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BACKGROUND The clinical characteristics of patients with allergic contact dermatitis (ACD) due to a skin adhesive containing 2-octyl cyanoacrylate, Dermabond®, have not yet been elucidated. OBJECTIVE To investigate the clinical characteristics of patients with ACD caused by Dermabond® application. METHODS In this retrospective study, 577 patch tested patients were included. We identified patients with positive patch test results for Dermabond® and evaluated their results concerning (meth)acrylates and ethyl cyanoacrylate adhesive. RESULTS Nine patients had positive patch test results to Dermabond®; six had developed secondary generalization.The mean time between Dermabond® application and ACD onset was 34 days (range, 27-44) in six patients with ACD after the first use, whereas, in the other three patients, it was 5.6 days (range, 4-8) after the second use. The time was significantly different between the two groups (P

Background: cold urticaria (ColdU), that is, the occurrence of wheals or angioedema in response to cold exposure, is classified into typical and atypical forms. The diagnosis of typical ColdU relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). We aimed to determine risk factors for ColdA in typical ColdU. Methods: an international, cross-sectional study COLD-CE was carried out at 32 urticaria centers of reference and excellence (UCAREs). Detailed history was taken and CST with an ice cube and/or TempTest(R) performed. ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms. Results: of 551 ColdU patients, 75% (n = 412) had a positive CST and ColdA occurred in 37% (n = 151) of the latter. Cold-induced generalized wheals, angioedema, acral swelling, oropharyngeal/laryngeal symptoms, and itch of earlobes were identified as signs/symptoms of severe disease. ColdA was most commonly provoked by complete cold water immersion and ColdA caused by cold air was more common in countries with a warmer climate. Ten percent (n = 40) of typical ColdU patients had a concomitant chronic spontaneous urticaria (CSU). They had a lower frequency of ColdA than those without CSU (4% vs. 39%, p = .003). We identified the following risk factors for cardiovascular manifestations: previous systemic reaction to a Hymenoptera sting, angioedema, oropharyngeal/laryngeal symptoms, and itchy earlobes. Conclusion: coldA is common in typical ColdU. High-risk patients require education about their condition and how to use an adrenaline autoinjector., GA(2)LEN UCARE Network

This document summarizes the aims of GA2 LEN/HAEi Angioedema Centers of Reference and Excellence (ACAREs) and elaborates the requirements that ACAREs must fulfill to become certified. It also provides (see Appendix S1) background information on GA2LEN and HAEi, including HAEi member organizations and regional patient advocates, on why we need an Angioedema Center of Reference and Excellence (ACARE) program and network, and on the accreditation and certification process, governance and funding, and on the interaction with other GA2LEN networks of centers of reference and excellence. The protocols, aims, requirements, and provisions related to becoming a certified CARE are based on (a) the experience of the GA2LEN UCARE network and (b) input from angioedema patients, general practitioners, and angioedema specialists.

Background To date, three orange allergens have been reported. However, it is still unclear whether gibberellin-regulated proteins (GRPs), identified as new allergens in other fruit allergies, are also involved in orange allergy. Objective To investigate the allergenicity of orange GRP and to determine the clinical characteristics of patients with orange allergy who are sensitized to orange GRP. Methods We enrolled 14 patients (four men, 10 women, mean age: 29.6 years) who were diagnosed with orange allergy based on relevant clinical history, positive skin test, and/or positive challenge test. Orange GRP (molecular weight: 6941.6 Da) was purified by ion-exchange column chromatography. To test for orange GRP-specific IgE, we performed ELISA, basophil activation tests, and skin prick tests. Cross-reactivity of orange GRP with native peach allergen nPru p 7 and Japanese apricot nPru m 7 was analysed by ELISA inhibition assays. IgE specific for orange, grapefruit, and peach allergens rPru p 1, rPru p 3, and rPru p 4 was measured using ImmunoCAP. Results Twelve of the 14 patients (85.7%) were positive for orange GRP allergy in at least one test: 71.4% (10/14) were positive by ELISA, 50% (3/6) were positive in the basophil activation test, and 100% (4/4) were positive in the skin prick test. ELISA inhibition assays revealed cross-reactivity of orange GRP with both nPru p 7 and nPru m 7. The patients showed variable positivity for specific IgE against orange, grapefruit, rPru p 1, rPru p 3, and rPru p 4 (57.1%, 71.4%, 7.1%, 0%, and 21.4%, respectively). The most frequent symptoms of orange GRP allergy were facial swelling and oropharyngeal symptoms. Conclusions and clinical relevance Orange GRP may be involved in orange allergy and may be a cross-reactive allergen between citrus fruits and the Rosaceae family of fruits.

Background Gibberellin-regulated protein (GRP, also known as peamaclein) was recently identified as a new marker allergen related to systemic reactions in peach allergy; however, its role in other fruit allergies is unknown. Objective To investigate the allergenicity of Japanese apricot (JA) GRP and clarify the clinical characteristics of JA allergy patients with GRP sensitization. Methods Seven patients (two males, five females, mean age 28.0 years) diagnosed with JA allergy based on relevant clinical history, positive skin test and/or challenge test were enrolled. JA GRP with a molecular weight of 6896.5 Da was purified by ion-exchange column chromatography. We performed enzyme-linked immunosorbent assay (ELISA), IgE-immunoblotting, basophil activating tests (BATs), and skin prick tests (SPTs) with purified JA GRP. To investigate the cross-reactivity between JA GRP and native Pru p 7 (nPru p 7), we performed ELISA inhibition tests. We measured specific IgE levels against apricot, peach, rPru p 1, rPru p 3, and rPru p 4 using ImmunoCAP. Results ELISA and IgE-immunoblotting using JA GRP showed positive reactions in six (85.7%) and seven (100%) patients, respectively. Five patients who provided informed consent for BATs and SPTs using JA GRP had positive results. In four patients who underwent ELISA inhibition tests using JA GRP and nPru p 7, IgE binding to one GRP inhibited binding to the other. The positivity for specific IgE against apricot, peach, rPru p 1, rPru p 3, and rPru p 4 was 14.3%, 57.1%, 0%, 0%, and 0%, respectively. Patients developed allergic reactions that were frequently accompanied with facial swelling, especially of the eyelids, which was dependent on cofactors, such as exercise. Conclusions and Clinical Relevance These results indicated that GRP might be a causative allergen of JA allergy, whose onset frequently requires a cofactor, such as exercise, and might be cross-reactive between JAs and peaches.

Background There have recently been reports suggesting that sensitization to food allergens may occur outside the intestinal tract, especially through the skin. To clarify the role of epicutaneous sensitization in food allergy, we investigated the clinical characteristics of adult patients with food allergies preceded by contact urticaria due to the same foods. Methods We investigated clinical characteristics of 15 patients (20–51 years of age; 5 men and 10 women), who had food allergies preceded by contact urticaria. Results Fourteen patients were contact urticaria due to the causative foods during occupationally cooking, whereas 1 patient during face pack. In the occupational group, causative foods included rice, wheat, fruits, vegetables, fish, shrimp and cuttlefish; in the fresh cucumber paste case the cause was cucumber. In the 15 patients, the causative foods were fresh, not processed, and were tolerated by most (9/15, 60%) after heating. Regarding to symptoms after ingestion of the causative foods, the most frequently induced symptoms was oral symptoms (14/15, 93.3%), followed by urticaria (4/15, 26.7%), abdominal symptoms (3/15, 20%). The duration between the start of jobs or face pack, and the onset of contact urticaria was from 1 month to 19 years (mean, 8.7 years). The duration between the onset of contact urticaria and the onset of food allergy was from a few weeks to 6 years (mean, 11 months). One sushi cook experienced severe anaphylactic shock after ingestion of fish. In the occupational group, 13 of 15 patients (86.7%) had atopic dermatitis or hand eczema, indicating that the impaired skin barrier might be a risk for food allergies induced by epicutaneous sensitization. Conclusions Epicutaneous sensitization of foods could induce food allergy under occupational cooking and skin-care treatment with foods in adults.

Background: Poly(γ-glutamic acid) (PGA) is an allergen in natto, fermented soybeans, which causes late-onset anaphylaxis. We hypothesized that jellyfish stings sensitize adults to PGA because a surfer had allergies to both natto and jellyfish, whose sting contains PGA. The aim of the study was to identify behavioral factors, such as marine sports, associated with PGA sensitization. Methods: Outpatients diagnosed with food allergies based on relevant clinical history, positive skin test and/or food challenge test answered a questionnaire during a regular visit in 2016. Results: Questionnaire data from 140 outpatients were analyzed. These patients were divided into two groups: natto allergy group (13 patients, M:F = 10:3, mean age 40.6 years) and non-natto allergy group (127 patients, M:F = 46:81, mean age 44.5 years). All patients with natto allergy had positive results in skin prick test and basophil activation test with PGA. Of these, 92.3% had a marine sport hobby, especially surfing (84.6%). PGA sensitization was independently associated with marine sports (odds ratio, 278.0, 95 percent confidence interval, 36.9–6315.9, p

Angioedema is the end result of deep dermal, subcutaneous and/or mucosal swelling, and is potentially a life- threatening condition in cases where the pharynx or larynx is involved. Drug-induced angioedema has been reported to occur in response to a wide range of drugs and vaccines. Drug-induced angioedema, like other cutaneous drug reactions, has been reported to be most frequently elicited by beta-lactam antibiotics and nonsteroidal anti-inflammatory drugs, although reliable data from epidemiologic studies are scarce. Recent reports suggested an increasing role of angiotensin-converting enzyme inhibitors (ACEIs) in the causation of life- threatening angioedema. ACEI-related angioedema is never accompanied by urticaria and occurs via a kinin- dependent mechanism. ACEI-related angioedema not only can start years after beginning the treatment, but it can then recur irregularly while under that treatment. Furthermore, allergy tests are unreliable for the diagnosis of ACEI-related angioedema, and so the relationship between angioedema and ACEIs is often missed and consequently quite underestimated. Accordingly, better understanding of the kinin-dependent mechanism, which is particular to angioedema, is necessary for the appropriate management of drug-induced angioedema.

Background Fermented soybeans (natto) have been reported to induce IgE-mediated, late-onset anaphylaxis without early-phase responses. However, the relevant allergens of natto allergy have never been identified. Case Summary A 38-year-old man developed an anaphylactic reaction accompanied by flashing, generalized urticaria, conjunctival redness, and dyspnea 3 hours after ingestion of commercial cold Chinese noodles. He had avoided natto for the past year due to developing several anaphylactic reactions half a day after natto ingestion. The results of skin prick tests (SPTs) were strongly positive for natto and the soup of cold Chinese noodles. Furthermore, SPTs showed positive for poly (γ-glutamic acid) (PGA), which is a major constituent of natto mucilage, alone among all the ingredients of the cold Chinese noodle soup. Therefore, he was diagnosed with late-onset anaphylaxis to PGA contained in natto and the cold Chinese noodle soup. Discussion These results indicated that in the present case, the relevant allergen of late-onset anaphylaxis may have been PGA in all episodes and that the patient had been sensitized by PGA through natto ingestion. PGA is produced by Bacillus subtilis during fermentation and is a high-molecular, biodegradable polymer. The late onset is therefore, hypothesized to be due to a delayed absorption of PGA, as PGA biodegrades to peptides sufficiently small to be absorbed in the bowel. PGA has recently been applied to a wide range of fields such as foods, cosmetics, and medicine. Therefore, patients with late-onset anaphylaxis to PGA of natto should avoid not only natto but also other materials containing PGA.

This review describes the diverse clinical manifestations of IgE-mediated allergy to ingested wheat and summarizes recent advances in characterization of clinically significant allergens and diagnostic workup.Recent population-based studies have shown the prevalence of wheat allergy and sensitization more precisely than past studies among small populations and in hospital settings. Intensive research has demonstrated the diverse profile of both water/salt-soluble and insoluble allergens involved in clinical types of wheat allergies determined depending on the patient age, the sensitization route, and the protein state during the exposure. Consequently, some new allergens, including nonspecific lipid transfer protein (Tri a 14), have been identified. For diagnosis, the role of water/salt-insoluble gliadins, particularly omega-5 gliadin, a major allergen of wheat-dependent, exercise-induced anaphylaxis, was assessed as compared with the results of oral challenges. The mechanisms of eliciting anaphylactic symptoms by exercise in wheat-dependent, exercise-induced anaphylaxis were speculated upon; one is the allergenicity strengthened by activated tissue transglutaminase and another is the increased absorption of allergens through the gastrointestinal tract.Findings of the recent studies show potential for more precise diagnosis in each clinical type of wheat allergies.

Background Allergic reactions after ingestion of fermented soybeans have rarely been reported. Fermented soybeans were recently reported to be a causative food of IgE-mediated, late-onset anaphylaxis without early phase responses. The objectives of our study are to clarify the clinical and laboratory features and to characterize the allergens in allergy due to fermented soybeans. Methods Seven patients with suspected hypersensitivity to fermented soybeans, from whom informed consent had been obtained, underwent skin prick-prick tests with fermented soybeans and challenge test with fermented soybeans. Additionally, specific IgE against fermented soybeans and the allergens of fermented soybeans were detected by ELISA and IgE-immunoblotting, respectively. Results Seven male patients, aged 26 to 42 years (mean age, 33.1 years), participated. All patients reported generalized urticaria and dyspnea; 5, loss of consciousness; 2, collapse; 2, vomiting; and 2, diarrhea after fermented soybean ingestion. The interval between fermented soybean ingestion and onset of symptoms was 5 to 14 hours (mean, 9.6 hours). All patients were positive on skin prick-prick tests with fermented soybeans. In 2 patients, oral challenge with fermented soybeans was positive 5.5 and 13 hours after ingestion. In ELISA, all 5 patients tested showed elevated IgE levels to the fermented soybean extract. Furthermore, IgE-immunoblotting using 5 patients' sera showed six bands, of which three bands at 38, 28, and 26-kd were bound to sera from 4 patients. Conclusions Cases with hypersensitivity after ingestion of fermented soybeans most frequently correspond to IgE-mediated, late-onset anaphylactic reactions due to fermented soybeans.

Background Reactivation of human herpesvirus (HHV) infection, especially HHV-6, has been observed in patients with drug-induced hypersensitivity syndrome (DIHS). In toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), the relevance of HHV infection to the symptoms is unclear. Methods Patients with a diagnosis of DIHS ( n = 7), TEN ( n = 5) and SJS ( n = 4) were included in the present study. These patients were evaluated for the presence of active HHV-6, HHV-7 and cytomegalovirus (CMV) infections by serological tests and polymerase chain reaction with blood. Results More than 3 weeks after the onset of DIHS, HHV-6 serological tests revealed a remarkable rise in IgG antibodies in six patients, including one treated without steroids. Human herpesvirus-6 DNA was detected in blood from three patients. In one patient with DIHS, reactivation of CMV was shown without reactivation of HHV-6, whereas in three patients anti-CMV IgG antibodies increased after the rise of anti-HHV-6 IgG antibodies. Anti-HHV-7 IgG antibodies did not show remarkable rises in any of these patients. As for patients with TEN and SJS, anti-HHV-6, anti-HHV-7 and anti-CMV IgG antibodies showed no significant increase, except for one patient in whom anti-HHV-6 and anti-HHV-7 IgG antibodies increased, but not more than 1: 160, after steroid therapy. Human herpesvirus-6 DNA was not detected in the blood of those patients. Conclusions Human herpesvirus-6 reactivation in patients with DIHS is not due to non-specific reactivation induced by steroid therapy, but to events specific to DIHS. We hypothesize that DIHS may occur as a result of reactivation of HHV, especially HHV-6, accompanied with an allergic reaction to drugs, followed by a substantial immune response to the virus that is probably responsible for visceral involvement.

The clinical features of patients with oral allergy syndrome (OAS) due to plant-derived foods related to pollen allergy have been rarely reported in Japan.To evaluate the characteristics of OAS and to investigate whether pollen sensitizations are correlated with the prevalence of OAS in Japan.We measured specific IgE antibodies against 5 pollens in 622 outpatients (277 males and 345 females; mean age, 37 years) with atopic dermatitis, urticaria, angioedema, and food allergy during a 2-year period. Furthermore, OAS is diagnosed based on anamnesis and positive skin prick test reactions to suspected foods.Eighteen of the 436 patients (4.1%) sensitized to pollens were diagnosed as having OAS. Rates of specific IgE antibody-positive responses against Japanese cedar, ragweed, orchard grass, mugwort, and alder pollen were 69.8%, 35.3%, 29.1%, 24.1%, and 19.6%, respectively. The prevalence of OAS showed a significant positive correlation with sensitization to alder (P.001). In addition, the most frequent causative foods were found to be apple, peach, and melon. The prevalence of OAS due to apple showed a significant positive correlation with sensitization to alder (P.001) pollen, due to peach showed a significant positive correlation with sensitization to alder (P.001) and orchard grass (P.05) pollen, and due to melon showed a significant positive correlation with sensitization to alder (P.005), orchard grass (P.05), and ragweed (P.05) pollen.Sensitization to pollens from species in the Betulaceae family is most strongly implicated in causing OAS in Japan.

Background Few cases of cashew nut (CN) allergy have been reported in Japan. We evaluated the clinical features of 4 cases with CN allergy and investigated the allergens involved. Methods In order to investigate the cross-reactivity between CN and pistachios, we performed ImmunoCAP inhibition tests using sera of 4 cases with positive histories of CN allergy and positive results of specific IgE measurement (ImmunoCAP) and skin prick tests. Furthermore, we analyzed the molecular weights of allergens of CN and pistachios by IgE-immunoblotting. Results Of the 4 cases (male : female = 1 : 3), there were 3 cases (patient #2-4) and 1 case (patient #1) of anaphylaxis and oral allergy syndrome, respectively. The initial symptom was an oropharyngeal symptom in 3 of the 4 cases, of which 2 cases developed anaphylaxis within 10 minutes after eating only a few pieces of CN. All 4 cases reacted positively to the skin prick test with CN, although 1 case of anaphylaxis tested negatively for CN by ImmunoCAP. Additionally, in 2 cases, IgE-binding to CN and pistachio were inhibited with both pistachios and CN, indicating cross-reactivity between CN and pistachios. IgE-immunoblotting of CN using sera from the 4 cases revealed 2 bands at molecular weights of approximately 33 kd and 42 kd, whereas that of pistachios showed a single band at 36 kd. However, IgE in all 4 sera did not bind to rAna o 2. Conclusions In CN allergy, a small amount of CN could induce a severe anaphylactic reaction. Moreover, in cases of suspected CN allergy, reactions to not only CN but also pistachio, which could be cross-reactive to CN, should be examined.

Background: Cases of multiple chemical sensitivities (MCS) have been reported predominantly in adult patients, but pediatric cases have rarely been reported. Methods: We present a 5-year-old girl who suffered from recurrent reactions accompanied by urticaria, angioedema, headaches, dyspnea, loss of consciousness, and abdominal pain that were not eradicated, but were instead exacerbated, by various treatments with antihistamines and intravenous corticosteroids. Her diet diary revealed that symptoms occurred after ingestion of colorful sweets such as candies and jellybeans. Open challenge tests with food additives and nonsteroidal anti-inflammatory drugs (NSAIDs) were performed after elimination of these items. Skin prick tests using additives and NSAIDs, which were dissolved in saline, and prickprick tests using candies and jellybeans, were carried out. Results: Open challenge tests with Tartrazine, aspirin and acetaminophen were positive, whereas skin prick tests using additives and NSAIDs and prick-prick tests using candies and jellybeans were all negative. Consequently, intolerance to azo dyes and NSAIDs such as aspirin was diagnosed. However, she appeared to react to multiple chemical odors such as those of cigarette smoke, disinfectant, detergent, cleaning compounds, perfume, and hairdressing, all while avoiding additives and NSAIDs. On the basis of her history and the neuroophthalmological abnormalities, a diagnosis of severe MCS was made and she was prescribed multiple vitamins and glutathione. Conclusions: The present results suggest that in pediatric MCS, food and drug additives containing azo dyes might play important roles as elicitors.

Background Late-onset anaphylactic reactions without early-phase reactions are rarely reported. The hypothesized mechanism of late-onset anaphylaxis to fermented soybeans is delayed absorption or release into the bowel rather than an immunologic phenomenon. Objectives To investigate the mechanisms of late-onset anaphylaxis to fermented soybeans in 2 patients and to characterize the allergens involved in anaphylaxis caused by fermented soybeans. Methods Two patients underwent skin prick-by-prick tests with fermented soybeans as is. We used an open challenge for the provocation test of anaphylaxis and measured changes in plasma histamine, plasma tryptase, serum eosinophil cationic protein, and plasma leukotriene B4 levels in 1 patient. In addition, specific IgE against fermented soybeans and the allergens of fermented soybeans were detected by enzyme-linked immunosorbent assay and immunoblotting, respectively. Results The results of the prick-by-prick tests with fermented soybeans as is were positive in both patients and negative in control subjects. The challenge with 50 g of fermented soybeans caused generalized urticaria and dyspnea 13 hours after ingestion of fermented soybeans in 1 patient. In addition, his plasma histamine and tryptase levels transiently elevated during the anaphylactic event. In enzyme-linked immunosorbent assay, the patients showed elevated IgE levels to the proteins of fermented soybeans. Serum IgE antibodies of patients 1 and 2 were bound to approximately 5- and 26-kDa proteins in immunoblotting of fermented soybeans, respectively. Conclusion To our knowledge, this is the first report of late-onset anaphylaxis provoked by the challenge test half a day after ingestion of fermented soybeans.