History of the World Allergy Organization: In 1951, the leaders in allergy from all over the world came together to form the International Association of Allergology and Clinical Immunology (IAACI). For the next 60 years, the allergy world converged at the IAACI triennial meetings, which became biennial in 2003. The international meetings, originally named the International Congress of Allergology and Clinical Immunology (ICACI), are now the World Allergy Congress (WAC) hosted by the World Allergy Organization (WAO). Everyone who has aspired to have worldwide recognition has played a part in IAACI-WAO. The History of the World Allergy Organization traces the global arc of the allergy field over the past 60 years. The current officers of WAO elected to focus on this rich history, inviting prominent leaders who are interested in being part of this history project to write about their time with IAACI-WAO. This series will be presented in Cancún, México as part of the XXII World Allergy Congress (December 4-8, 2011). Leading up to the Congress in Cancún, the World Allergy Organization Journal is presenting segments of the History as part of the "Notes of Allergy Watchers Series." Please enjoy.--Michael A. Kaliner, MDHistorian and Past President (2006-2007)World Allergy Organization

Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for 21-25% of reported adverse drug events which include immunological and nonimmunological hypersensitivity reactions. This study presents up-to-date information on pathomechanisms, clinical spectrum, diagnostic tools and management of hypersensitivity reactions to NSAIDs. Clinically, NSAID hypersensitivity is particularly manifested by bronchial asthma, rhinosinusitis, anaphylaxis or urticaria and variety of late cutaneous and organ-specific reactions. Diagnosis of hypersensitivity to a NSAID includes understanding of the underlying mechanism and is necessary for prevention and management. A stepwise approach to the diagnosis of hypersensitivity to NSAIDs is proposed, including clinical history, in vitro testing and/or provocation test with a culprit or alternative drug depending on the type of the reaction. The diagnostic process should result in providing the patient with written information both on forbidden and on alternative drugs.

Background: Patients who are clinically hypersensitive to nonsteroidal anti-inflammatory drugs (NSAIDs) sometimes present basophil activation in vitro, and in 50% of cases a parallel response to release of sulfidoleukotrienes (cellular allergen stimulation test) is observed. These phenomena occur not only in clinically hypersensitive patients, but also in some healthy controls who tolerate NSAIDs.Material and Methods: We studied 16 clinically hypersensitive patients, 22 controls tolerating NSAIDs, and 29 healthy blood donors (clinical NSAID status unknown) using 2 different basophil isolation techniques (buffy coat or plasma leukocytes).Results: In a population of 13 aspirin-tolerant healthy controls and 29 healthy blood donors, basophil activation with aspirin, diclofenac, and naproxen was analyzed at 4 different concentrations. The results in the 2 groups were quite similar in qualitative terms. Choosing a cutoff of 5% and a stimulation index >2, the proportion of positive results increased with the concentration. There were more positive results at all concentrations using the plasma leukocyte technique.Conclusions: The most important finding of this study is that basophil activation by NSAIDs occurs not only in clinically hypersensitive patients but also, to a very variable extent and on an individual basis, in apparently normal healthy individuals who tolerate NSAIDs. The phenomenon is clearly dose-related, and hypersensitive patients seem to react to lower NSAID concentrations.

Anaphylaxis is the maximal variant of an acute allergic reaction involving several organ systems. The phenomenon itself is old, but it was recognized and named at the beginning of the 20th century by Richet and Portier. The clinical symptoms of anaphylaxis affect various organs, most commonly starting in the skin and proceeding to the respiratory tract, to gastrointestinal involvement and to cardiovascular symptoms, and finally to cardiac and/or respiratory arrest. Anaphylaxis stricto sensu is an immunological reaction, mostly mediated by IgE antibodies, but also by IgG or IgM antibodies (immune complex anaphylaxis). There are cases with similar clinical symptomatology without detectable immunological sensitization which are called pseudo-allergic or anaphylactoid reactions. In the newer nomenclature, some authors tend to include these under the heading of 'anaphylaxis' which has then to be defined as an acute systemic hypersensitivity reaction. The most common elicitors of anaphylaxis include drugs, foods, additives, but also other allergens as well as physical factors (cold, heat, UV radiation). The clinical outcome--the intensity of the reaction--is not only influenced by the degree of sensitization, but also by concomitant other factors: sometimes, individuals only develop anaphylaxis after simultaneous exposure to the allergen and an infection, physical exercise, psychological stress or concomitant medication (e.g. beta blockers). The term 'summation anaphylaxis' has been proposed for this phenomenon which probably underlies many cases of so-called idiopathic anaphylaxis. In patients with insect venom anaphylaxis, decreased levels of plasma angiotensin have been measured in inverse correlation to the severity of the reaction. Certain differential diagnoses have to be distinguished from anaphylaxis. Every patient with a history of anaphylaxis should undergo allergy diagnosis with the aim to detect the eliciting agent, characterize the relevant pathomechanism (e.g. IgE-mediated reaction) and to offer a tolerable alternative (in food or drug allergy). In clear-cut IgE-mediated anaphylaxis, allergen-specific immunotherapy (hyposensitization) is the effective causal treatment, with success rates of 90% in insect venom anaphylaxis.

BACKGROUND:We present the results obtained from the largest series of in vitro diagnostic tests ever reported in patients with clinically validated hypersensitivity to acetylsalicylic acid (ASA)/nonsteroidal anti-inflammatory drugs (NSAID) compared with various categories of controls tolerating ASA/NSAIDs. This multicenter study, which was performed within the framework of the European Network for Drug Allergy (ENDA) group, showed that the basophil activation test (BAT), particularly when used with the 3 NSAIDs aspirin (ASA), diclofenac (DIC), and naproxen (NAP), allows us to confirm the diagnosis of NSAID hypersensitivity syndrome. The results of the cellular allergen stimulation test (CAST) frequently correlate with those of the BAT, although not always. An unexpected finding was that basophil activation by NSAIDs is not an all-or-nothing phenomenon restricted to clinically hypersensitive patients, but that it also occurs in a dose-related manner in some NSAID-tolerant control individuals.Therefore, NSAID hypersensitivity appears as a shift in the normal pharmacological response to NSAIDs. These findings allow us to formulate a new rational hypothesis about the mechanism of NSAID hypersensitivity syndrome, a mechanism that most authors continue to describe as "unknown."METHODS:We enrolled 152 patients with a history of hypersensitivity to NSAIDs and 136 control participants in 11 different centers between spring 2003 and spring 2006. Flowcytometric BAT was performed.RESULTS:The most noteworthy results of our study were that 57% of 140 patients presented very clear-cut positive BAT results to multiple NSAIDs, and 16% were entirely negative. In about 27% of cases, positive results were obtained with 1 or 2 concentrations of a single NSAID. There is clearly a correlation between the results of BAT and CAST.CONCLUSIONS:BAT seems particularly indicated in patients with a clinical history of NSAID intolerance, and in whom a provocation test is not advisable for ethical, clinical, or other reasons. Clear-cut positive results can be considered as confirming a history of NSAID hypersensitivity, although negative results may not exclude it.

Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA(2)LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD((R))) has been established under FileMaker((R)) Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA(2)LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA(2)LEN-ENDA-DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments.

INTRODUCTION:This multicenter study aimed to evaluate the diagnostic value of 2 cellular tests based on basophil reactivity--the basophil activation test (BAT, Flow-CAST) and the sulfidoleukotriene release assay (CAST-ELISA)--in immediate-type beta-lactam allergy, particularly in patients with a clinical history of allergy and a negative skin test result.MATERIAL AND METHODS:In a multicenter study encompassing 10 European centers, 181 patients with a history of immediate-type beta-lactam allergy, and 81 controls, we evaluated the diagnostic efficiency of specific IgE determinations and of 2 cellular tests based on basophil reactivity, the BAT and the sulfidoleukotriene release assay.RESULTS:With Flow-CAST, sensitivity varied for individual beta-lactam allergens from 16% for penicilloyl-polylysine to 33% for amoxicillin, reaching 50% when all 5 allergens were considered. In beta-lactam-allergic patients with negative skin test results (22.8%), Flow-CAST showed positive results for at least 1 of the 5 allergens in 37%. Specificity varied from 89% to 97%, depending on the allergens used. In CAST-ELISA, the overall sensitivity in skin test-positive patients was 41.7%; in patients with negative skin test results it was 27.9%. Both tests were not absolutely correlated, so that when all the results were considered together, sensitivity increased to 64.3% and specificity varied for both tests combined from 73% to 92%. In contrast, specific IgE determinations in the same population yielded a lower sensitivity (28.3%).CONCLUSIONS:A diagnostic algorithm including skin tests and specific IgE, followed by cellular tests in negative patients and controlled challenge enabled us to confirm beta-lactam allergy in 92% of cases. This procedure would also allow us to avoid two-thirds of the required controlled challenges.

The basis and rationale for the flow cytometric basophil activation test (BAT) are reviewed. Numerous clinical applications have been found and experimented, among which allergy to inhalant allerges, to hymenoptera venoms, to latex and to food play prominent place. BAT plays a particular role in drug hypersensitivity, particularly to myorelaxants, betalactam antibiotics, pyrazolones and non steroidal anti-inflammatory drugs (NSAIDs). However, several points about the indications, the performance and the interpretation must be considered in order to obtain optimal results.

Cellular basophil activation tests (BAT) such as histamine or sulfidoleukotriene-release tests for allergy diagnosis have been available for some time, but expression of basophil-activation markers such as CD63 and CD203c detected by flow cytometry has attracted particular attention in recent years. Not only the potential but also the possible pitfalls of flow-cytometric BAT have been stressed recently. Some authors have suggested that the technical problems are still such that BAT should only be performed in specialist laboratories. In an earlier review based on our clinical experience obtained over several years, we showed that, even using different protocols, reproducible and meaningful clinical results can be obtained. In this paper, we review the current knowledge in relation to several technical issues and show that flow-cytometric BAT already represents a major advance in the field of in vitro allergy diagnosis. We conclude that there are no serious technical justifications for depriving allergic patients of clinically indicated BAT tests, which can be performed reliably by any laboratory with the appropriate experience in allergy diagnosis and flow cytometry.

In recent years, the quantification of basophil activation by flow cytometry (basophil activation test, BAT) has proven to be a useful tool for the assessment of immediate-type responses to allergens mediated by IgE or other mechanisms in drug-allergic patients. To date, most BAT studies reported in the literature have used CD69 or CD203c as markers to quantify basophil activation after antigen-specific stimulation. Technical variations, such as the use of whole blood or isolated leukocytes, the addition of IL-3, the conditions of storage of the blood sample, the time of incubation with allergens and their concentration, can affect the results of the BATs. The BAT is more sensitive and specific than other in vitro diagnostic techniques in drug allergy. In various studies, its sensitivity in allergy to musclerelaxant drugs ranges between 36 and 97.7%, with a specificity of around 95%. For -lactam antibiotics, BAT sensitivity is 50% and its specificity 90%. For NSAIDs, sensitivity varies between 66 and 75%; specificity is about 93%. BAT is also a useful technique in the diagnosis of isolated cases of hypersensitivity to various other drugs and substances used in some therapeutic and diagnostic procedures.

Hypersensitivity to aspirin and other non steroidal anti-inflammatory drugs (NSAIDs) manifesting in the airways (rhinosinusitis, polyps, asthma) or in the skin (urticaria, angioedema) is the second most frequent untoward allergic reaction to drugs. Various aspects of this syndrome, such as its clinical features, the cell types and mediators involved, the role of underlying chronic inflammatory processes, the patterns of cross-reactivity between NSAIDs, the major role of sulfidoleukotrienes (LTC4) and of some other mediators such as prostaglandin E2 (PGE2) and C5a are briefly reviewed. It has been assumed for a long time that there were no reliable in vitro tests for that condition and that diagnostic confirmation can only be ascertained by provocation challenge. This appears no longer to be true, since several recent studies using a leukotriene release test (CAST) or a basophil activation test (BAT) on blood basophils, or a combination of both tests, yields positive results (70-75%) in a sizeable number of clinically validated cases, with a high specificity (above 85%). The finding in that syndrome of hyperreactive basophils suggests that the NSAID hypersensitivity syndrome is due to the associated effect of several factors: 1) Localized inflammatory processes causing a non specific cellular hyperreactivity; 2) An abnormal pharmacogenetic reaction to NSAIDs resulting in a hyperproduction of LTC4 and other mediators by activated mast cells, basophils and eosinophils.

L’hypersensibilité à l’aspirine se manifeste le plus souvent par un syndrome clinique associant une rhinite chronique, une polypose nasale et des crises d’asthme exacerbées par l’ingestion d’aspirine ou d’autres médicaments anti-inflammatoires non stéroidiens (AINS). Ce syndrome a été décrit pour la première fois par Widal en 1922. Jusqu’à récemment, le mécanisme pathophysiologique de l’hypersensibilité aux AINS était resté quelque peu mystérieux. Le fait que les médiateurs principalement impliqués sont les sulfidoleukotrienes (LTC4, LTD4, LTE4) et que les médicaments impliqués ont pour caractéristique commune d’inhiber la cyclooxygénase-1 ( COX-1 ) a fait présupposer une anomalie pharmacogénétique dans le métabolisme de l’acide arachidonique chez de tels patients. Une étude immunopharmacologique portant sur l’activation des basophiles détectée par cytométrie de flux et la production de sulfidoleukotrienes in vitro en présence d’ AINS, dont les résultats sont brièvement présentés, ainsi que d’autres études passées en revue permettent d’établir que : — les basophiles des patients atteints du syndrome de Widal sont hyperactivés de manière non spécifique, probablement sur la base d’une inflammation chronique au niveau de la peau ou des voies respiratoires ; — ces basophiles hyperactifs produisent des quantités augmentées de sulfidoleukotrienes mais diminuées de PGE2 sous Veffet d’AINS. Ces constatations ont permis pour la première fois d’établir un test diagnostique in vitro, susceptible de remplacer dans bien des cas le test de provocation, considéré jusqu’ici comme la seule procédure permettant objectivement de confirmer le diagnostic. Les données accumulées permettent désormais de formuler pour le syndrome de Widal une pathogénie impliquant Veffet conjoint d’une inflammation chronique entraînant une hyperactivité cellulaire non spécifique, particulièrement des mastocytes, basophiles et éosinophiles et d’une anomalie pharmacogénétique du métabolisme del’acide arachidonique. La combinaison de ces deux facteurs aboutit à une surproduction des médiateurs inflammatoires tels que les sulfidoleukotriènes et à une diminution de la prostaglandine antiinflammatoire PGE2. Ce concept permet d’expliquer la plupart des observations cliniques sur l’apparition et l’évolution du syndrome de Widal et offre une base rationnelle pour une approche thérapeutique.

Background: Drug allergy is an increasingly important clinical problem. About 5-10% of patients consulting allergy centers have some form of drug allergy or pseudo allergy. At present there is no consensus concerning the best way to study and diagnose hypersensitivity reactions to drugs. This leads both to practical difficulties in diagnosing individual patients and to more general problems in comparing protocols and results from different centers. Methods/Data base: The European Network for Drug Allergy (ENDA) Drug Ambassador Project aimed to collect information on the ways that different European centers approach these patients. Results: The present report summarizes data collected during this project, focussing on the organization of drug allergy consultations, diagnostic protocols and the various in vitro and in vivo investigation procedures in current use. The study revealed wide variation in the diagnostic procedures used for drug allergy in clinical practice, despite the apparent consensus achieved in recommendations and position papers. Conclusion: Reciprocal exchange of information and discussions based on these observations may help to achieve standardization and harmonization in this sector with significant potential benefits for patients with drug allergies.

Hypersensitivity to aspirin usually takes the form of a clinical syndrome combining chronic rhinitis, nasal polyposis and asthma attacks that are exacerbated by aspirin or other non steroidal anti-inflammatory drugs (NSAIDs). This syndrome, first described by Widal in 1922, is very frequent: it affects nearly 15% of asthmatic patients and is usually associated with severe and sometimes fatal asthma. In other instances, hypersensitivity to NSAIDs manifests in the form of skin lesions, such as urticaria and angioedema. Until recently, the pathophysiological mechanism of NSAID hypersensitivity was somewhat mysterious. The fact that the main mediators involved are sulfidoleukotrienes (LTC4, LTD4, LTE4) and that the drugs responsible all inhibit cyclooxygenase-1 (COX-1), pointed to a pharmacogenetic abnormality of arachidonic acid metabolism. An immunopharmacological study of basophil activation (detected by flow cytometry), sulfidoleukotriene production in the presence of NSAIDs in vitro, and other related studies reviewed here have revealed that: a) basophils from patients with the Widal syndrome are hyperactivated in a non specific manner, probably related to chronic inflammation in the skin or airways; b) these hyperactive basophils produce increased amounts of sulfidoleukotrienes but decreased amounts of PGE2 when exposed to NSAIDs in vitro. These observations led to the development of an in vitro diagnostic test which, in many cases, can replace challenge tests. The pathogenic mechanism of the Widal syndrome now appears to involve the combined effects of chronic inflammation (causing non specific cellular hyper-reactivity, particularly of mast cells, basophils and eosinophils) and a pharmacogenetic abnormality of arachidonic acid metabolism in response to NSAIDs. This leads to sulfidoleukotriene overproduction and to a decrease in the anti-inflammatory prostaglandin PGE2. This concept is compatible with the onset and outcome of most cases of the Widal syndrome, and provides a therapeutic rationale.