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Background Hypersensitivity to acetylsalicylic acid ( ASA) constitutes a serious problem for subjects with coronary artery disease. In such subjects, physicians have to choose the more appropriate procedure between challenge and desensitization. As the literature on this issue is sparse, this study aimed to establish in these subjects clinical criteria for eligibility for an ASA challenge and/or desensitization. Methods Collection and analysis of data on ASA challenges and desensitizations from 10 allergy centers, as well as consensus among the related physicians and an expert panel. Results Altogether, 310 subjects were assessed; 217 had histories of urticaria/angioedema, 50 of anaphylaxis, 26 of nonimmediate cutaneous eruptions, and 17 of bronchospasm related to ASA/nonsteroidal anti-inflammatory drugs ( NSAID) intake. Specifically, 119 subjects had index reactions to ASA doses lower than 300 mg. Of the 310 subjects, 138 had an acute coronary syndrome ( ACS), 101 of whom underwent desensitizations, whereas 172 suffered from a chronic ischemic heart disease ( CIHD), 126 of whom underwent challenges. Overall, 163 subjects underwent challenges and 147 subjects underwent desensitizations; 86 of the latter had index reactions to ASA doses of 300 mg or less. Ten subjects reacted to challenges, seven at doses up to 500 mg, three at a cumulative dose of 110 mg. The desensitization failure rate was 1.4%. Conclusions In patients with stable CIHD and histories of nonsevere hypersensitivity reactions to ASA/ NSAIDs, an ASA challenge is advisable. Patients with an ACS and histories of hypersensitivity reactions to ASA, especially following doses lower than 100 mg, should directly undergo desensitization. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions ( DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time-consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well-controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well-characterized patients with DHR and to develop new tests for diagnosis. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity includes allergic ( AR) and nonallergic reactions ( NARs) influenced by genetic predisposition. We performed a systematic review of genetic predictors of IgE-mediated AR and NAR with MEDLINE and PubMed search engine between January 1966 and December 2014. Among 3110 citations, the search selected 53 studies, 42 of which remained eligible. These eligible studies have evaluated genetic determinants of immediate reactions ( IR) to beta-lactams ( n = 19), NAR against aspirin ( n = 12) and other nonsteroidal anti-inflammatory drugs ( NSAIDs) ( n = 8), and IR to biologics ( n = 3). We reported two genomewide association studies and four case-control studies on candidate genes validated by replication. Genes involved in IR to beta-lactams belonged to HLA type 2 antigen processing, IgE production, atopy, and inflammation, including 4 genes validated by replications, HLA- DRA, ILR4, NOD2, and LGALS3. Genes involved in NAR to aspirin belonged to arachidonic acid pathway, membrane-spanning 4A gene family, histamine production pathway, and pro-inflammatory cytokines, while those involved in NAR to all NSAIDs belonged to arachidonic acid pathway and HLA antigen processing pathway. ALOX5 was a common predictor of studies on NAR to both aspirin and NSAIDs. Although these first conclusions could be drawn, this review highlights also the lack of reliable data and the need for replicating studies in contrasted populations, taking into account worldwide allele frequencies, gene-gene interactions, and contrasted situations of environmental exposure. [ABSTRACT FROM AUTHOR]

Background To date, genetic studies of hypersensitivity reactions to non-steroidal anti-inflammatory drugs ( NSAIDs) have been carried out mainly in aspirin-induced asthma and to a lesser extent in chronic urticaria, with no studies in patients with acute urticaria ( AU), the most common entity induced by these drugs. Objective In this work, we analysed the association of common variants of 15 relevant genes encoding both enzymes and receptors from the arachidonic acid ( AA) pathway with NSAID-induced AU. Methods Patients were recruited in several Allergy Services that are integrated into the Spanish network RIRAAF, and diagnosed of AU induced by cross-intolerance ( CRI) to NSAIDs. Genotyping was carried out by TaqMan allelic discrimination assays. Results A total of 486 patients with AU induced by CRI to NSAIDs and 536 unrelated controls were included in this large Spanish case-control study. Seven variants from 31 tested in six genes were associated in a discovery study population from Malaga (0.0003 ≤ p-value ≤ 0.041). A follow-up analysis in an independent sample from Madrid replicated three of the SNPs from the ALOX15 (rs7220870), PTGDR (rs8004654) and CYSLTR1 (rs320095) genes (1.055x10-6≤meta-analysis p-value ≤ 0.003). Conclusions and Clinical Relevance Genetic variants of the AA pathway may play an important role in NSAID-induced AU. These data may help understand the mechanism underlying this disease. [ABSTRACT FROM AUTHOR]

To cite this article: Doña I, Blanca-López N, Jagemann LR, Torres MJ, Rondón C, Campo P, Gómez AI, Fernández J, Laguna JJ, Rosado A, Blanca M, Canto G. Response to a selective COX-2 inhibitor in patients with urticaria/angioedema induced by nonsteroidal anti-inflammatory drugs. Allergy 2011; 66: 1428-1433. Abstract Background: In subjects with hypersensitivity reactions with cross-intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs), tolerance to selective COX-2 inhibitors has not been evaluated in large series of well-phenotyped cases. Methods: We evaluated 252 patients with urticaria and/or angioedema caused by hypersensitivity owing to cross-intolerance to NSAIDs. In addition to the clinical history, diagnosis was confirmed by provocation to an alternative NSAID. Two groups were considered: (A) patients with cross-intolerance to NSAIDs and intolerance to paracetamol and (B) patients with cross-intolerance to NSAIDs and good tolerance to paracetamol. Etoricoxib was administered to Group A patients and to a representative sample of Group B patients. In the event of a positive response, serum tryptase levels were determined and skin biopsy was performed in five patients in each group. Results: Ibuprofen was the most commonly implicated drug, followed by acetylsalicylic acid (ASA). Urticaria was the most common manifestation, followed by angioedema. Most of the patients developed symptoms within 1 h. Twenty-five percent in Group A ( n = 47) and 6% in Group B ( n = 50) were intolerant to etoricoxib. Skin biopsy showed mast cell activation with the release of tryptase to the extracellular space but without the increase in serum tryptase levels. Conclusion: Selective COX-2 inhibitors may be unsafe in subjects with urticaria and/or angioedema caused by hypersensitivity reactions to NSAIDs with cross-intolerance if they are intolerant to paracetamol. A quarter of patients who were intolerant to this drug were also intolerant to etoricoxib. In subjects with hypersensitivity to NSAIDs and intolerance to paracetamol, selective COX-2 inhibitors should be administered as a controlled, incremental dose provocation test to assess tolerance. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently involved groups of medicines in hypersensitivity drug reactions. Two mechanisms can induce the reaction: immunological (sensitization) due to a specific IgE or T cell response and pharmacological (cyclooxygenase inhibition). The contribution of each of these mechanisms to the reactions is not well known. To analyse a large group of subjects with confirmed hypersensitivity reactions to NSAIDs. The drugs involved, the clinical entities induced and the time interval between drug intake and appearance of the reaction were studied. In cases where the diagnosis was not confirmed, a drug provocation test was carried out. Atopy status was also assessed with prick test and total IgE in serum. A total of 659 patients were finally considered to have had hypersensitivity reactions to NSAIDs; 76% had cross-intolerance (CI) and 24% were selective responders (SR). The most important drugs involved in CI were propionic acid derivatives, in most cases ibuprofen, and in SR pyrazolones. In CI, the most frequent clinical entity was urticaria and angio-oedema and to a lesser extent airway involvement. The skin and airways were both involved in an important proportion of cases. The most frequent entities in SR were urticaria and/or angio-oedema followed by anaphylaxis. Atopy was significantly associated in the CI group ( P<0.005). Cutaneous hypersensitivity reactions by CI to NSAIDs are the most frequent entities induced by these compounds. In addition to aspirin, other NSAIDs are taking on a predominant role. Atopy can be a predisposing factor in patients with CI. Cite this as: I. Doña, N. Blanca-López, J. A. Cornejo-García, M. J. Torres, J. J. Laguna, J. Fernández, A. Rosado, C. Rondón, P. Campo, J. A. Agúndez, M. Blanca and G. Canto, Clinical & Experimental Allergy, 2011 (41) 86-95. [ABSTRACT FROM AUTHOR]

To cite this article: Torres MJ, Ariza A, Fernández J, Moreno E, Laguna JJ, Montañez MI, Ruiz-Sanchez AJ, Blanca M. Role of minor determinants of amoxicillin in the diagnosis of immediate allergic reactions to amoxicillin. Allergy 2010; 65: 590–596. Background: Skin testing of subjects with immediate hypersensitivity to amoxicillin is performed using major and minor determinants of benzylpenicillin plus amoxicillin. However, sensitivity is not optimal, and other determinants need to be considered. We assessed the sensitivity of stable, well-characterized minor determinants of amoxicillin in subjects with immediate allergic reactions to amoxicillin to improve skin test sensitivity. Methods: Amoxicillin, amoxicilloic acid, and diketopiperazine were prepared and characterized by reverse-phase HPLC, tested in vivo by skin testing and in vitro by basophil activation test and RAST inhibition assay. Results: Patients with immediate hypersensitivity to amoxicillin were selected: Group A ( n = 32), skin test positive just to amoxicillin; Group B ( n = 19), skin test positive to benzylpenicillin determinants; Group C ( n = 10), skin test negative and amoxicillin drug provocation test positive. In Group A, 27 subjects (81.8%) were skin test positive to amoxicillin, ten (30.3%) to amoxicilloic acid, two (6.1%) to diketopiperacine, and six (18.2%) negative. In Group B, nine (50%) were positive to amoxicillin, eight (42.1%) to amoxicilloic acid, none to diketopiperacine, and nine (50%) negative. In Group C, skin tests were negative. BAT was positive to amoxicillin in 26 patients (50.9%), to amoxicilloic acid in 15 (29.1%), and diketopiperazine in four (7.8%). RAST inhibition studies showed > 50% inhibition in all sera, with the highest concentration of amoxicillin and amoxicilloic acid. Conclusions: The combination of minor determinants of amoxicillin, amoxicilloic acid, and diketopiperazine seems to be of no greater value than the use of amoxicillin alone. Further efforts are needed to find new structures to improve sensitivity in the diagnosis of immediate hypersensitivity to betalactams. [ABSTRACT FROM AUTHOR]