Food allergies, defined as an immune response to food proteins, affect as many as 8% of young children and 2% of adults in westernized countries, and their prevalence appears to be rising like all allergic diseases. In addition to well-recognized urticaria and anaphylaxis triggered by IgE antibody-mediated immune responses, there is an increasing recognition of cell-mediated disorders such as eosinophilic esophagitis and food protein-induced enterocolitis. New knowledge is being developed on the pathogenesis of both IgE and non-IgE mediated disease. Currently, management of food allergies consists of educating the patient to avoid ingesting the responsible allergen and initiating therapy if ingestion occurs. However, novel strategies are being studied, including sublingual/oral immunotherapy and others with a hope for future.

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Diagnosis of food allergy should be based on the observation of allergic symptoms after intake of the suspected food. The oral food challenge test (OFC) is the most reliable clinical procedure for diagnosing food allergy. The OFC is also applied for the diagnosis of tolerance of food allergy. The Japanese Society of Pediatric Allergy and Clinical Immunology issued the 'Japanese Pediatric Guideline for Oral Food Challenge Test in Food Allergy 2009' in April 2009, to provide information on a safe and standardized method for administering the OFC. This review focuses on the clinical applications and procedure for the OFC, based on the Japanese OFC guideline.

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In 2005, the "Food Allergy Management Guideline 2005" was published. In order to encompass food allergy from infancy to adulthood, the project committee included not only pediatricians, but also internists, dermatologists, and otolaryngologists. After the release of the guideline, oral food challenge tests were approved as a medical examination on hospital admission by the national health insurance system in 2006, and the tests at outpatient clinics were also approved in 2008. As clearly stated in the guideline, it is essential for general practitioners to refer food allergy patients to specialists to receive accurate diagnosis. A specialist is needed because the oral food challenge test, which is sometimes required for accurate diagnosis, carries the potential risk of developing an adverse reaction. In 2008, the "Food Allergy Management Guideline 2008" was revised to update recent advances, such as the appropriate conditions needed to perform oral food challenge tests and probability curves for hen's egg and cow's milk developed in Japan. In the same year, "The Guidelines for the Treatment of Allergic Diseases in Schools" was published by the Japanese Society of School Health. In addition to the guideline, "School Life Management Certificate (for Allergic Diseases) " was developed in order to allow the verification of the diagnosis and encourage the discussion of countermeasures by parents/guardians and school teachers for students requiring special care. It is hoped that this review article will be useful for doctors treating food allergy and that the quality of life of food allergy patients and their parents will be improved.

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Oral allergy syndrome (OAS) is defined as the symptoms of IgE-mediated immediate allergy localized in the oral mucosa, and the characteristics depend on the lability of the antigen. Another term used for this syndrome is pollen-food allergy (PFS); the patient is sensitized with pollen via the airways and exhibits an allergic reaction to food antigen with a structural similarity to the pollen (class 2 food allergy). In addition to PFS, latex-fruit syndrome is also well-known as the disease exhibiting OAS. In treating the condition, it must be noted that most but not all symptoms of PFS are those of OAS. In many cases, antigens become edible by heating, but some are resistant to heating. Also, since the exacerbation of atopic dermatitis is occasionally observed after the intake of cooked antigens in asymptomatic individuals, careful inquiry of the history is important in designing the treatment. Immunotherapy against the cross-reacting pollen has also been attempted in PFS.

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Food-dependent exercise-induced anaphylaxis (FDEIA) is a special form of food allergy where a food-intake alone does not induce any symptoms. However, allergic symptoms are elicited when triggering factors such as exercise or aspirin-intake are added after ingestion of the causative food. The most frequent causative foodstuff in Japan is wheat. The triggering factors, both exercise and aspirin-intake, facilitate allergen absorption from the gastrointestinal tract, resulting in allergic symptoms in the patients with wheat-dependent exercise-induced anaphylaxis (WDEIA). Analysis using purified wheat proteins revealed that approximately 80% of the patients with WDEIA have IgE reacting to omega-5 gliadin and the remaining of the patients to high molecular weight glutenin (HMW-glutenin). Simultaneous measurement of specific IgE to omega-5 gliadin and HMW-glutenin was found to be highly useful in diagnosing WDEIA compared with the routine diagnostic system for wheat.

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Background: Differential expression of chemokine genes were investigated in various types of ocular surface cells.
Methods: Primary cultures of human corneal epithelial cells (n = 3), corneal fibroblasts (n = 2), conjunctival epithelial cells (n = 2) and conjunctival fibroblasts (n = 2) were established and incubated with or without interleukin (IL)-4 (30ng/ml) and tumor necrosis factor (TNF)-α(30ng/ml) for 24 hours. Gene transcription levels of 33 chemokines and production of 4 chemokines were analyzed.
Results: After stimulation, chemokine expression increased for 18 of 33 coded chemokine gene transcripts. In stimulated conjunctival and corneal cells, CC chemokine genes increased in fibroblasts (expression of 6 out of 8 genes), while CXC chemokine genes increased in both epithelial cells (expression of 4 out of 9 genes in conjunctival epithelial cells and 7 out of 9 genes in corneal epithelial cells) and in fibroblasts (expression of 8 out of 9 genes in conjunctival and corneal fibroblasts). Except for MCP-1, gene transcription levels for most CC chemokines were inducible and, except for IP-10 and I-TAC, most CXC chemokines were constitutively expressed. Corneal epithelial cell and fibroblast production patterns for eotaxin-1, MCP-1 and IP-10 were comparable to the mRNA expression pattern.
Conclusions: Corneal and conjunctival fibroblasts exhibited marked increases in the expression of chemokines upon stimulation with TNF-α and IL-4, suggesting that fibroblasts may be one of the primary sources of chemokines in allergic conjunctival diseases. Therefore, regulation of chemokine production from these cells may be an effective strategy for treating such diseases.

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Background: Whether the additive effects of the tulobuterol patch (TP), the world's first transdermal beta2-agonist preparation, are useful in asthma patients receiving inhaled corticosteroid (ICS) is unclear. To examine the add-on effects of TP on bronchial hyperresponsiveness and reduction of the percentage of sputum eosinophils, and to compare add-on effects of TP, slow-release theophylline (SRT), and a leukotriene receptor antagonist (LTRA) in patients with asthma receiving ICS.
Methods: Study 1: We randomly allocated 24 patients with asthma receiving ICS alone in equal numbers to either control treatment (ICS alone at conventional doses) or TP treatment (ICS at conventional doses plus TP at 2mg/day). Following a 2-week observation period, patients received the allocated drug regimens for 4 weeks. Methacholine challenge test and measurement of percentage of eosinophils in hypertonic saline-induced sputum were performed before and after the treatment period. Study 2: We compared add-on effects of TP, SRT, and LTRA in 65 patients with asthma receiving ICS alone, using spirometry and peak expiratory flow (PEF). Participants in these studies had experienced decrease in morning PEF to <80% of the predicted value at least twice a week.
Results: Study 1: In the TP group, improvement of bronchial hyperresponsiveness and decrease in percentage of sputum eosinophils both indicated a statistically significant difference (p < 0.01, and p < 0.05, respectively). These findings were not observed in the control group. Study 2: forced expiratory volume in 1 second (FEV₁) and PEF markedly increased after treatment with TP compared with treatment with SRT or LTRA.
Conclusions: These findings suggest that TP can be used as a long-term add-on controller for patients with asthma receiving ICS.

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Background: It is known that a wide variety of factors exacerbate asthma; however, few studies have investigated the factors that exacerbate asthma from a patient's perspective. The aim of this study was to analyze the factors that exacerbate asthma, based on a questionnaire completed by asthma patients in Niigata Prefecture.
Methods: Based on questionnaires given to 3085 patients who visited the medical institutes in the Niigata Prefecture monthly from September through October 2006, groups stratified by sex, age, disease type and disease severity, were analyzed for factors contributing to asthma exacerbation, as described in the guideline of the Japanese Society of Allergology.
Results: The leading exacerbating factor chosen by patients was a change in the weather, followed by smoking, allergen exposure, fatigue, stimulants, and air pollutants. Respiratory infection, widely recognized as a critical factor of severe exacerbation, was ranked seventh. Allergen exposure and air pollutants were prominent in younger individuals, whereas respiratory infection tended to be more common in elderly subjects. Allergen exposure, air pollutants, and exercise were significantly more common in atopic-type patients, in contrast with respiratory infection in non-atopic-type patients. According to multiple regression analysis, poor asthma control during the last one year was associated with changes in the weather, whereas the non-atopic disease type was related to exacerbation by respiratory infection. Current smoking was associated with both factors.
Conclusions: Many factors exacerbate asthma, depending on the individual case and his/her background. These data suggest that changes in the weather may be more important factor for patients in asthma exacerbation.

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Background: We compared the bronchodilative effects of salbutamol delivered via 3 different mesh nebulizers, Aeroneb-go^®(AE), Omron-NE-U22^®(OM) and Pari-eMotion^®(PA).
Methods: We enrolled 36 children with asthma who visited the Kurosaka Pediatrics and Allergy Clinic, randomly assigned to 3 groups for treatment with AE, OM or PA. The dose of salbutamol in the solution was 0.15mg× body weight (kg)(minimum 2.5mg, maximum 5mg). FEV₁, PEFR and V₅₀ were measured in these patients before treatment, and at 15 and 30 minutes after salbutamol inhalation using one of the 3 mesh nebulizers.
Results: All groups showed a significant improvement of FEV₁, PEFR and V₅₀ at 30 minutes after salbutamol inhalation. The AE group did not show a significant improvement in PEFR at 15 minutes after inhalation, whereas a significant improvement in FEV₁ and V₅₀ was evident at the same time point. The OM group showed no significant improvement in V₅₀ at 15 minutes after inhalation, whereas this group clearly showed a significant improvement in PEFR and FEV₁ at the same time point.
Conclusions: Overall, all 3 mesh nebulizers were useful devices in treating bronchial asthma, although some differences in lung function improvement were evident. The limitation of this study is that subjects did not include patients with severe asthma attacks.

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Background: The fraction of exhaled nitric oxide (FeNO) is a useful marker of eosinophilic airway inflammation in asthmatics. No studies have examined the relationship between the change in FeNO levels measured offline and changes in bronchial hyperresponsiveness (BHR) in asthmatic patients treated with inhaled corticosteroids (ICS). The objective of this study was to investigate the relationship between the change in FeNO levels measured offline and the change in BHR to acetylcholine in asthmatic patients taking ICS.
Methods: The study population comprised 41 ICS-treated asthmatics from our outpatient clinic. We measured FeNO levels by two methods -with a Sievers kit ("FeNOs") and with a kit from the Center for Environmental Information Science, Japan ("FeNOc") at baseline and after 1 year of regular treatment. We also used spirometry to test BHR to acetylcholine (PC_20Ach).
Results: The mean of duration of observation was 406 days. There were significant relationships between ΔlogPC_20Ach and logPC_20Ach (r = -0.877, P < 0.001), FeNOs (r = 0.465, P = 0.002), and FeNOc (r = 0.524, P = 0.004) at baseline, but not with age, the dose of ICS, FEV₁, or %FEV₁. Moreover, there was a significant relationship between ΔlogPC_20Ach and ΔFeNOs (r = -0.386, P = 0.013) and ΔFeNOc (r = -0.473, P = 0.004), but not with ΔFEV₁.
Conclusions: Changes in FeNOs and FeNOc correlated with improvements in BHR to acetylcholine in adult asthmatics after ICS therapy. Our findings suggest that offline monitoring of FeNO will facilitate the management of bronchial asthma in patients treated with ICS.

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Background: Published data regarding changes in the prevalence of childhood allergic diseases in Japan have been limited.
Methods: To observe changes in the recent trends of the childhood allergy epidemic in Japan, a population-based questionnaire survey of allergic diseases was conducted among 13,215 schoolchildren, aged 7 to 15 years, in Kyoto, Japan in 2006. The results were compared with those obtained in the 1996 survey using the same scale and methods in the same region.
Results: The prevalences of bronchial asthma (BA), atopic dermatitis (AD), allergic rhinitis (AR), and allergic conjunctivitis (AC) in 1996 and 2006 were 5.1% and 5.0% (p = 0.58), 4.2% and 5.6% (p < 0.0001), 20.3% and 27.4% (p < 0.0001), and 13.3% and 25.2% (p < 0.0001), respectively. Although the distribution of BA severity improved, the severity distribution of AD, AR, and AC all deteriorated. The lifetime prevalence (present prevalence and past history combined) of BA increased from 6.5% to 7.6% (p < 0.0001). The sex ratio analysis showed that the female predominance in the prevalence of AD observed in 1996 disappeared in 2006, indicating a particular rise in AD prevalence among boys.
Conclusions: Overall, the results indicate that the rising trend of allergic diseases, especially in AD, AR, and AC, continues among schoolchildren living in Kyoto, Japan. Special attention should be paid to skin and nasoocular symptoms.

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Background: Recently, extensive research has established that epidemiologic and therapeutic links exist between allergic rhinitis and asthma. The objective of this study was to clarify this association in Iraq.
Methods: The data included in this study were collected from five surveys for asthma and allergic rhinitis that were performed during the period from September 2000 to July 2008. These surveys were parts of Tikrit University College of Medicine PHC program.
Results: The frequency of allergic rhinitis (AR) was 61.6% among individuals with asthma versus 6% among non-asthmatic (control) subjects (Odd Ratio [OR] = 25.5; P < 0.0001). All studies indicated a significant frequency of AR among asthmatic patients in comparison with non-asthmatic subjects, whether the patients were adults or children (OR for adults = 14.9 and 22.5, for children 34.7 and 48.4; P < 0.001 for all). Furthermore, the high frequency of AR in asthmatic patients was seen whether the study was a community based study (CBS)(OR = 14.9 and 48.4; P < 0.0001) or a hospital based study (HBS)(OR = 22.5 & 34.7; P < 0.0001). The frequency of current asthma was 51.8% among individuals with AR versus 5.4% among control subjects (OR = 23.1; P < 0.0001).
Conclusions: This study provided evidence that AR and asthma are strongly associated with each other and the treatment approach should consider the entire airway rather than only a part.

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Background: Allergenic cross reactivity between the members of the Pooids (Lolium perenne, Phleum pratense, and Poa pratensis) and Chloridoids (Cynodon dactylon and Paspalum notatum) is well established. Studies using crude extracts in the past have demonstrated limited cross reactivity between the Pooids and the Chloridoids suggesting separate diagnosis and therapy. However, little is known regarding the molecular basis for the limited cross reactivity observed between the 2 groups of grasses. The present study was undertaken to gain insights into the molecular basis of cross allergenicity between the major allergens from rye and Bermuda grass pollens.
Methods: Immunoblot inhibition tests were carried out to determine the specificity of the proteins involved in cross reactivity. Crude pollen extract and bacterially expressed and purified recombinant Lol p 1and Lol p 5 from rye grass were subjected to cross inhibition experiments with crude and purified recombinant Cyn d 1 from Bermuda grass using sera from patients allergic to rye grass pollen.
Results: The immunoblot inhibition studies revealed a high degree of cross inhibition between the group 1 allergens. In contrast, a complete lack of inhibition was observed between Bermuda grass group 1 allergen rCyn d 1, and rye grass group 5 allergen rLol p 5. Crude rye grass extract strongly inhibited IgE reactivity to Bermuda grass, whereas crude Bermuda grass pollen extract showed a weaker inhibition.
Conclusions: Our data suggests that a possible explanation for the limited cross reactivity between the Pooids and Chloridoids may, in part, be due to the absence of group 5 allergen from Chloridoid grasses. This approach of using purified proteins may be applied to better characterize the cross allergenicity patterns between different grass pollen allergens.

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Background: Allergen immunotherapy is effective in allergic individuals however efforts are being made to improve its safety, convenience, and efficacy. It has recently been demonstrated that allergen-linked immunostimulatory DNA (ISS) is effective in stimulating an allergen-specific Th1 response with decreased allergenicity. The objective of this study is to investigate whether ISS linked to purified ragweed allergen Amb-a-1 (AIC) can inhibit local allergen-specific Th2 and induce allergen-specific Th1 responses in explanted nasal mucosa of ragweed-sensitive subjects. In addition, we set out to determine whether AIC is more effective compared to stimulation with unlinked Amb a 1 and ISS.
Methods: Tissue from ragweed-sensitive patients (n = 12) was cultured with whole ragweed allergen (RW), Amb-a-1, AIC, Amb-a-1 and ISS (unlinked), or tetanus toxoid (TT) for 24 hours. IL-4, -5, -13, TNF-α and IFN-γ mRNA-positive cells were visualized by in situ hybridization and T cells, B cells and neutrophils were enumerated using immunocytochemistry.
Results: RW or Amb-a-1 increased the number of IL-4, IL-5, and IL-13 mRNA+ cells in the tissue compared to medium alone. AIC had similar cytokine mRNA reactivity as control tissue. AIC and TT increased IFNγ-mRNA expression. Unlinked Amb-a-1 and ISS showed similar effects to AIC, however this response was weaker. The number of TNF mRNA+ cells, T cells, B cells and neutrophils remained unchanged.
Conclusions: AIC is effective in stimulating a local allergen-specific Th1- and abolishing Th2-cytokine mRNA reactivity in the nose and may be considered as a strong candidate for an improved approach to immunotherapy in ragweed-sensitive individuals.

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Background: B7-H2 is a ligand for the inducible costimulator (ICOS). The aim of this study was to examine the expression and function of B7-H2 in human airway smooth muscle (ASM) cells and compare them with those of CD40 or OX40 ligand (OX40L).
Methods: Expression of B7-H2, CD40 and OX40L in ASM cells and their respective counterparts in T cells was analyzed by RT-PCR or flow cytometry. The modulating effect of polyinosinic-polycytidylic acid (poly I:C) on expression of B7-H2, CD40 and OX40L was also examined. The function of these three molecules was evaluated by virtue of adhesion of anti-CD3-activated T cells, IL-6 and IL-8 production and DNA synthesis.
Results: ASM cells constitutively expressed B7-H2, CD40 and OX40L that mediated adhesion of activated T cells expressing ICOS, CD40L and OX40. ASM cells responded to poly I:C with upregulated expression of B7-H2, CD40 and OX40L and displayed enhanced adhesion of activated T cells. Functional analysis performed on untreated ASM cells showed that engagement of B7-H2 with ICOS-Ig clearly induced DNA synthesis, whereas that of CD40 or OX40L with trimeric CD40L or OX40-Ig greatly increased IL-6 and IL-8 production. These responses were enhanced in poly I:C-treated ASM cells.
Conclusions: The data demonstrate that ASM cells express functionally active B7-H2, CD40 and OX40L and suggest that B7-H2-dependent signaling may play an active role in a proliferative response rather than in cytokine and chemokine production. In addition, the modulation of B7-H2, CD40 and OX40L expression and function by poly I:C may have important implications for the function of virus-infected ASM cells.

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Background: The determination of total IgE in tears is useful as a diagnostic tool in allergic conjunctivitis disease (ACD). We evaluated the efficacy of this diagnostic tool for ACD, which is a clinically applicable novel immunochromagraphic method to determine total IgE in tears.
Methods: The subjects comprised 4 groups: 15 patients with vernal keratoconjunctivitis (VKC group), 8 patients with atopic keratoconjunctivitis (AKC group), 18 patients with allergic conjunctivitis (AC group), and 7 normal healthy volunteers as a control (control group). Tears were sampled using filter paper, and the total IgE in tears was determined by immunochromatography assay. Semiquantitative determination was carried out by examining the intensity of the colored line using an immunochromatoreader (IgE index). The relationship between IgE indices in tears and total IgE levels in serum or between IgE indices and the clinical scores of ACD was examined.
Results: The positive ratio obtained by this novel application of the immunochromatography assay was 38 of the 41 in the patients with ACD and none in the 7 controls. IgE indices for the VKC group, AKC group and AC group were 27.5 ± 15.6, 19.8 ± 15.8, and 4.0 ± 3.1 (mean ± SD), respectively. IgE indices in tears showed significant correlation with both total IgE levels in serum (P < 0.001, r = 0.76) and clinical scores of ACD (P < 0.001, r = 0.57).
Conclusions: The novel application of the immunochromatography assay to assess the total IgE in tears is a useful clinical tool to investigate ACD.

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Background: The objective of this study is to evaluate the practical usefulness of a scoring system using the 5-5-5 exacerbation grading scale for allergic conjunctivitis disease (ACD).
Methods: Subjects were 103 patients with ACD including 40 patients with vernal keratoconjunctivitis (VKC), 20 patients with atopic keratoconjunctivitis (AKC), and 43 patients with allergic conjunctivitis (AC).
The 5-5-5 exacerbation grading scale consists of the following 3 graded groups of clinical observations: the 100-point-grade group (100 points for each observation) includes active giant papillae, gelatinous infiltrates of the limbus, exfoliative epithelial keratopathy, shield ulcer and papillary proliferation at lower palpebral conjunctiva; the 10-point-grade group (10 points for each observation) includes blepharitis, papillary proliferation with velvety appearance, Horner-Trantas spots, edema of bulbal conjunctiva, and superficial punctate keratopathy; and the 1-point-grade group (1 point for each observation) includes papillae at upper palpebral conjunctiva, follicular lesion at lower palpebral conjunctiva, hyperemia of palpebral conjunctiva, hyperemia of bulbal conjunctiva, and lacrimal effusion. The total points in each grade group were determined as the severity score of the 5-5-5 exacerbation grading scale.
Results: The median severity scores of the 5-5-5 exacerbation grading scale in VKC, AKC and AC were 243 (range: 12-444), 32.5 (11-344), and 13 (2-33), respectively. The severity score of each ACD disease type was significantly different (P < 0.001, Kruskal-Wallis test). The severity of each type of ACD was classified as severe, moderate, or mild according to the severity score.
Conclusions: The 5-5-5 exacerbation grading scale is a useful clinical tool for grading the severity of each type of ACD.

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Background: Since the first suggestion of threshold values for food specific IgE antibody levels in relation to clinical reactivity, several authors have proposed different threshold values for different allergens. We investigated the relationship between wheat/soybean specific IgE antibody levels and the outcome of wheat/soybean allergy diagnosis in children of different ages.
Methods: A retrospective study was conducted in 536 children admitted consecutively to our clinic with the suspicion of wheat and/or soybean allergy. The children underwent an oral food challenge and blood samples for specific IgE measurement were obtained.
Results: The children who reacted to the oral food challenge had higher specific IgE titers to the specific allergen compared to the non-reacting group. The risk for reaction increased 2.33-fold (95% CI 1.90-2.87) for wheat and 2.08-fold (95% CI 1.65-2.61) for soybean, with increasing levels of specific IgE. A significant difference between the ages of subjects pertained only to wheat.
Conclusions: We found a relationship between the probability of failed challenge and the concentration of IgE antibodies to both wheat and soybean. Age influences the relationship of allergen specific IgE levels to wheat and oral food challenge outcome. Younger children are more likely to react to low levels of specific IgE antibody concentration to wheat than older children.

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Refer to: Enhanced Goblet Cell Hyperplasia in HDC Knockout Mice with Allergic Airway Inflammation Allergology International 2009; 58: 125-134.

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