systemic reactions most frequently following ingestion compared to adults. Act d 1 and Act d 2 are major allergens in the pediatric age group.
actinidin; SDS-PAGE immunoblotting; pediatric; kiwifruit; food allergy
Anti-asthma herbal medicine intervention (ASHMI™), a combination of three traditional Chinese medicinal herbs developed in our laboratory, has demonstrated efficacy in both mouse models of allergic asthma, and a double-blind placebo-controlled clinical trial in patients with asthma. This study was designed to determine if the anti-inflammatory effects of individual herbal constituents of ASHMI™ exhibited synergy.
Effects of ASHMI and its components aqueous extracts of Lingzhi (Ganoderma lucidum), Kushen (Sophora flavescens) and Gancao (Glycyrrhiza uralensis), on Th2 cytokine secretion by murine memory Th2 cells (D10.G4.1) and eotaxin-1 secretion by human lung fibroblast (HLF-1) cells were determined by measuring levels in culture supernatants by enzyme-linked immunosorbent assay. Potential synergistic effects were determined by computing interaction indices from concentration-effect curve parameters.
Individual Lingzhi, Kushen and Gancao extracts and ASHMI (the combination of individual extracts) inhibited production of interleukin (IL)-4 and IL-5 by murine memory Th2 cells and eotaxin-1 production by HLF-1 cells. The mean 25%-inhibitory-concentration (IC25) values (mg/mL) for ASHMI, Lingzhi, Kushen and Gancao for IL-4 production were 30.9, 79.4, 123, and 64.6, respectively; for IL-5 production were 30.2, 263, 123.2 and 100, respectively; for eotaxin-1 were 13.2, 16.2, 30.2, and 25.1, respectively. The IC50 values (mg/mL) for ASHMI, Lingzhi, Kushen and Gancao for IL-4 production were 158.5, 239.9, 446.7, and 281.8, respectively; for eotaxin-1 were 38.1, 33.1, 100, and 158.5, respectively. The interaction indices of ASHMI constituents at IC25 were 0.35 for IL-4, 0.21 for IL-5 and 0.59 for eotaxin-1. The interaction indices at IC50 values were 0.50 for IL-4 and 0.62 for eotaxin-1 inhibition. Inhibition of IL-5 did not reach IC50 values. All interaction indices were below 1 which indicated synergy.
By comparing the interaction index values, we find that constituents in ASHMI™ synergistically inhibited eotaxin-1 production as well as Th2 cytokine production.
medicine, Chinese traditional; medicine, herbal; plant extracts; anti-asthma herbal medicine intervention (ASHMI); anti-asthmatic agents; chemokine CCL11; interleukin-4; interleukin -5; in vitro
Food allergy; peanut allergy; basophil; omalizumab
The purpose of this brief communication is to highlight emerging evidence to existing guidelines regarding potential benefits of supporting early, rather than delayed, peanut introduction during the period of complementary food ntroduction in infants. This document should be considered as interim guidance based on consensus among the following organizations: American Academy of Allergy, Asthma & Immunology; American Academy of Pediatrics; American College of Allergy, Asthma & Immunology; Australasian Society of Clinical Immunology and Allergy; Canadian Society of Allergy and Clinical Immunology; European Academy of Allergy and Clinical Immunology; Israel Association of Allergy and Clinical Immunology; Japanese Society for Allergology; Society for Pediatric Dermatology; and World Allergy Organization. More formal guidelines regarding early-life, complementary feeding practices and the risk of allergy development will follow in the next year from the National Institute of Allergy and Infectious Diseases – sponsored Working Group and the European Academy of Allergy and Clinical Immunology.
Allergy prevention; Complementary feeding; Peanut allergy
The purpose of this brief communication is to highlight emerging evidence to existing guidelines regarding potential benefits of supporting early, rather than delayed, peanut introduction during the period of complementary food introduction in infants. This document should be considered as interim guidance based on consensus among the following organizations: American Academy of Allergy, Asthma & Immunology; American Academy of Pediatrics; American College of Allergy, Asthma & Immunology; Australasian Society of Clinical Immunology and Allergy; Canadian Society of Allergy and Clinical Immunology; European Academy of Allergy and Clinical Immunology; Israel Association of Allergy and Clinical Immunology; Japanese Society for Allergology; Society for Pediatric Dermatology; and World Allergy Organization. More formal guidelines regarding early-life, complementary feeding practices and the risk of allergy development will follow in the next year from the National Institute of Allergy and Infectious Diseases – sponsored Working Group and the European Academy of Allergy and Clinical Immunology.
Allergy prevention; Complementary feeding; Peanut allergy
asthma; vitamin D; food allergy; peanut; milk; egg; wheat; soy; inner city
There is a growing consensus that the long term solution to the asthma epidemic lies in prevention and not in treatment of established disease. Atopic asthma arises from gene x environment interactions which most commonly occur during a relatively narrow window period in pre- and postnatal development. These interactions are incompletely understood, and hence the holy grail of primary prevention remains an elusive goal. We contend that a lack of understanding of the role of atopy in early life in the development of persistent asthma in children exists amongst primary care physicians, paediatricians and specialists. In this review we argue that early identification of high risk children is feasible based on currently available technology, and worthwhile in relation to potential benefits to the children so identified. Knowledge of an asthmatic child's atopic status in early life has practical clinical and prognostic implications, as well as forming the basis for future preventative strategies.
Oral immunotherapy (OIT) with cow's milk (CM) has been reported to induce a number of specific antibody responses, but these remain to be fully characterized. Our objective was to explore whether IgE and IgG4 epitope binding profiles could predict the risk of side effects during cow's milk OIT.
The study population consisted of 32 children (6 – 17 years of age) with cow's milk allergy: 26 children who successfully completed OIT and 6 children who discontinued therapy due to adverse reactions. We investigated sera drawn before and after OIT. We analyzed specific IgE and IgG4 binding to CM protein derived peptides with a microarray based immunoassay. Antibody binding affinity was analyzed with a competition assay where CM proteins in solution competed with peptides printed on the microarray.
IgE binding to CM peptides decreased and IgG4 binding increased following the OIT in children who attained desensitization. Compared with children who successfully completed OIT, those who discontinued OIT due to adverse reactions developed increased quantities and affinity of epitope-specific IgE antibodies and a broader diversity of IgE and IgG4 binding, but less overlap in IgE and IgG4 binding to CM peptides.
Detailed analysis of IgE and IgG4 binding to CM peptides may help in predicting whether CM OIT will be tolerated successfully. It may thus improve the safety of the therapy.
antibody affinity; cow's milk allergy; epitope; IgE; IgG4; oral immunotherapy; peptide