Hypersensitivity reactions to aspirin (acetylsalicylic acid) and other nonsteroidal anti-inflammatory drugs (NSAIDs) constitute only a subset of all adverse reactions to these drugs, but due to their severity pose a significant burden to patients and are a challenge to the allergist. In susceptible individuals, NSAIDs induce a wide spectrum of hypersensitivity reactions with various timing, organ manifestations, and severity, involving either immunological (allergic) or nonimmunological mechanisms. Proper classification of reactions based on clinical manifestations and suspected mechanism is a prerequisite for the implementation of rational diagnostic procedures and adequate patient management. This document, prepared by a panel of experts from the European Academy of Allergy and Clinical Immunology Task Force on NSAIDs Hypersensitivity, aims at reviewing the current knowledge in the field and proposes uniform definitions and clinically useful classification of hypersensitivity reactions to NSAIDs. The document proposes also practical algorithms for the diagnosis of specific types of NSAIDs hypersensitivity (which include drug provocations, skin testing and in vitro testing) and provides, when data are available, evidence-based recommendations for the management of hypersensitive patients, including drug avoidance and drug desensitization.Nonsteroidal anti-inflammatory drugs (NSAIDs) induce a whole range of adverse reactions related to their pharmacological properties. In susceptible individuals, NSAIDs may induce hypersensitivity reactions varying in timing (immediate/delayed), organ involvement (skin, airways, or other organs), and severity (from mild dyspnea, rhinorrhea, exanthema, or urticaria, to anaphylaxis and death). Since aspirin (acetylsalicylic acid; ASA), the first synthetic compound with antipyretic, analgesic, and anti-inflammatory activity, was synthesized in 1893, dozens of compounds with similar activity have been developed and commercialized and almost all of them were reported to induce hypersensitivity reactions in susceptible subjects. The large variety of NSAIDs inducing hypersensitivity reactions, the wide spectrum of symptoms observed, and different pathomechanisms involved create a challenge to an allergist especially if an unified and practical Allergy 68 (2013) 1219-1232

Skin prick testing is an essential test procedure to confirm sensitization in IgE-mediated allergic disease in subjects with rhinoconjunctivitis, asthma, urticaria, anapylaxis, atopic eczema and food and drug allergy. This manuscript reviews the available evidence including Medline and Embase searches, abstracts of international allergy meetings and position papers from the world allergy literature. The recommended method of prick testing includes the appropriate use of specific allergen extracts, positive and negative controls, interpretation of the tests after 15 – 20 minutes of application, with a positive result defined as a wheal ≥3 mm diameter. A standard prick test panel for Europe for inhalants is proposed and includes hazel (Corylus avellana), alder (Alnus incana), birch (Betula alba), plane (Platanus vulgaris), cypress (Cupressus sempervirens), grass mix (Poa pratensis, Dactilis glomerata, Lolium perenne, Phleum pratense, Festuca pratensis, Helictotrichon pretense), Olive (Olea europaea), mugwort (Artemisia vulgaris), ragweed (Ambrosia artemisiifolia), Alternaria alternata (tenuis), Cladosporium herbarum, Aspergillus fumigatus, Parietaria, cat, dog, Dermatophagoides pteronyssinus, Dermatophagoides farinae, and cockroach (Blatella germanica). Standardization of the skin test procedures and standard panels for different geographic locations are encouraged worldwide to permit better comparisons for diagnostic, clinical and research purposes.

The results of this large pan-European study demonstrate for the first time sensitization patterns for different inhalant allergens in patients across Europe. The standardized skin prick test with the standardized allergen battery should be recommended for clinical use and research. Further EU-wide monitoring of sensitization patterns is urgently needed.

This study strongly emphasizes the importance of evaluating the clinical relevance of positive skin prick tests and calls for further studies, which may, ultimately, help increase the positive predictive value of allergy testing.

Background-Although downregulation of L-type Ca 2ϩ current (I Ca,L ) in chronic atrial fibrillation (AF) is an important determinant of electrical remodeling, the molecular mechanisms are not fully understood. Here, we tested whether reduced I Ca,L in AF is associated with alterations in phosphorylation-dependent channel regulation. Methods and Results-We used whole-cell voltage-clamp technique and biochemical assays to study regulation and expression of I Ca,L in myocytes and atrial tissue from 148 patients with sinus rhythm (SR) and chronic AF. Basal I Ca,L at ϩ10 mV was smaller in AF than in SR (Ϫ3.8Ϯ0.3 pA/pF, nϭ138/37 [myocytes/patients] and Ϫ7.6Ϯ0.4 pA/pF, nϭ276/86, respectively; PϽ0.001), though protein levels of the pore-forming ␣ 1c and regulatory ␤ 2a channel subunits were not different. In both groups, norepinephrine (0.01 to 10 mol/L) increased I Ca,L with a similar maximum effect and comparable potency. Selective blockers of kinases revealed that basal I Ca,L was enhanced by Ca 2ϩ /calmodulindependent protein kinase II in SR but not in AF. Norepinephrine-activated I Ca,L was larger with protein kinase C block in SR only, suggesting decreased channel phosphorylation in AF. The type 1 and type 2A phosphatase inhibitor okadaic acid increased basal I Ca,L more effectively in AF than in SR, which was compatible with increased type 2A phosphatase but not type 1 phosphatase protein expression and higher phosphatase activity in AF. Conclusions-In AF, increased protein phosphatase activity contributes to impaired basal I Ca,L . We propose that protein phosphatases may be potential therapeutic targets for AF treatment.

Eight to ten allergens allowed the identification of the majority of sensitized subjects. For clinical care of individual patients, the whole battery of 18 allergens is needed to appropriately assess sensitization across Europe.

L-type calcium current and I(to) are reduced in early phases of electrical remodeling. A major mechanism appears to be transcriptional downregulation of underlying ion channels, which partially preceded ion current changes.

This study does not support a role for selenium in protection against asthma, but effect modification and confounding cannot be ruled out.