History and classification of anaphylaxis.

Anaphylaxis as the maximal variant of an acute systemic hypersensitivity reaction can involve several organ systems, particularly the skin, respiratory tract, gastrointestinal tract and the cardiovascular system. The severity of anaphylactic reaction is variable and can be classified into severity grades I-IV. Some reactions are fatal. Most frequent elicitors of anaphylaxis are foods in childhood, later insect stings and drugs. The phenomenon itself has been described in ancient medical literature, but was actually recognized and named at the beginning of the 20th century by Charles Richet and Paul Portier. In the course of experiments starting on the yacht of the Prince of Monaco and continued in the laboratory in Paris, they tried to immunize dogs with extracts of Physalia species in an attempt to develop an antitoxin to the venom of the Portuguese man-of-war. While Charles Richet believed that anaphylaxis was a 'lack of protection', it has become clear that an exaggerated immune reaction, especially involving immunoglobulin E antibodies, is the underlying pathomechanism in allergic anaphylaxis besides immune complex reactions. Non-immunologically mediated reactions leading to similar clinical symptomatology have been called 'anaphylactoid' or 'pseudo-allergic'--especially by Paul Kallos--and are now called 'non-immune anaphylaxis' according to a consensus of the World Allergy Organization (WAO). The distinction of different pathophysiological processes is important since non-immune anaphylaxis cannot be detected by skin test or in vitro allergy diagnostic procedures. History and provocation tests are crucial. The intensity of the reaction is not only influenced by the degree of sensitization but also by concomitant other factors as age, simultaneous exposure to other allergens, underlying infection, physical exercise or psychological stress or concomitant medication (e.g. beta-blockers, NSAIDs); this phenomenon has been called augmentation or summation anaphylaxis.

Drug hypersensitivities: which room for biological tests?

Drug allergic reactions frequently represent a serious diagnostic problem. In this paper we summarise the most relevant data published in recent years on the diagnostic reliability of the in vitro techniques in drug allergy diagnosis. The lymphocyte transformation test (LTT) offers a sensitivity of 58% in the diagnosis of late allergic reactions to betalactams and 64.5% in the immediate allergic reactions. The basophil activation test and the antigen-specific sulphidoleukotriene determination have an acceptable diagnostic reliability in muscle relaxant drug-induced reactions and in betalactam allergy. BAT sensitivity in betalactam allergy was 50.7% and its specificity 93.3%, whereas CAP had a sensitivity of 36.7% and a specificity of 83.3%, and CAST, a sensitivity of 47.7% and a specificity of 83.3%. For NSAID hypersensitivity, BAT sensitivity was 63.3% and specificity 93.3%, CAST sensitivity was 38.3% and specificity 76.6%. BAT sensitivity in metamizol allergy was 42.3% and the specificity 100% and CAP was negative in all the 17 cases in which it was performed. The joint use of BAT and CAP (specific IgE) allows diagnosis of 65.2% of the betalactam allergic patients with a specificity of 83.3%. The combined use of CAST and BAT in metamizol allergy detects 76% of the cases and 76.9% when associating the skin tests. In NSAID hypersensitivity, the joint use of BAT and CAST does not increase the diagnostic reliability of BAT alone. BAT is a non-invasive useful technique in the in vitro diagnosis of betalactam and metamizol allergy, and NSAID hypersensitivity.

[New pathophysiological concepts on aspirin hypersensitivity (Widal syndrome); diagnostic and therapeutic consequences]. / Nouvelles données pathophysiologiques sur l'hypersensibilité à l'aspirine (syndrome de Widal); conséquences diagnostiques et thérapeutiques.

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.

Oral administration of specific antigens to allergy-prone infant dogs induces IL-10 and TGF-beta expression and prevents allergy in adult life.

BACKGROUND: Oral administration of allergens can induce immune tolerance to specific allergens in rodents and hence might be a possibility to prevent and treat allergic diseases in human subjects. However, the gastrointestinal tract of mice is different from that of human subjects. The absorption of specific antigens and subsequent antigen presentation to intestinal T cells is different in both species, making it difficult to extrapolate results. OBJECTIVE: We investigated primary oral tolerance to ovalbumin (OVA) in an IgE high-responder dog model, which is more predictive for human allergic diseases than corresponding rodent models. METHODS: Oral tolerance was induced by means of a 28-day treatment with OVA dissolved in cow's milk. RESULTS: We observed reduced OVA-specific IgE and IgG production in response to ensuing subcutaneous challenges. Allergic conjunctivitis induced by means of ocular and airway provocation was significantly reduced in tolerized animals compared with that seen in nontolerized control animals. In addition, eosinophilia and neutrophilia in bronchoalveolar lavage fluid and bronchoconstriction after airway allergen challenge were significantly suppressed in tolerized animals. Cytokine analysis by means of real-time PCR on bronchoalveloar fluid cells after allergen challenge revealed a high-level expression of IL-10 and transforming growth factor beta, predominantly in the CD14(+) population. CONCLUSION: Feeding infant beagles with OVA for 4 weeks is sufficient to prevent hallmark manifestations of asthma and allergy in adult life. The mechanism of oral tolerance involved an increased expression of IL-10 and transforming growth factor beta cytokines.

Flow-cytometric cellular allergen stimulation test in latex allergy.

BACKGROUND: The use of flow-cytometric basophil activation to different allergens has been recommended in recent years. In this study, we analyzed the diagnostic reliability of the flow-cytometric allergen stimulation test (FAST) after latex-specific stimulation in vitro. The diagnostic reliability of the technique was assessed as well as its correlation with other in vitro diagnostic parameters. METHODS: 43 patients allergic to latex with a positive history and skin test participated in the study. Thirty subjects (20 of them exposed to latex) with a negative history, skin tests and serum-specific IgE determination to latex were used as controls. In FAST the percentage of basophils that express CD63 as an activation marker after in vitro stimulation with allergen (latex) is determined by flow cytometry, following double labelling with the monoclonal antibodies anti-CD63-PE and anti-IgE FITC. RESULTS: Intraclass correlation coefficient in FAST with latex was 0.995 (p < 0.0001), which demonstrates the excellent reproducibility of this technique. Taking a cutoff point of 10% by means of ROC curves, FAST yields a sensitivity of 93% and a specificity of 100%. The FAST positive predictive value in latex allergy was 100% and the negative predictive value was 99.9%. We found a positive and significant correlation between FAST and specific IgE (CAP) with the histamine release test and specific sulphidoleukotriene production [cellular allergen stimulation test (CAST); p < 0.05]. CONCLUSIONS: FAST is a highly reliable technique (93% sensitivity and 100% specificity) in the in vitro diagnosis of IgE-mediated latex allergy.