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1.  Persistence of IgE-Associated Allergy and Allergen-Specific IgE despite CD4+ T Cell Loss in AIDS 
PLoS ONE  2014;9(6):e97893.
The infection of CD4+ cells by HIV leads to the progressive destruction of CD4+ T lymphocytes and, after a severe reduction of CD4+ cells, to AIDS. The aim of the study was to investigate whether HIV-infected patients with CD4 cell counts <200 cells/µl can suffer from symptoms of IgE-mediated allergy, produce allergen-specific IgE antibody responses and show boosts of allergen-specific IgE production. HIV-infected patients with CD4 counts ≤200 cells/µl suffering from AIDS and from IgE-mediated allergy were studied. Allergy was diagnosed according to case history, physical examination, skin prick testing (SPT), and serological analyses including allergen microarrays. HIV infection was confirmed serologically and the disease was staged clinically. The predominant allergic symptoms in the studied patients were acute allergic rhinitis (73%) followed by asthma (27%) due to IgE-mediated mast cell activation whereas no late phase allergic symptoms such as atopic dermatitis, a mainly T cell-mediated skin manifestation, were found in patients suffering from AIDS. According to IgE serology allergies to house dust mites and grass pollen were most common besides IgE sensitizations to various food allergens. Interestingly, pollen allergen-specific IgE antibody levels in the patients with AIDS and in additional ten IgE-sensitized patients with HIV infections and low CD4 counts appeared to be boosted by seasonal allergen exposure and were not associated with CD4 counts. Our results indicate that secondary allergen-specific IgE production and IgE-mediated allergic inflammation do not require a fully functional CD4+ T lymphocyte repertoire.
PMCID: PMC4045723  PMID: 24896832
2.  Variably severe systemic allergic reactions after consuming foods with unlabelled lupin flour: a case series 
Lupin allergy remains a significant cause of food-induced allergic reactivity and anaphylaxis. Previous work suggests a strong association with legume allergy and peanut allergy in particular. Both doctors and the public have little awareness of lupin as an allergen.
Case presentation
Case 1 was a 41-year-old Caucasian woman without previous atopy who developed facial swelling, widespread urticaria with asthma and hypotension within minutes of eating a quiche. Her lupin allergy was confirmed by both blood and skin tests. Her lupin sensitivity was so severe that even the miniscule amount of lupin allergen in the skin testing reagent produced a mild reaction.
Case 2 was a 42-year-old mildly atopic Caucasian woman with three episodes of worsening urticaria and asthma symptoms over 6 years occurring after the consumption of foods containing lupin flour. Blood and skin tests were positive for lupin allergy.
Case 3 was a 38-year-old Caucasian woman with known oral allergy syndrome who had two reactions associated with urticaria and vomiting after consuming foods containing lupin flour. Skin testing confirmed significant responses to a lupin flour extract and to one of the foods inducing her reaction.
Case 4 was a 54-year-old mildly atopic Caucasian woman with a 7 year history of three to four episodes each year of unpredictable oral tingling followed by urticaria after consuming a variety of foods. The most recent episode had been associated with vomiting. She had developed oral tingling with lentil and chickpeas over the previous year. Skin and blood tests confirmed lupin allergy with associated sensitivity to several legumes.
Lupin allergy can occur for the first time in adults without previous atopy or legume sensitivity. Although asymptomatic sensitisation is frequent, clinical reactivity can vary in severity from severe anaphylaxis to urticaria and vomiting. Lupin allergy may be confirmed by skin and specific immunoglobulin E estimation. Even skin testing can cause symptoms in some highly sensitive individuals. The diagnosis of lupin allergy in adults may be difficult because it is frequently included as an undeclared ingredient. Better food labelling and medical awareness of lupin as a cause of serious allergic reactions is suggested.
PMCID: PMC3943371  PMID: 24529316
Anaphylaxis; Food labelling; Gluten-free spaghetti; Lupin allergy; Oral allergy
3.  The acute and long-term management of food allergy: protocol for a rapid systematic review 
Allergic reactions to plant and animal derived food allergens can have serious consequences for sufferers and their families. The associated social, emotional and financial costs make it a priority to understand the best ways of managing such immune-mediated hypersensitivity responses. Conceptually, there are two main approaches to managing food allergy: those targeting immediate symptoms and those aiming to support long-term management of the condition. The European Academy of Allergy and Clinical Immunology is developing guidelines about what constitutes an effective treatment for food allergies. As part of the guidelines development process, a systematic review is planned to examine published research about the management of food allergy in adults and children.
Seven bibliographic databases were searched from their inception to September 30, 2012 for systematic reviews, randomized controlled trials, quasi-randomized controlled trials, controlled clinical trials, controlled before-and-after studies and interrupted time series. Experts were consulted for additional studies. There were no language or geographic restrictions. Studies were critically appraised using the Critical Appraisal Skills Program and Cochrane EPOC Risk of Bias tools. Only studies where people had a diagnosis of food allergy or reported a history of food allergy were included. This means that many studies of conditions that may be caused by food allergy are omitted, because only research in people with an explicit diagnosis or history was eligible.
Many initiatives have been tested to treat the immediate symptoms of food allergy (acute management) and to deal with longer lasting symptoms or induce tolerability to potential allergens (long-term management). The best management strategies for people with food allergy are likely to depend on the type of allergy, symptom manifestations and age. There is a real need to increase the amount of high quality research devoted to treatment strategies for food allergy. Food allergy can be debilitating and is affecting an increasing number of children and adults. With such little known about how to effectively manage the condition and its manifestations, this appears a priority for future research.
PMCID: PMC3637062  PMID: 23547741
Food allergy; LgE-mediated; Management; Treatment
4.  Manifestations of food protein induced gastrointestinal allergies presenting to a single tertiary paediatric gastroenterology unit 
Food protein induced gastrointestinal allergies are difficult to characterise due to the delayed nature of this allergy and absence of simple diagnostic tests. Diagnosis is based on an allergy focused history which can be challenging and often yields ambiguous results. We therefore set out to describe a group of children with this delayed type allergy, to provide an overview on typical profile, symptoms and management strategies.
This retrospective analysis was performed at Great Ormond Street Children’s Hospital. Medical notes were included from 2002 – 2009 where a documented medical diagnosis of food protein induced gastrointestinal allergies was confirmed by an elimination diet with resolution of symptoms, followed by reintroduction with reoccurrence of symptoms. Age of onset of symptoms, diagnosis, current elimination diets and food elimination at time of diagnosis and co-morbidities were collected and parents were phoned again at the time of data collection to ascertain current allergy status.
Data from 437 children were analysis. The majority (67.7%) of children had an atopic family history and 41.5% had atopic dermatitis at an early age. The most common diagnosis included, non-IgE mediated gastrointestinal food allergy (n = 189) and allergic enterocolitis (n = 154) with symptoms of: vomiting (57.8%), back-arching and screaming (50%), constipation (44.6%), diarrhoea (81%), abdominal pain (89.9%), abdominal bloating (73.9%) and rectal bleeding (38.5%). The majority of patients were initially managed with a milk, soy, egg and wheat free diet (41.7%). At a median age of 8 years, 24.7% of children still required to eliminate some of the food allergens.
This large retrospective study on children with food induced gastrointestinal allergies highlights the variety of symptoms and treatment modalities used in these children. However, further prospective studies are required in this area of food allergy.
PMCID: PMC3828665  PMID: 23919257
5.  Colorectal mucosal histamine release by mucosa oxygenation in comparison with other established clinical tests in patients with gastrointestinally mediated allergy 
AIM: This study evaluated colorectal mucosal histamine release in response to blinded food challenge-positive and -negative food antigens as a new diagnostic procedure.
METHODS: 19 patients suffering from gastrointestinally mediated allergy confirmed by blinded oral provocation were investigated on grounds of their case history, skin prick tests, serum IgE detection and colorectal mucosal histamine release by ex vivo mucosa oxygenation. Intact tissue particles were incubated/stimulated in an oxygenated culture with different food antigens for 30 min. Specimens challenged with anti-human immunoglobulin E and without any stimulus served as positive and negative controls, respectively. Mucosal histamine release (% of total biopsy histamine content) was considered successful (positive), when the rate of histamine release from biopsies in response to antigens reached more than twice that of the spontaneous release. Histamine measurement was performed by radioimmunoassay.
RESULTS: The median (range) of spontaneous histamine release from colorectal mucosa was found to be 3.2 (0.1%-25.8%) of the total biopsy histamine content. Food antigens tolerated by oral provocation did not elicit mast cell degranulation 3.4 (0.4%-20.7%, P = 0.4), while anti-IgE and causative food allergens induced a significant histamine release of 5.4 (1.1%-25.6%, P = 0.04) and 8.1 (1.5%-57.9%, P = 0.008), respectively. 12 of 19 patients (63.1%) showed positive colorectal mucosal histamine release in accordance with the blinded oral challenge responding to the same antigen (s), while the specificity of the functional histamine release to accurately recognise tolerated foodstuffs was found to be 78.6%. In comparison with the outcome of blinded food challenge tests, sensitivity and specificity of history (30.8% and 57.1%), skin tests (47.4% and 78.6%) or antigen-specific serum IgE determinations (57.9% and 50%) were found to be of lower diagnostic accuracy in gastrointestinally mediated allergy.
CONCLUSION: Functional testing of the reactivity of colorectal mucosa upon antigenic stimulation in patients with gastrointestinally mediated allergy is of higher diagnostic efficacy.
PMCID: PMC4087836  PMID: 16937442
Gut; Histamine release; Mucosa oxygenation; Food allergy diagnostics; Gastrointestinally mediated allergy
6.  Colonoscopic allergen provocation (COLAP): a new diagnostic approach for gastrointestinal food allergy. 
Gut  1997;40(6):745-753.
BACKGROUND: The clinical relevance of gastrointestinal food allergy in adults is largely unknown because the mechanisms are poorly understood and the diagnosis is difficult to confirm. AIMS: To improve the diagnostic means for confirming intestinal food allergy on an objective basis, a new colonoscopic allergen provocation (COLAP) test was developed. PATIENTS: The COLAP test was performed in 70 adult patients with abdominal symptoms suspected to be related to food allergy, and in five healthy volunteers. METHODS: During the COLAP test, the caecal mucosa was challenged endoscopically with three food antigen extracts, a buffer control, and a positive control (histamine). The mucosal weal and flare reaction was registered semiquantitatively 20 minutes after challenge, and tissue biopsy specimens were examined for mast cell and eosinophil activation. RESULTS: No severe systemic anaphylactic reactions were found in response to intestinal challenge. The COLAP test was positive to at least one food antigen in 54 of 70 patients (77%), whereas no reaction in response to antigen was found in healthy volunteers. Antigen induced weal and flare reactions were correlated with intestinal mast cell and eosinophil activation, as well as with patients' history of adverse reactions to food, but not with serum concentrations of total or specific IgE or skin test results. CONCLUSION: The COLAP test may be a useful diagnostic measure in patients with suspected intestinal food allergy and may provide a new tool for the study of underlying mechanisms.
PMCID: PMC1027199  PMID: 9245928
7.  Food allergy in gastroenterologic diseases: Review of literature 
Food allergy is a common and increasing problem worldwide. The newly-found knowledge might provide novel experimental strategies, especially for laboratory diagnosis. Approximately 20% of the population alters their diet for a perceived adverse reaction to food, but the application of double-blind placebo-controlled oral food challenge, the “gold standard” for diagnosis of food allergy, shows that questionnaire-based studies overestimate the prevalence of food allergies. The clinical disorders determined by adverse reactions to food can be classified on the basis of immunologic or nonimmunologic mechanisms and the organ system or systems affected. Diagnosis of food allergy is based on clinical history, skin prick tests, and laboratory tests to detect serum-food specific IgE, elimination diets and challenges. The primary therapy for food allergy is to avoid the responsible food. Antihistamines might partially relieve oral allergy syndrome and IgE-mediated skin symptoms, but they do not block systemic reactions. Systemic corticosteroids are generally effective in treating chronic IgE-mediated disorders. Epinephrine is the mainstay of treatment for anaphylaxis. Experimental therapies for IgE-mediated food allergy have been evaluated, such as humanized IgG anti-IgE antibodies and allergen specific immunotherapy.
PMCID: PMC4087536  PMID: 17203514
Food intolerance; Food allergy; Skin prick test; Serum food-specific IgE; Oral food challenges
8.  Allergen Component Testing for Food Allergy: Ready for Prime Time? 
Food allergies can cause life-threatening reactions and greatly influence quality of life. Accurate diagnosis of food allergies is important to avoid serious allergic reactions and prevent unnecessary dietary restrictions, but can be difficult. Skin prick testing (SPT) and serum food-specific IgE (sIgE) levels are extremely sensitive testing options, but positive test results to tolerated foods are not uncommon. Allergen component-resolved diagnostics (CRD) have the potential to provide a more accurate assessment in diagnosing food allergies. Recently, a number of studies have demonstrated that CRD may improve the specificity of allergy testing to a variety of foods including peanut, milk, and egg. While it may be a helpful adjunct to current diagnostic testing, CRD is not ready to replace existing methods of allergy testing, as it not as sensitive, is not widely available, and evaluations of component testing for a number of major food allergens are lacking.
PMCID: PMC4276333  PMID: 23011598
Food allergy; Diagnosis; Skin prick testing; Food-specific IgE; Sensitivity; Specificity; Oral food challenge; Component-resolved diagnostics; Microarray; Milk allergy; Hazelnut allergy; Egg allergy; Peanut allergy; Shrimp allergy
9.  Active or Passive Exposure to Tobacco Smoking and Allergic Rhinitis, Allergic Dermatitis, and Food Allergy in Adults and Children: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(3):e1001611.
In a systematic review and meta-analysis, Bahi Takkouche and colleagues examine the associations between exposure to tobacco smoke and allergic disorders in children and adults.
Please see later in the article for the Editors' Summary
Allergic rhinitis, allergic dermatitis, and food allergy are extremely common diseases, especially among children, and are frequently associated to each other and to asthma. Smoking is a potential risk factor for these conditions, but so far, results from individual studies have been conflicting. The objective of this study was to examine the evidence for an association between active smoking (AS) or passive exposure to secondhand smoke and allergic conditions.
Methods and Findings
We retrieved studies published in any language up to June 30th, 2013 by systematically searching Medline, Embase, the five regional bibliographic databases of the World Health Organization, and ISI-Proceedings databases, by manually examining the references of the original articles and reviews retrieved, and by establishing personal contact with clinical researchers. We included cohort, case-control, and cross-sectional studies reporting odds ratio (OR) or relative risk (RR) estimates and confidence intervals of smoking and allergic conditions, first among the general population and then among children.
We retrieved 97 studies on allergic rhinitis, 91 on allergic dermatitis, and eight on food allergy published in 139 different articles. When all studies were analyzed together (showing random effects model results and pooled ORs expressed as RR), allergic rhinitis was not associated with active smoking (pooled RR, 1.02 [95% CI 0.92–1.15]), but was associated with passive smoking (pooled RR 1.10 [95% CI 1.06–1.15]). Allergic dermatitis was associated with both active (pooled RR, 1.21 [95% CI 1.14–1.29]) and passive smoking (pooled RR, 1.07 [95% CI 1.03–1.12]). In children and adolescent, allergic rhinitis was associated with active (pooled RR, 1.40 (95% CI 1.24–1.59) and passive smoking (pooled RR, 1.09 [95% CI 1.04–1.14]). Allergic dermatitis was associated with active (pooled RR, 1.36 [95% CI 1.17–1.46]) and passive smoking (pooled RR, 1.06 [95% CI 1.01–1.11]). Food allergy was associated with SHS (1.43 [1.12–1.83]) when cohort studies only were examined, but not when all studies were combined.
The findings are limited by the potential for confounding and bias given that most of the individual studies used a cross-sectional design. Furthermore, the studies showed a high degree of heterogeneity and the exposure and outcome measures were assessed by self-report, which may increase the potential for misclassification.
We observed very modest associations between smoking and some allergic diseases among adults. Among children and adolescents, both active and passive exposure to SHS were associated with a modest increased risk for allergic diseases, and passive smoking was associated with an increased risk for food allergy. Additional studies with detailed measurement of exposure and better case definition are needed to further explore the role of smoking in allergic diseases.
Please see later in the article for the Editors' Summary
Editors' Summary
The immune system protects the human body from viruses, bacteria, and other pathogens. Whenever a pathogen enters the body, immune system cells called T lymphocytes recognize specific molecules on its surface and release chemical messengers that recruit and activate other types of immune cells, which then attack the pathogen. Sometimes, however, the immune system responds to harmless materials (for example, pollen; scientists call these materials allergens) and triggers an allergic disease such as allergic rhinitis (inflammation of the inside of the nose; hay fever is a type of allergic rhinitis), allergic dermatitis (also known as eczema, a disease characterized by dry, itchy patches on the skin), and food allergy. Recent studies suggest that all these allergic (atopic) diseases are part of a continuous state called the “atopic march” in which individuals develop allergic diseases in a specific sequence that starts with allergic dermatitis during infancy, and progresses to food allergy, allergic rhinitis, and finally asthma (inflammation of the airways).
Why Was This Study Done?
Allergic diseases are extremely common, particularly in children. Allergic rhinitis alone affects 10%–30% of the world's population and up to 40% of children in some countries. Moreover, allergic diseases are becoming increasingly common. Allergic diseases affect the quality of life of patients and are financially costly to both patients and health systems. It is important, therefore, to identify the factors that cause or potentiate their development. One potential risk factor for allergic diseases is active or passive exposure to tobacco smoke. In some countries up to 80% of children are exposed to second-hand smoke so, from a public health point of view, it would be useful to know whether exposure to tobacco smoke is associated with the development of allergic diseases. Here, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical approach for combining the results of several studies) to investigate this issue.
What Did the Researchers Do and Find?
The researchers identified 196 observational studies (investigations that observe outcomes in populations without trying to affect these outcomes in any way) that examined the association between smoke exposure and allergic rhinitis, allergic dermatitis, or food allergy. When all studies were analyzed together, allergic rhinitis was not associated with active smoking but was slightly associated with exposure to second-hand smoke. Specifically, compared to people not exposed to second-hand smoke, the pooled relative risk (RR) of allergic rhinitis among people exposed to second-hand smoke was 1.10 (an RR of greater than 1 indicates an increased risk of disease development in an exposed population compared to an unexposed population). Allergic dermatitis was associated with both active smoking (RR = 1.21) and exposure to second-hand smoke (RR = 1.07). In the populations of children and adolescents included in the studies, allergic rhinitis was associated with both active smoking and exposure to second-hand smoke (RRs of 1.40 and 1.09, respectively), as was allergic dermatitis (RRs of 1.36 and 1.06, respectively). Finally food allergy was associated with exposure to second-hand smoke (RR = 1.43) when cohort studies (a specific type of observational study) only were examined but not when all the studies were combined.
What Do These Findings Mean?
These findings provide limited evidence for a weak association between smoke exposure and allergic disease in adults but suggest that both active and passive smoking are associated with a modestly increased risk of allergic diseases in children and adolescents. The accuracy of these findings may be affected by the use of questionnaires to assess smoke exposure and allergic disease development in most of the studies in the meta-analysis and by the possibility that individuals exposed to smoke may have shared other characteristics that were actually responsible for their increased risk of allergic diseases. To shed more light on the role of smoking in allergic diseases, additional studies are needed that accurately measure exposure and outcomes. However, the present findings suggest that, in countries where many people smoke, 14% and 13% of allergic rhinitis and allergic dermatitis, respectively, among children may be attributable to active smoking. Thus, the elimination of active smoking among children and adolescents could prevent one in seven cases of allergic rhinitis and one in eight cases of allergic dermatitis in such countries.
Additional Information
Please access these websites via the online version of this summary at
The UK National Health Service Choices website provides information about allergic rhinitis, hay fever (including personal stories), allergic dermatitis (including personal stories), and food allergy (including personal stories)
The US National Institute of Allergy and Infectious Disease provides information about allergic diseases
The UK not-for-profit organization Allergy UK provides information about all aspects of allergic diseases and a description of the atopic march
MedlinePlus encyclopedia has pages on allergic rhinitis and allergic dermatitis (in English and Spanish)
MedlinePlus provides links to further resources about allergies, eczema, and food allergy (in English and Spanish)
PMCID: PMC3949681  PMID: 24618794
10.  Prevention of Birch Pollen-Related Food Allergy by Mucosal Treatment with Multi-Allergen-Chimers in Mice 
PLoS ONE  2012;7(6):e39409.
Among birch pollen allergic patients up to 70% develop allergic reactions to Bet v 1-homologue food allergens such as Api g 1 (celery) or Dau c 1 (carrot), termed as birch pollen-related food allergy. In most cases, specific immunotherapy with birch pollen extracts does not reduce allergic symptoms to the homologue food allergens. We therefore genetically engineered a multi-allergen chimer and tested if mucosal treatment with this construct could represent a novel approach for prevention of birch pollen-related food allergy.
BALB/c mice were poly-sensitized with a mixture of Bet v 1, Api g 1 and Dau c 1 followed by a sublingual challenge with carrot, celery and birch pollen extracts. For prevention of allergy sensitization an allergen chimer composed of immunodominant T cell epitopes of Api g 1 and Dau c 1 linked to the whole Bet v 1 allergen, was intranasally applied prior to sensitization.
Intranasal pretreatment with the allergen chimer led to significantly decreased antigen-specific IgE-dependent β-hexosaminidase release, but enhanced allergen-specific IgG2a and IgA antibodies. Accordingly, IL-4 levels in spleen cell cultures and IL-5 levels in restimulated spleen and cervical lymph node cell cultures were markedly reduced, while IFN-γ levels were increased. Immunomodulation was associated with increased IL-10, TGF-β and Foxp3 mRNA levels in NALT and Foxp3 in oral mucosal tissues. Treatment with anti-TGF-β, anti-IL10R or anti-CD25 antibodies abrogated the suppression of allergic responses induced by the chimer.
Our results indicate that mucosal application of the allergen chimer led to decreased Th2 immune responses against Bet v 1 and its homologue food allergens Api g 1 and Dau c 1 by regulatory and Th1-biased immune responses. These data suggest that mucosal treatment with a multi-allergen vaccine could be a promising treatment strategy to prevent birch pollen-related food allergy.
PMCID: PMC3387141  PMID: 22768077
11.  428 Comparison Skin Prick Test Using Commercial and Native Extracts of Allergens in Diagnosis of Food Allergy 
The World Allergy Organization Journal  2012;5(Suppl 2):S153-S154.
Patients with the birch pollen allergy frequently develop hypersensitive reactions to certain plant food. These reactions result from the similarity of allergen proteins structure, which are sometimes unbound phylogenetically. The aim of this study was to investigate the diagnostic value of immunoblotting method for patients with pollinosis.
Fifty eight patients were included in the study. The clinical history: the positive result of the skin prick test with the birch extract and symptoms after consumption plant food were the condition for qualifications. The immunoblotting was performed for the patients with the positive value of birch, apple, celery and/or carrot specific IgE to confirm the cross-reactivity.
Sera of 13 patients (18 patients were analyzed) revealed positive results in the immunoblotting method. Sera of only 12 patients revealed the reaction against the birch pollen protein with a molecular weight 17 to 18 kDa corresponding to the main birch allergen Bet v 1. Sera of only 2 of these patients revealed the presence of antibodies cross-reacting with the apple protein with the same molecular weight, which may indicate the main allergens of these foods – Mal d 1. Serum of 6 patients revealed the presence of antibodies cross-reacting with apple and celery protein with the same molecular weight, which may indicate the main allergens of these foods – Mal d 1 and Api g 1. Serum of only one patient revealed the presence of antibodies cross-reacting with the apple, celery and carrot protein with the same molecular weight, which may correspond the main allergens of these foods – Mal d 1, Api g 1 Dau c 1. Additionally sera of 6 persons demonstrated the presence of antibodies reacting with apple protein with the molecular weight 10 kDa which may correspond to the lipid transfer protein (LTP). Among some of the patients, antibodies which have not been identified so far reacted with birch, apple and celery proteins.
Although the immunoblotting is an effective method confirming the existences of the cross-reactivity, it still remains the method of verifying and supplementing other diagnostic tests, and a negative result doesn't exclude the existence of this kind of allergy.
PMCID: PMC3513103
12.  Nonmurine animal models of food allergy. 
Environmental Health Perspectives  2003;111(2):239-244.
Food allergy can present as immediate hypersensitivity [manifestations mediated by immunoglobulin (Ig)E], delayed-type hypersensitivity (reactions associated with specific T lymphocytes), and inflammatory reactions caused by immune complexes. For reasons of ethics and efficacy, investigations in humans to determine sensitization and allergic responses of IgE production to innocuous food proteins are not feasible. Therefore, animal models are used a) to bypass the innate tendency to develop tolerance to food proteins and induce specific IgE antibody of sufficient avidity/affinity to cause sensitization and upon reexposure to induce an allergic response, b) to predict allergenicity of novel proteins using characteristics of known food allergens, and c) to treat food allergy by using immunotherapeutic strategies to alleviate life-threatening reactions. The predominant hypothesis for IgE-mediated food allergy is that there is an adverse reaction to exogenous food proteins or food protein fragments, which escape lumen hydrolysis, and in a polarized helper T cell subset 2 (Th2) environment, immunoglobulin class switching to allergen-specific IgE is generated in the immune system of the gastrointestinal-associated lymphoid tissues. Traditionally, the immunologic characterization and toxicologic studies of small laboratory animals have provided the basis for development of animal models of food allergy; however, the natural allergic response in large animals, which closely mimic allergic diseases in humans, can also be useful as models for investigations involving food allergy.
PMCID: PMC1241358  PMID: 12573913
13.  Cow’s milk allergy: evidence-based diagnosis and management for the practitioner 
European Journal of Pediatrics  2014;174:141-150.
This review summarizes current evidence and recommendations regarding cow’s milk allergy (CMA), the most common food allergy in young children, for the primary and secondary care providers. The diagnostic approach includes performing a medical history, physical examination, diagnostic elimination diets, skin prick tests, specific IgE measurements, and oral food challenges. Strict avoidance of the offending allergen is the only therapeutic option. Oral immunotherapy is being studied, but it is not yet recommended for routine clinical practice. For primary prevention of allergy, exclusive breastfeeding for at least 4 months and up to 6 months is desirable. Infants with a documented hereditary risk of allergy (i.e., an affected parent and/or sibling) who cannot be breastfed exclusively should receive a formula with confirmed reduced allergenicity, i.e., a partially or extensively hydrolyzed formula, as a means of preventing allergic reactions, primarily atopic dermatitis. Avoidance or delayed introduction of solid foods beyond 4–6 months for allergy prevention is not recommended.
Conclusion: For all of those involved in taking care of children’s health, it is important to understand the multifaceted aspects of CMA, such as its epidemiology, presentation, diagnosis, and dietary management, as well as its primary prevention.
PMCID: PMC4298661  PMID: 25257836
Allergy; Children; Infants; Pediatrics
14.  Reduction of Cross-Reactive Carbohydrate Determinants in Plant Foodstuff: Elucidation of Clinical Relevance and Implications for Allergy Diagnosis 
PLoS ONE  2011;6(3):e17800.
A longstanding debate in allergy is whether or not specific immunoglobulin-E antibodies (sIgE), recognizing cross-reactive carbohydrate determinants (CCD), are able to elicit clinical symptoms. In pollen and food allergy, ≥20% of patients display in-vitro CCD reactivity based on presence of α1,3-fucose and/or β1,2-xylose residues on N-glycans of plant (xylose/fucose) and insect (fucose) glycoproteins. Because the allergenicity of tomato glycoallergen Lyc e 2 was ascribed to N-glycan chains alone, this study aimed at evaluating clinical relevance of CCD-reduced foodstuff in patients with carbohydrate-specific IgE (CCD-sIgE).
Methodology/Principal Findings
Tomato and/or potato plants with stable reduction of Lyc e 2 (tomato) or CCD formation in general were obtained via RNA interference, and gene-silencing was confirmed by immunoblot analyses. Two different CCD-positive patient groups were compared: one with tomato and/or potato food allergy and another with hymenoptera-venom allergy (the latter to distinguish between CCD- and peptide-specific reactions in the food-allergic group). Non-allergic and CCD-negative food-allergic patients served as controls for immunoblot, basophil activation, and ImmunoCAP analyses. Basophil activation tests (BAT) revealed that Lyc e 2 is no key player among other tomato (glyco)allergens. CCD-positive patients showed decreased (re)activity with CCD-reduced foodstuff, most obvious in the hymenoptera venom-allergic but less in the food-allergic group, suggesting that in-vivo reactivity is primarily based on peptide- and not CCD-sIgE. Peptide epitopes remained unaffected in CCD-reduced plants, because CCD-negative patient sera showed reactivity similar to wild-type. In-house-made ImmunoCAPs, applied to investigate feasibility in routine diagnosis, confirmed BAT results at the sIgE level.
CCD-positive hymenoptera venom-allergic patients (control group) showed basophil activation despite no allergic symptoms towards tomato and potato. Therefore, this proof-of-principle study demonstrates feasibility of CCD-reduced foodstuff to minimize ‘false-positive results’ in routine serum tests. Despite confirming low clinical relevance of CCD antibodies, we identified one patient with ambiguous in-vitro results, indicating need for further component-resolved diagnosis.
PMCID: PMC3056789  PMID: 21423762
15.  Food allergy 
Food allergy is defined as an adverse immunologic response to a dietary protein. Food-related reactions are associated with a broad array of signs and symptoms that may involve many bodily systems including the skin, gastrointestinal and respiratory tracts, and cardiovascular system. Food allergy is a leading cause of anaphylaxis and, therefore, referral to an allergist for appropriate and timely diagnosis and treatment is imperative. Diagnosis involves a careful history and diagnostic tests, such as skin prick testing, serum-specific immunoglobulin E (IgE) testing and, if indicated, oral food challenges. Once the diagnosis of food allergy is confirmed, strict elimination of the offending food allergen from the diet is generally necessary. For patients with significant systemic symptoms, the treatment of choice is epinephrine administered by intramuscular injection into the lateral thigh. Although most children “outgrow” allergies to milk, egg, soy and wheat, allergies to peanut, tree nuts, fish and shellfish are often lifelong. This article provides an overview of the epidemiology, pathophysiology, diagnosis, management and prognosis of patients with food allergy.
PMCID: PMC3245440  PMID: 22166142
16.  404 Allergen Specific Immunotherapy as a Treatment for Eosinophilic Esophagitis 
Eosinophilic Esophagitis (EoE) is an inflammatory disease that reduces the ability of the esophagus to pass food, often leading to dysphagia. A relationship between EoE and food allergies has been determined. However, there have been several documented cases in which patients had negative prick skin testing (PST) results for food allergens and positive results for airborne environmental allergens, and still have a confirmed diagnosis of EoE. Recently, airborne allergens have been implicated in the onset of this condition. Studies have shown that patients sensitive to airborne allergens such as pollen have a seasonal biannual component in which the severity of EoE symptoms increase, coinciding with high pollen seasons.
We followed a 65-year-old man with a history of allergies complaining of an increase in his symptoms of allergic rhinitis and asthma. He also noted dysphagia and occasional vomiting. We noted the disease and medication course over 5 years of treatment.
The patient underwent an esophagogastroduodenoscopy with biopsy, in which midesophageal rings as well as an 8 mm sessile polyp were found, suggesting EoE. Histological analysis confirmed EoE, having found >20 intraepithelial eosinophils/HPF. The patient was treated with a short term prednisone regimen, as well as maintenance medications consisting of inhaled corticosteroids and antihistamines. The patient returned 6 months after the initial consultation and still presented symptoms of EoE, at which point the patient was prescribed proton pump inhibitors. In addition, allergen specific immunotherapy was initiated for confirmed airborne allergens. The patient was examined after 5 years of immunotherapy treatment. Not only did he report that his allergic rhinitis and asthma symptoms were controlled, but his EoE symptoms had resolved.
Results suggest that immunotherapy for airborne allergens could be a successful treatment for EoE. A larger study is needed to determine if allergen specific immunotherapy is a viable treatment option for EoE in similar cases. Such a study could include patients with EoE and confirmed airborne allergies treated with immunotherapy while monitoring a number of eosinophilic and lymphocytic markers.
PMCID: PMC3512974
17.  435 Increasing Incidence of Food Allergy in Zimbabwe 
The World Allergy Organization Journal  2012;5(Suppl 2):S155-S156.
Data relating to allergic diseases in general and food allergies in particular in the Central African region is scant. Despite observations by the ISAAC studies that airborne allergen sources were common, little has been reported about food allergens. We reviewed data from our laboratory and outpatient records of patients consulted to estimate the magnitude of the disease in our population.
Patients attending the only specialist allergy diagnostic facility in the country (Asthma, Allergy and Immune Dysfunction Clinic) were offered semi-quantitative allergen specific IgE antibody determination as part of their diagnostic work-up. Alongside skin-prick testing, the Euroimmun immunoblots were used to establish IgE reactivity to a variety of allergen sources.
Six hundred thirty five patients were enrolled between January 2009 and April 2011. These were born between 1931 and 2010. IgE reactivity to egg, codfish, cows milk, wheat flour, rice, soya bean, peanut, hazelnut, carrot, potato and apple was investigated using the immunoblot technique. Results were scored negative or positive. The grades of positive were weak (±), low (+), moderate (++) and high (+++). Overall, 47% of the patients reacted to one or multiple allergen sources. Across the age spectrum, allergen specific IgE reactivity was most frequent against potato (16%) and peanut (15%) and lowest against milk (2.7%) and codfish (2.7%), others were intermediate. Egg white reactivity was highest in those below the age of 5 years (7%). IgE reactivity in patients born before 1959 was less than 1%. This increased to 3.4%, 4.8% and 64% respectively in those born before 1969, 1979 and 1989. Nineteen (19%) of patients born in 1990 to 1999 were reactive to a variety of food allergen sources. Likewise, 12% of those born between 2000 and 2011 were reactive. Food allergen reactivity paralleled inhalant allergen source sensitisation in all age groups.
In this sample of symptomatic patients we have shown that allergen specific IgE reactivity to dietary sources was high. An exponential increase in IgE reactivity in patients born between 1990 and 2011 was a surprising observation. Possible explanations include urbanisation, life-style and dietary changes in this predominantly urban population. The results call for a systematic investigation of the predisposing factors.
PMCID: PMC3512812
18.  Diet and Dermatitis: Food Triggers 
Given increasing awareness of the link between diet and health, many patients are concerned that dietary factors may trigger dermatitis. Research has found that dietary factors can indeed exacerbate atopic dermatitis or cause dermatitis due to systemic contact dermatitis. In atopic dermatitis, dietary factors are more likely to cause an exacerbation among infants or children with moderate-to-severe atopic dermatitis relative to other populations. Foods may trigger rapid, immunoglobulin E-mediated hypersensitivity reactions or may lead to late eczematous reactions. While immediate reactions occur within minutes to hours of food exposure, late eczematous reactions may occur anywhere from hours to two days later. Screening methods, such as food allergen-specific serum immunoglobulin E tests or skin prick tests, can identify sensitization to specific foods, but a diagnosis of food allergy requires specific signs and symptoms that occur reproducibly upon food exposure. Many patients who are sensitized will not develop clinical findings upon food exposure; therefore, these tests may result in false-positive tests for food allergy. This is why the gold standard for diagnosis remains the double-blind, placebo-controlled food challenge. In another condition, systemic contact dermatitis, ingestion of a specific food can actually cause dermatitis. Systemic contact dermatitis is a distinct T-cell mediated immunological reaction in which dietary exposure to specific allergens results in dermatitis. Balsam of Peru and nickel are well-known causes of systemic contact dermatitis, and reports have implicated multiple other allergens. This review seeks to increase awareness of important food allergens, elucidate their relationship with atopic dermatitis and systemic contact dermatitis, and review available diagnostic and treatment strategies.
PMCID: PMC3970830  PMID: 24688624
19.  Impact of primary food allergies on the introduction of other foods amongst Canadian children and their siblings 
Food-allergic children frequently avoid other highly allergenic foods. The NIAID 2010 guidelines state that individuals with an IgE-mediated food allergy should avoid their specific allergens and physicians should help patients to decide whether certain cross-reactive foods also should be avoided. Patients at risk for developing food allergy do not need to limit exposure to foods that may be cross-reactive with the major food allergens. The purpose of this study was to determine if parents of food-allergic children are given advice regarding introduction of allergenic foods; if these foods are avoided or delayed; if there is anxiety when introducing new foods; and if introducing other allergenic foods leads to any allergic reaction. The study also determined if there was a similar pattern seen amongst younger siblings.
An online survey was administered between December 2011 and March 2012 via Anaphylaxis Canada’s website, available to Canadian parents and caregivers who are registered members of the organization and who have a child with a food allergy.
644 parents completed the online survey. 51% of families were given advice regarding the introduction of other allergenic foods. 72% were told to avoid certain foods, and 41% to delay certain foods. 58% of parents did avoid or delay other highly allergenic foods, mainly due to a fear of allergic reaction. 69% of children did not have an allergic reaction when these foods were subsequently introduced. 68% of parents felt moderate or high levels of anxiety when introducing other foods. A similar pattern was seen amongst the younger siblings.
Canadian parents and caregivers of children with food allergies receive varied advice from health care professionals regarding the introduction of new allergenic foods, and feel moderate to high levels of anxiety. A similar pattern may be seen amongst younger siblings. While the majority of children in our study did not have an allergic reaction to a new food, a significant proportion of children did react. A more consistent approach to the advice given by health care professionals may decrease parental anxiety. Further research to support the 2010 NIAID guidelines may be necessary to clarify recommendations.
PMCID: PMC4063690  PMID: 24949023
Food allergy; Siblings; Food introduction; Anxiety
20.  The Impact of Family History of Allergy on Risk of Food Allergy: A Population-Based Study of Infants 
The apparent rapid increase in IgE-mediated food allergy and its implications are now widely recognized, but little is known about the relationship between family history (an indirect measure of genetic risk) and the risk of food allergy. In a population-based study of 5,276 one year old infants (HealthNuts), the prevalence of oral food challenge-confirmed food allergy was measured. Associations between family history of allergic disease and food allergy in infants were examined using multiple logistic regression. Food allergy was diagnosed in 534 infants. Compared to those with no family history of allergic disease, children meeting the current definition of “high risk” for allergic disease (one immediate family member with a history of any allergic disease) showed only a modest increase (OR 1.4, 95% CI 1.1–1.7) in food allergy, while having two or more allergic family members was more strongly predictive of food allergy in the child (OR 1.8, 95% CI 1.5–2.3). There were also differences in the associations between family history and egg and peanut allergy in the child. Re-defining “high risk” as two or more allergic family members may be more useful for identification of groups with a significantly increased risk of food allergy both clinically and within research studies.
PMCID: PMC3863850  PMID: 24284354
food allergy; family history; genetics; heritability; siblings; maternal; paternal; egg allergy; peanut allergy
21.  Food allergy in children 
Postgraduate Medical Journal  2005;81(961):693-701.
Food allergy is being increasingly recognised with the highest prevalence being in preschool children. Pathogenesis varies so diagnosis rests on careful history and clinical examination, appropriate use of skin prick and serum-specific IgE testing, food challenge, and supervised elimination diets. A double blind placebo controlled food challenge is the gold standard diagnostic test. Avoidance of the allergenic food is the key towards successful management. IgE mediated food allergy may present as a potentially fatal anaphylactic reaction, and management consists of the appropriate use of adrenaline (epinephrine) and supportive measures. Sensitisation remains a key target for intervention. Disease modifying agents are currently under trial for managing difficult allergies. Management requires a multidisciplinary approach and follow up.
PMCID: PMC1743387  PMID: 16272231
22.  Relationships between IgE/IgG4 Epitopes, Structure and Function in Anisakis simplex Ani s 5, a Member of the SXP/RAL-2 Protein Family 
Anisakiasis is a re-emerging global disease caused by consumption of raw or lightly cooked fish contaminated with L3 Anisakis larvae. This zoonotic disease is characterized by severe gastrointestinal and/or allergic symptoms which may misdiagnosed as appendicitis, gastric ulcer or other food allergies.
The Anisakis allergen Ani s 5 is a protein belonging to the SXP/RAL-2 family; it is detected exclusively in nematodes. Previous studies showed that SXP/RAL-2 proteins are active antigens; however, their structure and function remain unknown.
The aim of this study was to elucidate the three-dimensional structure of Ani s 5 and its main IgE and IgG4 binding regions.
Methodology/Principal Findings
The tertiary structure of recombinant Ani s 5 in solution was solved by nuclear magnetic resonance. Mg2+, but not Ca2+, binding was determined by band shift using SDS-PAGE. IgE and IgG4 epitopes were elucidated by microarray immunoassay and SPOTs membranes using sera from nine Anisakis allergic patients.
The tertiary structure of Ani s 5 is composed of six alpha helices (H), with a Calmodulin like fold. H3 is a long, central helix that organizes the structure, with H1 and H2 packing at its N-terminus and H4 and H5 packing at its C-terminus. The orientation of H6 is undefined. Regarding epitopes recognized by IgE and IgG4 immunoglobulins, the same eleven peptides derived from Ani s 5 were bound by both IgE and IgG4. Peptides 14 (L40-K59), 26 (A76-A95) and 35 (I103-D122) were recognized by three out of nine sera.
This is the first reported 3D structure of an Anisakis allergen. Magnesium ion binding and structural resemblance to Calmodulin, suggest some putative functions for SXP/RAL-2 proteins. Furthermore, the IgE/IgG4 binding regions of Ani s 5 were identified as segments localized on its surface. These data will contribute towards a better understanding of the interactions that occur between immunoglobulins and allergens and, in turn, facilitate the design of novel diagnostic tests and immunotherapeutic strategies.
Author Summary
Knowledge of potential pathogens in seafood is of major significance for human health. The high rates of parasitation of fish all over the world make Anisakis a serious health hazard. In fact, Anisakiasis is a growing zoonotic disease in countries where consumption of raw/marinated fish is high. Moreover, Anisakiasis could be under diagnosed in countries where the consumption of these dishes is less common, since it could be easily misdiagnosed as appendicitis, gastric ulcer or other food allergies. Allergen structural studies are essential for the development of specific diagnostic tests and novel immunotherapy strategies. In the present study, we have elucidated for the first time the tertiary structure of Ani s 5 Anisakis allergen and its IgE and IgG4 regions implicated in allergic response. Ani s 5 belongs to the SXP/RAL-2 protein family. Several members of this family have been detected in animal and plant parasitic nematodes. As no homologs have been identified outside the Nematoda, these proteins may be suitable targets for controlling the damage caused by these parasites. Our work reveals that the structure of Ani s 5 resembles that of Calmodulin but binds Mg2+ instead of Ca2+, which suggests some putative functions for SXP/RAL-2 proteins.
PMCID: PMC3945735  PMID: 24603892
23.  A bioinformatics approach to identify patients with symptomatic peanut allergy using peptide microarray immunoassay 
Peanut allergy is relatively common, typically permanent, and often severe. Double-blind, placebo-controlled food challenge is considered the gold standard for the diagnosis of food allergy–related disorders. However, the complexity and potential of double-blind, placebo-controlled food challenge to cause life-threatening allergic reactions affects its clinical application. A laboratory test that could accurately diagnose symptomatic peanut allergy would greatly facilitate clinical practice.
We sought to develop an allergy diagnostic method that could correctly predict symptomatic peanut allergy by using peptide microarray immunoassays and bioinformatic methods.
Microarray immunoassays were performed by using the sera from 62 patients (31 with symptomatic peanut allergy and 31 who had outgrown their peanut allergy or were sensitized but were clinically tolerant to peanut). Specific IgE and IgG4 binding to 419 overlapping peptides (15 mers, 3 offset) covering the amino acid sequences of Ara h 1, Ara h 2, and Ara h 3 were measured by using a peptide microarray immunoassay. Bioinformatic methods were applied for data analysis.
Individuals with peanut allergy showed significantly greater IgE binding and broader epitope diversity than did peanut-tolerant individuals. No significant difference in IgG4 binding was found between groups. By using machine learning methods, 4 peptide biomarkers were identified and prediction models that can predict the outcome of double-blind, placebo-controlled food challenges with high accuracy were developed by using a combination of the biomarkers.
In this study, we developed a novel diagnostic approach that can predict peanut allergy with high accuracy by combining the results of a peptide microarray immunoassay and bioinformatic methods. Further studies are needed to validate the efficacy of this assay in clinical practice.
PMCID: PMC3631605  PMID: 22444503
Epitope mapping; peptide microarray; peanut allergy; bioinformatics; machine learning; allergy diagnosis; epitope biomarker
24.  430 Comparative Analysis of Patients with Birch Pollinosis and Patients with Associated Plant Food Allergy 
Even 70% patients allergic to pollens of plants are developing undesirable symptoms after eating foods of the plant origin. It is most often a result of the cross-allergy between these allergens. The aim of the study was to compare the group of patients with pollinosis with patients with pollinosis and food allergy.
Fifty eight patients at the age above 16 were included in the study. Patients were divided into 2 groups. Patients included in the first group were birch allergic without any symptoms after eating food (23 persons). Patients in the other group had birch pollen allergy and they had reported clinical symptoms after eating foods such as: apple, celery, carrot, tomato, banana, peach, peanut and hazelnut (35 persons). The skin prick tests with pollen and food allergens (commercial and native) and serum IgE concentration (total and specific) were determined for all individuals. The immunoblotting was performed for the patients with the positive value of birch, apple, celery and/or carrot specific IgE to confirm the cross-reactivity.
Patients with pollinosis and symptoms after eating plant foods were characterized by a significantly larger percentage of positive skin tests with the hazel allergen. In the first group patients revealed positive results of skin tests with food allergens, although they didn't reported the problem after consumption of them. No difference in total IgE levels was found between the 2 groups (271.5 ± 403.8 IU/mL vs 242.5 ± 340.9 IU/mL). Patients with birch allergy and hypersensitivity to food allergens showed significantly higher birch pollen specific IgE levels (11.8 ± 14.1 IU/mL vs 4.1 ± 6.6 IU/mL).
Sixty percent of all the patients with birch pollinosis reported manifestations symptoms after eating certain kind of food. These patients had most often clinical symptoms after eating apples, hazelnuts and of peaches, and less frequently symptoms after eating carrots, celery, peanuts, tomatoes and bananas. Although it seems that false positive results of skin tests with food allergens in the control group and the high level of the birch specific IgE might be the predictive factor of the allergy which may develop later; they require further studies.
PMCID: PMC3513115
25.  Diagnosis of Food Allergy 
Pediatric annals  2013;42(6):102-109.
Diagnosis of food allergy can be challenging. Given the limited specificity of available allergy tests, these need to be interpreted in light of pre-test probability that is determined by a careful history. Using likelihood ratios calculated from previous publication may allow a more individualized assessment. This approach is likely to be most useful in patients with low to moderate results, below the 95% positive predictive value for that food. This review covers the diagnostic approach of immunoglobulin E-mediated food allergy. We first focus on the pre-test clinical assessment of a patient with a suspected food allergy. We then compare currently available diagnostic tests and discuss their performance for frequent food allergens. Finally, we conclude with the interpretation of allergy tests in light of the pre-test assessment to determine final probability of food allergy and indications for referral to an allergy specialist for food challenge.
PMCID: PMC4161456  PMID: 23718238

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