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The most important peach fruit allergen is Pru p 3, followed by Pru p 1, Pru p 4, and Pru p 7. We aimed to assess their role in subjects with peach fruit-induced allergy (anaphylaxis and OAS) and compare skin prick tests (SPT) vs. specific immunoglobulin E (sIgE) for predicting anaphylaxis. We also selected a control group. SPT included prevalent inhalant and plant food allergens plus peach peel extract. The sIgE to Pru p 1, Pru p 3, Pru p 4, and Pru p 7 were quantified. Compared with controls (n = 42), cases (n = 41) were younger (P = 0.003), more frequently female (P < 0.05) and had higher SPT positivity to peach peel (44% vs. 2.4%, P < 0.0001). There were significant differences in sensitization to several pollens: Olea europaea, Artemisia vulgaris, Prunus persica, Platanus acerifolia (all P < 0.001); and fruits: apple (P < 0.04), peanut (P < 0.002), tomato (P < 0.005), and melon (P < 0.05). Pru p 3 sIgE was detected in 61% of all cases (85% anaphylaxis and 38% OAS; P < 0.01 each) and 5% of controls (P < 0.001). Pru p 4 sIgE was present in 19% of cases and 7% of controls. The sIgE to Pru p 1 and Pru p 7 were not found. The odds ratio to predict anaphylaxis for peach peel SPT was 113 (confidence interval [CI], 20-613; P < 0.0001); for sIgE to Pru p 3, 22 (CI, 5.3-93; P < 0.0001); and for SPT positivity to selected plant food allergens, 5 (CI, 1-19; P < 0.05). In our study group, SPT with peel peach extract was a better predictor of anaphylaxis than Pru p 3 sIgE or other variables considered. The role of sIgE to Pru p 1, Pru p 4, and Pru p 7 seemed negligible.

Background: Component-resolved diagnosis reveals the IgE response to many inhaled, food, and other allergens, improving the understanding and diagnosis of allergic diseases. Objective: The aims of the study are to study the recognition of different lipid transfer proteins (LTPs) and other allergen families in a large group of people sensitized to Pru p 3 and to analyze the relationship between the clinical entities and the allergens. Methods: This cross-sectional study included a large cohort of patients with positive skin tests to peach fruit and Pru p 3 specific IgE antibodies. Respiratory and food allergy symptoms were collected, and we performed prick tests with pollen, plant food, and other allergens plus the ImmunoCAP ISAC assay. Results: Our sample consisted of 421 people with a mean age of 33.25 years (range 16–68); 54.6% were women. Clinical entities included anaphylaxis (37.1%), urticaria (67.9%), and oral allergy syndrome (59.1%). Rhinitis, rhinoconjunctivitis, and/or asthma were diagnosed in 71.8% of the participants. The most pronounced correlation existed between sensitization to Pru p 3 and to Jug r 3, Pla a 3, Ara h 9, and Cor a 8. We found a higher incidence of anaphylaxis in people with 5 or more recognized LTPs. No association was observed between inhaled and food allergies. Conclusion: Most Pru p 3-sensitized participants were sensitized to additional allergens from the same family and, to a lesser extent, to other allergens, mainly in the profilin and PR-10 protein families. Anaphylaxis occurred in more than a third of the cases evaluated, and almost three-quarters of them had respiratory symptoms. Respiratory and food allergies involving LTPs do not seem to be associated.

Cross-hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is a relatively common, non-allergic, adverse drug event triggered by two or more chemically unrelated NSAIDs. Current evidence point to COX-1 inhibition as one of the main factors in its etiopathogenesis. Evidence also suggests that the risk is dose-dependent. Therefore it could be speculated that individuals with impaired NSAID biodisposition might be at increased risk of developing cross-hypersensitivity to NSAIDs. We analyzed common functional gene variants for CYP2C8, CYP2C9, and CYP2C19 in a large cohort composed of 499 patients with cross-hypersensitivity to NSAIDs and 624 healthy individuals who tolerated NSAIDs. Patients were analyzed as a whole group and subdivided in three groups according to the main enzymes involved in the metabolism of the culprit drugs as follows: CYP2C9, aceclofenac, indomethacin, naproxen, piroxicam, meloxicam, lornoxicam, and celecoxib; CYP2C8 plus CYP2C9, ibuprofen and diclofenac; CYP2C19 plus CYP2C9, metamizole. Genotype calls ranged from 94 to 99%. No statistically significant differences between patients and controls were identified in this study, either for allele frequencies, diplotypes, or inferred phenotypes. After patient stratification according to the enzymes involved in the metabolism of the culprit drugs, or according to the clinical presentation of the hypersensitivity reaction, we identified weak significant associations of a lower frequency (as compared to that of control subjects) of CYP2C8*3/*3 genotypes in patients receiving NSAIDs that are predominantly CYP2C9 substrates, and in patients with NSAIDs-exacerbated cutaneous disease. However, these associations lost significance after False Discovery Rate correction for multiple comparisons. Taking together these findings and the statistical power of this cohort, we conclude that there is no evidence of a major implication of the major functional CYP2C polymorphisms analyzed in this study and the risk of developing cross-hypersensitivity to NSAIDs. This argues against the hypothesis of a dose-dependent COX-1 inhibition as the main underlying mechanism for this adverse drug event and suggests that pre-emptive genotyping aiming at drug selection should have a low practical utility for cross-hypersensitivity to NSAIDs.

ObjectivesSeveral studies have described peach tree (PT) as an occupational allergen. The aim of this work was to assess the effect ofPrunus persica9 (Pru p 9), a recently identified allergen from PT pollen, in exposed workers.MethodsThe study included people who reported respiratory symptoms after handling PT in orchards during the flowering period (Blanca village, Murcia region, south-east Spain). After completing a detailed questionnaire, participants underwent skin prick test (SPT) and nasal provocation test (NPT). The IgE response was analysed by SDS-PAGE and immunoblotting assays.ResultsA total of 21 cases were included (mean age 45 years; 57% women). Most were polysensitised to common pollens, although one person was sensitised only to PT pollen. All cases had a positive SPT to this pollen, and 43% also to Pru p 9. All participants reported having rhinitis, and six participants reported having also asthma. Immunoblotting showed a heterogeneous IgE pattern for several proteins, with Pru p 9 recognised in nine cases. Most participants sensitised to PT pollen and Pru p 9 had positive NPTs, while those who were not sensitised to Pru p 9 tested negative.ConclusionsWe demonstrate for the first time that Pru p 9, an allergen from PT pollen, can induce respiratory symptoms following occupational exposure. This must be considered a relevant allergen when people working with PT cultivars develop respiratory symptoms.

Purpose Elderly people thought to have an allergy to beta-lactams (BLs) may tolerate the drugs in subsequent exposures due to initial false labeling of allergies, the spontaneous loss of sensitivity to BLs over time or age-related decline in sensitization. As a result, they may be treated with less appropriate antibiotics, causing more side effects and entailing increased costs for health systems. The aim of this investigation was to assess whether patients in the third and fourth age with previously confirmed allergies to BLs had lost sensitization and could tolerate these antibiotics. Patients and methods Patients allergic to BLs were divided into group A (aged 60-79 years) and B (aged ≥80 years). Clinical history, skin testing, drug challenge tests (DCT) and evaluation of resensitization were used to classify participants as showing immediate reactions, non-immediate reactions, or tolerance. We compared clinical entities, drugs involved, and final outcome by age group. Results Of 1362 cases evaluated, 565 underwent an allergological study. The skin was the most common organ involved. Anaphylaxis and side chain reactions were more frequent in group A (p

Background Beta-lactams generate different allergenic determinants that induce selective or cross-reactive drug hypersensitivity reactions (DHRs). We aimed to identify the drugs involved, the selectivity of the response, the mechanism, and the value of the different diagnostic tests for establishing a diagnosis in children evaluated for DHRs to beta-lactams. Methods Prospective study evaluating children aged under 16 years reporting DHRs to beta-lactams. Reactions were classified as immediate and nonimmediate reactions. The work-up included sIgE, skin testing and drug provocation tests (DPTs) for immediate reactions and patch testing and DPTs for nonimmediate ones. Results Of the 510 children included, 133 were evaluated for immediate reactions and confirmed in 8.3%. Skin test/in vitro IgE contributed to diagnosing half of the cases. Selective reactions occurred with amoxicillin (63%), followed by common penicillin determinants (27%) and cephalosporins (0.9%). Among nonimmediate reactions (11,4% of the 377 children evaluated), most required DPTs, 52.7% of which were positive at 6-7 days of drug challenge. Selective reactions were identified with amoxicillin (80%), penicillin G (7.5%), cephalosporins (7.5%), and clavulanic acid (5%). Urticaria and maculopapular exanthema were the most frequent entities. Conclusions There were few confirmed cases of either type of reaction. Skin testing proved less valuable in nonimmediate reactions, over half of which would also have been lost in a short DPT protocol. Selective responders to amoxicillin were more likely to have nonimmediate reactions, while clavulanic acid-selectivity was exclusive to the nonimmediate typology. Over half the cases with DPTs required 6-7 days of treatment for DHR confirmation.

International audience; Background: β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE.Objective: We sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics.Methods: Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort.Results: Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10-14); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10-7) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10-7). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10-9). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams.Conclusions: HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.

International audience; Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell-mediated reactions classically occur more than 6 hours after drug administration and include life-threatening conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA-B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA-compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim-sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future.

Background: Although plant and fruit pollens are entomophilous and relevant in exposed workers, we have shown a high frequency of sensitisation and symptoms induction of peach tree pollen (PTP) and Prunus persica 9 (Pru p 9) in adults from areas of peach cultivars. Methods: We studied the sensitisation and clinical relevance of PTP and Pru p 9 in a large group of children and adolescents aged 3–19 years. A detailed questionnaire plus skin prick testing to prevalent allergens, PTP, and Pru p 9 were carried out. The clinical relevance was established by nasal provocation test (NPT) and symptom score index. Results: We evaluated 685 children (mean age 8.75 ± 3.3 years, median 9 years), 52% of them female. Sensitisation to PTP occurred in 20% of the cases following olive tree (33%) and Phleum pratense (26%). In a randomly selected subgroup of subjects sensitised to PTP, 30% were skin prick test-positive to Pru p 9. Most cases had rhinitis or rhinoconjunctivitis. NPT showed the relevance of PTP and Pru p 9 in the induction of symptoms. Conclusion: PTP and Pru p 9 are relevant in the induction of sensitisation and respiratory symptoms in children and adolescents. This allergen should be evaluated in children living in regions of peach tree cultivars.

Purpose of review NSAIDs are the drugs most frequently involved in hypersensitivity reactions (HSR). These are frequently prescribed at all ages. HSR are of great concern and can affect people at any age. These drugs can induce reactions by stimulating the adaptive immune system (IgE or T cell), known as selective responders or more frequently by abnormalities in biochemical pathways related with prostaglandin metabolism. These are known as cross-intolerant. With some exceptions, skin testing and in-vitro studies are of little value in selective responders. Recent findings In the last years, several classifications have been provided based on clinical symptoms, time interval between drug intake and appearance of symptoms, response to other nonchemically related NSAIDs and the underlying disease. Based on this classification, several well differentiated categories within each group of entities cross-intolerant and selective responders are now recognized. The most complex groups for evaluation are cross-intolerant in which three major groups exist: NSAIDs exacerbated respiratory disease, NSAIDs exacerbated cutaneous disease and NSAIDs-induced urticaria/angioedema in the absence of chronic spontaneous urticaria. Within the selective responders, there are two mechanisms involved: drug-specific IgE or T-cell effector responses. New entities have been added to this classification like mixed reactions within the cross-intolerant category, that must manifest as anaphylaxis and multiple immediate selective reactions. Summary The precise evaluation of patients with NSAIDs hypersensitivity following established guidelines will improve not only our understanding but also the management of these entities. As the number of patients affected with NSAIDs is important, further studies are warranted.

Background Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in children are becoming a great concern. Most studies have focused on adults, with noted discrepancies observed in the classification of hypersensitivity reactions to NSAIDs in children when compared with adults. Objective To phenotype a group of children with hypersensitivity reactions to NSAIDs, including paracetamol, and analyze the degree of agreement with the entities reported in adults and how they fit the proposed classifications. Methods The study comprised 116 children aged 0.5 to 14 years, with a clinical history indicative of hypersensitivity reactions to NSAIDs. They all underwent a single-blind oral provocation test with acetyl salicylic acid, except in those cases when this was the suspected drug, in which case the challenge was done first with ibuprofen. If positive, cross-intolerance was established and if negative, an oral provocation test with the culprit drug was performed to establish a selective response or exclude allergy. Results Of the 26% diagnosed as hypersensitive to NSAIDs, 83% were cross-intolerant and 17% selective reactors. The highest significant differences between reactors and nonreactors were observed in the time to reaction after drug intake and the clinical entity (P Conclusions From the total number of cases confirmed with NSAID hypersensitivity, 83% were cross-intolerant. In cross-intolerant reactions, both cutaneous and respiratory manifestations are common. Acetyl salicylic acid challenge as the first approach proved to be safe and useful to establish the diagnosis.

16 p.-3 fig.-4 tab., Introduction: Beta-lactams (BL) are the main cause of allergic drug reactions mediated by specific immunological mechanisms. Reactions can be IgE or effector T-cell mediated. The new antigenic determinants are recognized by the immunological system in the context of the common betalactam structure or the specific differences in the side chains of the antibiotics of this family plus the protein carrier., Areas covered: We have reviewed the recent clinical literature concerning new clinical entities, the progress in diagnosis including the difficulties for in in vivo and or in vitro testing as well as the new algorithms proposed for delabelling subjects classified as allergic to beta-lactams, and recommendations for desensitization procedures., Expert opinion: The knowledge gained over the last years on beta-lactam hypersensitivity has enabled a better understanding and management of cases with allergic reactions to beta-lactams., This work was supported by ISCIII Grants, the Network RIRAAF and ARADyAL [RD16/0006/0021, RD16/0006/0024 and RD16/0006/0032],SAF2015-68590-R and FEDER Funds.

Purpose: The etiopathogenesis of drug-induced liver injury (DILI) is still far from being elucidated. This study aims to the study of genetic variations in DILI, related to the drug target, and specifically in the genes coding for the cyclooxygenase enzymes.Methods: By using Next-generation Sequencing we analyzed the genes coding for COX enzymes (PTGS1 and PTGS2) in 113 individuals, 13 of which were patients with DILI caused by COX-inhibitors.Results: The key findings of the study are the increased frequency, among DILI patients, of SNPs causing alterations in transcription factor binding sites and non-synonymous PTGS gene variants, as compared to control subjects. Moreover, the association with non-synonymous SNPs was exclusive of DILI patients with late-onset (50 days or more) Pc < 0.001 as compared to DILI patients with early onset, or with control subjects.Conclusions: Our findings suggest an interaction of long-term exposure to COX inhibitors combined with functional variants of the COX enzymes in the risk of developing DILI. This is a novel observation that might have been overlooked by previous genetic studies on DILI because of the limited coverage of PTGS genes in exome chips.

International audience; An accurate diagnosis of β‐lactam (BL) allergy can reduce patient morbidity and mortality. Our aim was to investigate the availability of BL reagents, their use and test procedures in different parts of Europe, as well as any differences in the diagnostic workups for evaluating subjects with BL hypersensitivity. A survey was emailed to all members of the EAACI Drug Allergy Interest Group (DAIG) between February and April 2016, and the questionnaire was meant to study the management of suspected BL hypersensitivity. The questionnaire was emailed to 82 DAIG centres and answered by 57. Amoxicillin alone or combined to clavulanic acid were the most commonly involved BL except in the Danish centre, where penicillin V was the most frequently suspected BL. All centres performed an allergy workup in subjects with histories of hypersensitivity to BL: 53 centres (93%) followed DAIG guidelines, two national guidelines and two local guidelines. However, there were deviations from DAIG recommendations concerning allergy tests, especially drug provocation tests. A significant heterogeneity exists in current practice not only among countries, but also among centres within the same country. This suggests the need to re‐evaluate, update and standardize protocols on the management of patients with suspected BL allergy.

In the past years, several investigators have demonstrated the existence of local nasal responses in some patients with typical allergic rhinitis symptoms but without atopy and have defined a new phenotype called local allergic rhinitis (LAR) or 'entopy'. In a percentage of LAR subjects, the upper airway disease is also associated with lower airway symptoms. After the description of this phenotype, the differential diagnosis between LAR and nonallergic rhinitis (NAR) has become a challenge for the clinician. To correctly identify LAR patients is of high importance for treatment and management of these patients, and for an appropriate inclusion of patients in clinical trials and genetics studies. The treatment of LAR patients, in contrast with NAR, is oriented to allergen avoidance and specific treatment. Allergen immunotherapy, the aetiological treatment for allergic respiratory diseases, has demonstrated to be an effective and safe treatment in LAR, increasing immunological tolerance, and reducing the clinical symptoms and the use of medication. In this article, the important and novel aspects of LAR in terms of mechanisms, diagnosis and treatment will be discussed. Also, the involvement of the lower airway and the potential role of IgE in the bronchial disease will be also reviewed.

OBJECTIVE Cross-intolerance to NSAIDs is a class of drug hypersensitivity reaction, of which NSAIDs-induced urticaria and/or angioedema (NIUA) are the most frequent clinical entities. They are considered to involve dysregulation of the arachidonic acid pathway; however, this mechanism has not been confirmed for NIUA. In this work, we assessed copy number variations (CNVs) in eight of the main genes involved in the arachidonic acid pathway and their possible genetic association with NIUA. MATERIALS AND METHODS CNVs in ALOX5, LTC4S, PTGS1, PTGS2, PTGER1, PTGER2, PTGER3, and PTGER4 were analyzed using TaqMan copy number assays. Genotyping was carried out by real-time quantitative PCR. Individual genotypes were assigned using the CopyCaller Software. Statistical analysis was carried out using GraphPad prism 5, PLINK, EPIDAT, and R version 3.1.2. RESULTS AND CONCLUSION A total of 151 cases and 139 controls were analyzed during the discovery phase and 148 cases and 140 controls were used for replication. CNVs in open reading frames were found for ALOX5, PTGER1, PTGER3, and PTGER4. Statistically significant differences in the CNV frequency between NIUA and controls were found for ALOX5 (Pc=0.017) and PTGER1 (Pc=1.22E-04). This study represents the first analysis showing an association between CNVs in exonic regions of ALOX5 and PTGER1 and NIUA. This suggests a role of CNVs in this pathology that should be explored further.

Background: There have been few studies conducted on the efficacy and safety of specific immunotherapy with allergen extracts of fungi compared with other allergen extracts, and there are no data on the major allergen Alt a 1 of the fungus Alternaria alternata. Objectives: We sought to evaluate the efficacy and safety of subcutaneous immunotherapy with 2 different doses of Alt a 1 in patients with rhinoconjunctivitis caused by sensitization to A alternata. Method: We performed a multicenter, randomized, double-blind, placebo-controlled trial with Alt a 1 administered subcutaneously in patients with allergic rhinoconjunctivitis with or without controlled asthma aged 12 to 65 years. Three groups were included: the placebo group and active groups receiving 0.2 or 0.37 mu g of Alt a 1 per dose. The main end point was the combined symptom and medication score. Secondary end points were cutaneous reactivity and serum IgE and IgG(4) levels to Alt a 1. Recorded adverse reactions were graded according to World Allergy Organization criteria. Results: There were significant reductions in the combined symptom and medication score for the 0.37-mu g dose of Alt a 1 compared with placebo at 12 months of treatment. Reduced cutaneous reactivity and IgE levels, together with increased IgG(4) levels, were demonstrated for the 2 active groups versus the placebo group. A similar safety profile was found for both active groups compared with the placebo group. No serious adverse drug reactions were reported. Conclusion: Immunotherapy with Alt a 1 was efficacious and safe, reducing the symptoms and medication consumption associated with rhinoconjunctivitis after only 1 year of treatment. The clinical benefits were associated with reduced skin reactivity and specific IgE levels and increased IgG(4) levels.

NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence-based recommendations for the diagnosis and management of N-ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N-ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N-ERD. Recommendations for the most effective management of a patient with N-ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub-phenotypes and emerging sub-endotypes of N-ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N-ERD and unmet needs, which should be addressed in the future.

International audience; Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in drug hypersensitivity reactions through mechanisms that may involve genetic predisposition. We performed a fine-mapping GWAS in patients with NSAID-induced hypersen-sitivity reactions with cross-intolerance belonging to the group of NSAID-induced urticaria, angioedema, and anaphylaxis (NIUAA) (2) and matched controls from South Spain, and we replicated the re-sults in patients and paired controls from central Spain. GNAI2 was a significant predictor of NSAID-induced hypersensitivity reactions. This association may reflect its influence on the activation of leukot-riene receptors and the recruitment of immune cells involved in the pathological mechanisms of NSAID hypersensitivity.

Drug-induced anaphylaxis can be a life-threatening condition occurring after drug intake by any route, including non-therapeutic exposure due to accidental contact. The most common culprit drugs are non-steroidal anti-inflammatory drugs and beta-lactam antibiotics. Other antibiotics, such as quinolones, are also becoming important elicitors. In the hospital setting, neuromuscular blocking agents and contrast media play an important role. In addition to specific immunological mechanisms (IgE-mediated), other non-immunological mechanisms may participate, including the generation of vasoactive mediators through the arachidonic acid metabolic pathway, direct stimulation of mast cells and the activation of other inflammatory cascades. Diagnosis of drug-induced anaphylaxis includes skin testing, in vitro testing in some instances, and very often requires drug provocation to search for alternatives or in some cases for diagnosis confirmation. Often, the diagnosis must be performed in the context of confounding agents. Factors contributing to the degree of severity include previous diseases (e.g. cardiovascular disease) and the intake of other drugs such as beta-blockers. In circumstances where the culprit drug must be administered, patients should be desensitised if possible. This may be carried out for drug-induced anaphylaxis caused by both immunological and non-immunological reactions, such as cross-intolerance to NSAIDs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in the pediatric population as antipyretics/analgesics and anti-inflammatory medications. Hypersensitivity (HS) reactions to NSAID in this age group, while similar to adults, have unique diagnostic and management issues. Although slowly accumulating, published data in this age group are still relatively rare and lacking a unifying consensus. This work is a summary of current knowledge and consensus recommendations utilizing both published data and expert opinion from the European Network of Drug Allergy (ENDA) and the Drug Hypersensitivity interest group in the European Academy of Allergy and Clinical Immunology (EAACI). This position paper summarizes diagnostic and management guidelines for children and adolescents with NSAIDs hypersensitivity.

Allergen immunotherapy (AIT), the etiologic treatment of allergic rhinoconjunctivitis and allergic asthma, has been shown to be an effective and safe treatment in patients with allergic respiratory disease. The efficacy of AIT in reducing symptoms and medication requirements has been demonstrated not only during treatment but also after it is discontinued. AIT is the only treatment that has the ability to modify the natural course of allergic rhinoconjunctivitis and asthma. In recent years, a new entity—local allergic rhinitis (LAR)—has been reported, which is characterized by the presence of a local allergic response to inhalant allergens, with negative skin tests and no detection of specific IgE antibodies in the peripheral blood. Patients had a nasal-specific response after nasal allergen challenge and a nasal Th2 inflammatory response with specific IgE antibodies, and showed clinical improvement with the classical treatment for allergic rhinitis (antihistamines and nasal corticosteroids). Ongoing evidence indicates that these patients benefit from subcutaneous AIT and supports this indication for LAR.

Background: Immediate hypersensitivity reactions to clavulanic acid (CLV) seem to be on the increase. Diagnosis is mainly based on skin testing and the drug provocation test (DPT), procedures that are not risk free. The aim of this study was to evaluate whether the histamine release test (HRT) could help evaluate patients with selective hypersensitivity to CLV. Methods: Eighteen patients with immediate selective hypersensitivity reactions to CLV (positive skin tests to CLV but negative to the major and minor determinants of benzylpenicillin and amoxicillin; negative DPT to benzylpenicillin and amoxicillin) and 21 controls with tolerance to CLV were included. Direct and passive HRT, using patient whole blood or ‘IgE-stripped' donor blood sensitized by patient serum, respectively, were performed by stimulating the blood with CLV, and basophil histamine release was detected by fluorometric determination. Results: The clinical symptoms were anaphylaxis (n = 6), urticaria (n = 9) and urticaria-angioedema (n = 3). The median time interval between the reaction and the study was 225 days (interquartile range, IQR: 120-387.5) and between drug intake and the development of symptoms 30 min (IQR: 6.25-30). We obtained similar data for both the direct and passive HRT, with a sensitivity and specificity of 55 and 85%, respectively, a positive predictive value of 76% and a negative predictive value of 69%. Conclusions: The sensitivity of both the direct and passive HRT for diagnosing patients with immediate allergy to CLV is less than 60%. However, the passive HRT has the advantage that it is based on the testing of serum samples that can be handled more easily than fresh blood samples.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently involved in drug hypersensitivity reactions (DHR). NSAIDs are prescribed for different processes and some NSAIDs can be obtained over the counter. Areas covered: We analyse the practical approaches for managing and treating NSAID-DHR considering the five major groups of entities recognised, divided into two categories: those responding to strong COX-1 inhibitors and possibly weak COX-1 or selective COX-2 inhibitors named cross-intolerant (CI), and those induced by a single drug or drug group with good tolerance to strong COX-1 inhibitors, known as allergic reactions (SR). An analysis of the recent literature indicates that two approaches can be followed for CI: to give acetyl salicylic acid to confirm NSAID hypersensitivity or to give alternative drugs to provide a solution for the treatment of pain, fever, inflammation or other conditions. Desensitisation approaches have been undertaken, but mainly for CI cases with respiratory airway involvement and they are very rarely used for CI with cutaneous involvement or SR. Expert commentary: DHR to NSAIDs are now recognised as one of the most important problems in the evaluation and management of drug allergy. Because no diagnostic tests exist, important resources are needed to evaluate these patients.

Non-immediate drug reactions (NIR) are induced by specific immunological mechanisms and involve the recognition of hapten molecules by the immune system, with the participation of dendritic cells and other antigen-presenting cells. This process is followed by an effector response that can induce several clinical entities, ranging from mild to severe. The type of immunological recognition can be used as the basis for the diagnostic approach. Both in vivo and in vitro tests are available for the diagnosis of NIR. In vivo tests consist of the reproduction of a diminished immune response with the culprit drug and in vitro tests are based on the stimulation of memory cells in culture. If both tests give negative results, a drug provocation test can be used.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most commonly involved in hypersensitivity drug reactions. Such reactions can be due to the release of inflammatory mediators in the absence of specific immunologic recognition, or immunoglobulin E (IgE)- or T-cell-selective responses. The former include upper and lower airway symptoms in patients with chronic underlying respiratory disease, the exacerbation of chronic spontaneous urticaria, and the induction of cutaneous symptoms. The latter include selective responses to a single NSAID with good tolerance to strong cyclooxygenase-1 inhibitors, with a putative IgE or T-cell mechanism proposed. These reactions can be acute or delayed.

Background Drugs are responsible for 40% to 60% of anaphylactic reactions treated in the emergency department. A global research agenda to address uncertainties in anaphylaxis includes studies that identify factors associated with morbidity and mortality. Objective The present study investigated drug-induced anaphylaxis, etiologies, aggravating factors, and treatment. Methods A total of 806 patients with adverse drug reactions were screened, and those who had a clinical diagnosis of anaphylaxis were included in the study. Clinical and demographic characteristics of anaphylaxis were described, including etiologies, pathophysiologic mechanisms involved in the reactions, and a personal history of atopy and asthma. Factors associated with disease severity also were identified. Results Anaphylaxis was diagnosed in 117 patients (14.5%). The etiologies were defined in 76% of the cases, nonsteroidal anti-inflammatory drugs being the most frequent. Seventy-eight patients (66.7%) reported a previous reaction to the drug involved in the current reaction or to a drug from the same class and/or group. Epinephrine was used to treat 34.2% of patients who presented with anaphylaxis, and 40.8% of those with anaphylactic reactions with cardiovascular involvement. IgE-mediated reactions were associated with greater severity, manifested by the rates of cardiovascular dysfunction, hospitalization, and use of epinephrine. Conclusions The prevalence of anaphylaxis is high in patients who seek medical assistance for drug reactions, but its diagnosis is missed in emergency services, and adrenaline is underused. Drugs were prescribed to many patients despite a history of previous reaction. Nonsteroidal anti-inflammatory drugs were implicated in most cases of anaphylaxis induced by drugs, and IgE-mediated reactions were less frequent but more severe.

Metamizole is a NSAID that has been banned in several countries because of its toxicity. It is often involved in selective hypersensitivity reactions and most hypersensitivity patients develop anaphylaxis. Metamizole is rapidly metabolized, and metabolic profiles are related to genetic factors. We analyzed whether genetic determinants of metamizole metabolism influence the risk of developing hypersensitivity in 265 patients diagnosed with hypersensitivity to metamizole and 362 healthy individuals who tolerated metamizole. Slow acetylation is associated with an increased risk of developing selective hypersensitivity to metamizole [odds ratio for slow alleles=2.17 (95% confidence interval=1.44-3.27); P=0.00016], and particularly anaphylaxis [odds ratio=4.77 (95% confidence interval=2.28-9.98); P=0.000006], with a significant gene-dose effect. The association was not identified in patients with cross-hypersensitivity. Cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) genotypes did not influence risk association. Our findings raise the hypothesis of genetically determined metabolic variability as a risk factor for developing anaphylaxis with metamizole.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in allergic reactions of which two main types exist: IgE-mediated and crossintolerance. The diagnosis of crossintolerance reactions is often based on the drug provocation test. The potential value of the basophil activation test (BAT) was evaluated using different basophil markers in the diagnosis of patients with crossintolerance to NSAIDs and cutaneous symptoms. We studied 46 patients with crossintolerance to NSAIDs and 45 tolerant controls. BAT was performed with acetyl salicylic acid, paracetamol, diclofenac, dipyrone, naproxen, and ibuprofen at four different concentrations using CD193 and CD203c as basophil markers and CD63 as activation marker. We compared BAT results using CD193+ or CD193+CD203c+ for basophil selection and found a significant increase in the stimulation index when using CD193+CD203c+ in both patients and controls (P = 0.004 and P = 0.017, respectively). Selection of living cells only produced an increase in basophil stimulation in patients for both CD193+ and CD193+CD203c+ (P

Introduction Hypersensitivity reactions to beta-lactams (BLs) are often reported in children, with amoxicillin and, to a lesser extent, cephalosporins being the most frequent drugs involved. Although many of these children are considered to be allergic, a careful evaluation only confirms a low percentage. Objectives To analyse the clinical data, sensitization profile and diagnostic methods used in a large group of children with a clinical history of hypersensitivity reactions to BLs. Methods The study included children aged 1–14 yr with symptoms suggestive of hypersensitivity to BLs from January 2006–December 2012. Diagnosis was confirmed from a clinical history, specific IgE determination, skin testing and, if necessary, a drug provocation test (DPT). Results Of a total of 783 patients studied, only 62 (7.92%) were confirmed as being allergic, 9 (14.52%) with immediate and 53 (85.48%) with non-immediate reactions. In those with immediate reactions, 2 (22.22%) were diagnosed by in vitro test, 2 (22.22%) by skin testing and 5 (55.56%) by DPT; in those with non-immediate reactions, 2 (3.77%) were diagnosed by skin testing and 51 (96.23%) by DPT. In all cases, DPT was positive to the culprit drug (29 AX-CLV, 26 AX, 1 cefixime and 1 cefaclor), and the most usual symptoms were exanthema in 43 cases, urticaria in 12, urticaria–angio-oedema in 1 and erythema in 1 case. Conclusion After an allergological work-up, over 90% of the children evaluated were finally confirmed as tolerant to BLs. Most reactions were of the non-immediate type, and DPT was an essential tool for diagnosis.

This review focuses on the epidemiology and different risk factors related to the development of hypersensitivity reactions to antibiotics, with a focus on betalactams and fluoroquinolones, the compounds most frequently involved in these reactions, due to their high level of consumption. The true prevalence of allergic drug reactions is unknown and the corresponding morbidity, mortality and associated economic costs are often underestimated. It is reported that multiple risk factors, related to both the drug and the patient, can modify the clinical expression of immune-mediated drug reactions. These include the chemical properties, molecular weight and administration route of the drug and the age, gender, concomitant diseases and genetic factors of the patient.

Background Although allergic drug reactions have been considered to be immediate (IgE mediated) or delayed (T-cell effector mechanisms), accelerated reactions have also been defined; however, they have not been sufficiently studied. Objective To study the mechanisms involved in accelerated reactions to amoxicillin. Methods We monitored the response in 3 patients who had an accelerated reaction to amoxicillin. A T-cell effector response was searched after a Drug Provocation Test. Symptoms were recorded after initiation of the reaction, and sequential samples were taken at different intervals after challenge. Skin biopsy specimens were also taken, and a lymphocyte transformation test (LTT) was performed. Results After the drug provocation test, all 3 patients had a positive response within 2 to 6 hours of drug administration, with full expression at 6 hours, requiring corticoids and antihistamine treatment. They had generalized erythema with facial angioedema but no cardiovascular or respiratory symptoms. Monitoring of the response revealed the presence in the skin of CD4 and CD8 lymphocytes with increased expression of homing and cell activation markers. Immunohistochemistry revealed a perivascular mononuclear cell infiltrate with activated CD4 and CD8 cells expressing perforin and granzyme B. No tryptase release was detected in either the affected tissue or the peripheral blood. The LTT result was positive in all 3 patients. Conclusion We found that accelerated reactions to β-lactams are mediated by effector T cells. The increase in different T-cell markers and a positive LTT result to amoxicillin, in parallel with the occurrence of symptoms after challenge, support this mechanism.

Introduction Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently reported reaction to drugs. They can be induced by pharmacological mechanisms (cyclooxygenase inhibition), with patients classified as cross-intolerant (CI), or by specific immunological mechanisms, IgE or T cell, with patients classified as selective reactors (SR). Objective To analyse a large group of children with a history of NSAID hypersensitivity diagnosed by drug provocation test (DPT). Methods A group of 63 children with a history of NSAID hypersensitivity were evaluated by DPT. The children were classified as CI or SR depending on the acetyl salicylic acid (ASA) response in DPT. The atopic status was also assessed by prick tests and total IgE in serum. Results Using DPT, 68.2% were confirmed as having hypersensitivity, 58.1% classified as CI and 41.9% as SR. Of the 119 DPT performed, 73 were positive (53.4% to ibuprofen, 37% to ASA, 8.2% to metamizol and 14% to paracetamol); angio-oedema was present in 86.3% of cases. All CI cases tolerated the administration of paracetamol. A significant number of the CI children were atopic compared with the SR children and non-allergic controls. Conclusion In these children, CI hypersensitivity to NSAIDs was the most frequent type of hypersensitivity reaction. Ibuprofen was the drug most often involved, angio-oedema the most common entity, and frequently associated with atopy. DPT proved a safe approach for diagnosing these patients.

JOURNAL ARTICLE; The high-affinity IgE receptor (Fcε RI) is a heterotetramer of three subunits: Fcε RIα, Fcε RIβ, and Fcε RIγ (αβγ2) encoded by three genes designated as FCER1A, FCER1B (MS4A2), and FCER1G, respectively. Recent evidence points to FCERI gene variability as a relevant factor in the risk of developing allergic diseases. Because Fcε RI plays a key role in the events downstream of the triggering factors in immunological response, we hypothesized that FCERI gene variants might be related with the risk of, or with the clinical response to, selective (IgE mediated) non-steroidal anti-inflammatory (NSAID) hypersensitivity. From a cohort of 314 patients suffering from selective hypersensitivity to metamizole, ibuprofen, diclofenac, paracetamol, acetylsalicylic acid (ASA), propifenazone, naproxen, ketoprofen, dexketoprofen, etofenamate, aceclofenac, etoricoxib, dexibuprofen, indomethacin, oxyphenylbutazone, or piroxicam, and 585 unrelated healthy controls that tolerated these NSAIDs, we analyzed the putative effects of the FCERI SNPs FCER1A rs2494262, rs2427837, and rs2251746; FCER1B rs1441586, rs569108, and rs512555; FCER1G rs11587213, rs2070901, and rs11421. Furthermore, in order to identify additional genetic markers which might be associated with the risk of developing selective NSAID hypersensitivity, or which may modify the putative association of FCERI gene variations with risk, we analyzed polymorphisms known to affect histamine synthesis or metabolism, such as rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742, and rs1049793 in the HDC, HNMT, and DAO genes. No major genetic associations with risk or with clinical presentation, and no gene-gene interactions, or gene-phenotype interactions (including age, gender, IgE concentration, antecedents of atopy, culprit drug, or clinical presentation) were identified in patients. However, logistic regression analyses indicated that the presence of antecedents of atopy and the DAO SNP rs2052129 (GG) were strongly related (P < 0.001 and P = 0.005, respectively) with selective hypersensitivity to ibuprofen. With regard to patients with selective hypersensitivity to ASA, men were more prone to develop such a reaction than women (P = 0.011), and the detrimental DAO SNP rs10156191 in homozygosity increased the risk of developing such hypersensitivity (P = 0.039). Yes

BACKGROUND Local allergic rhinitis (LAR) is a phenotype of allergic rhinitis characterized by the presence of a localized immune response in the nasal mucosa of patients with negative skin prick test (SPT) results and undetectable serum specific IgE (sIgE). It unknown whether LAR is limited to areas with low or moderate aeroallergen exposure. OBJECTIVE To explore the presence of LAR and the clinical and immunological characteristics of this entity in geographic areas with high grass pollen loads. METHODS A cross-sectional observational study was carried out in 2 hospitals in central Spain (Madrid and Ciudad Real). Sixty-one patients with seasonal rhinitis and negative SPT results and undetectable serum sIgE were evaluated using a clinical questionnaire, determination of serum total IgE, and a nasal allergen provocation test (NAPT) with Phleum species. The response to NAPT was monitored using assessment of nasal symptoms, acoustic rhinometry, and determination of sIgE, tryptase, and eosinophil cationic protein in the nasal cavity. RESULTS Seasonal LAR was detected in 37 patients (61%) using the techniques described above. Eleven percent of patients with LAR were adolescents or children, and 14% reported onset of rhinitis in childhood. Most patients reported persistent-moderate seasonal nasal symptoms, and 41% reported worsening of the disease during the last 2 years. Conjunctivitis was the most common comorbidity, affecting 95% of cases. CONCLUSIONS LAR to grass pollen is relevant in patients with seasonal symptoms indicative of allergic rhinitis but with a negative skin test result who live in areas with high allergenic pollen loads. This entity should be included the differential diagnosis of rhinitis.

The effects of allergen immunotherapy (AIT) on local allergic rhinitis (LAR) are largely unknown. We conducted the first randomized, double-blind, placebo-controlled (DBPC), phase II trial of D. pteronyssinus (DP) subcutaneous AIT (DP-AIT) on LAR (clinicaltrials.gov identifier: NCT02123316). Thirty-six LAR patients received Pangramin PLUS DP or placebo for 24 months. The primary endpoints were symptoms, medication scores, and medication-free days. The secondary included skin test, serum specific IgE and IgG4, nasal allergen provocation test (NAPT), and adverse events. AIT-DP produced significant improvements in both primary and secondary endpoints vs placebo. After 12 months of AIT-DP, we detected a significant and marked increase in allergen tolerance with negative NAPT in 50% of patients, and significant increases of serum sIgG4. Immunotherapy was well tolerated; no systemic reactions were reported. This study demonstrated that AIT-DP is a safe and clinically effective treatment for LAR, confirming that LAR is a new indication for AIT.

Hypersensitivity drug reactions (HDR) consist of an individual abnormal response with the involvement of the immunological system. In addition to specific immunological mechanisms where specific antibodies or sensitised T cells participate, release of inflammatory mediators by non-specific immunological recognition may also occur. Within this category are one of the most common groups of drugs, the non-steroidal anti-inflammatory drugs. In addition to chemical drugs new emerging ones with an increasing protagonism are biological agents like humanised antibodies and others. For IgE dependent reactions both in vivo and in vitro tests can be used for the immunological evaluation. Sensitivity of these is not optimal and very often a drug provocation test must be considered for knowing the mechanism involved and/or establishing the diagnosis. For non-immediate reactions also both in vivo and in vitro tests can be used. Sensitivity for in vivo tests is generally low and in vitro tests may be needed for the immunological evaluation. Immunohistochemical studies of the affected tissue enable a more precise classification of non-immediate reactions. The monitorization of the acute response of the reactions has given clues for understanding these reactions and has promising results for the future of the immunological evaluation of HDR.