Following the first description of hypersensitivity reaction to aspirin (ASA) by Hirschberg in 1902, several types of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) have been described. The NSAIDs-induced hypersensitivity reactions involve different mechanisms and present a wide range of clinical manifestations from anaphylaxis AbstractNonsteroidal 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.

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.

In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21st century.The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients’ Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients’ organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels.Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders...

103Sinusitis 104 105 Conflicts of interest 106Jan Lötvall has received consultancy and speaker fees from AstraZeneca, GlaxoSmithKline, MSD/Merck, 107Novartis, and Schering-Plough. 109Author contributions 110PT, RN, RH, and DJ analyzed the data and wrote the manuscript. WF, CB, PB and DJ conceived and supervised 111 the study. All authors collected data and critically revised the manuscript. 113Body word count: 2673 114Page 3 of 17 Allergy 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 118in epidemiological studies, the definition is based on symptoms only. We aimed to assess the reliability and 119validity of a symptom based definition of CRS using data from the GA2LEN European survey. 120Methods: On two separate occasions, 1700 subjects from 11 centers provided information on symptoms of CRS, 121allergic rhinitis and asthma. CRS was defined by the epidemiological EP3OS symptom criteria. The difference in 122prevalence of CRS between two study points, the standardized absolute repeatability and the chance corrected 123 repeatability (kappa) were determined. In two centers 342 participants underwent nasal endoscopy. The 124 association of symptom-based CRS with endoscopy and self-reported doctor-diagnosed CRS was assessed. 125Results: There was a decrease in prevalence of CRS between the two study phases, and this was consistent 126across all centers (-3.0%, 95% CI: -5.0 to -1.0%, I 2 =0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 160Study design 161In a first cross-sectional phase (the GA²LEN Survey), 11 participating centers sent a questionnaire by mail to a 162 random sample of at least 3000 subjects aged 15 to 75 years, with up to three attempts to elicit a response. 163Samples were identified by random sampling from a population based local sampling frame. 164The questionnaire was newly developed for the diagnosis of chronic rhinosinusitis ( (Table 1); additionally, subjects were asked if a doctor had ever told whether the subject had CRS 167(further referred to as 'self-reported doctor-diagnosed CRS'). Asthma was defined as reporting 'having ever had 168 asthma' and at least one of the following symptoms in the last 12 months: 1) wheeze or whistling in the chest; or 1692) waking up with chest tightness, shortness of breath or an attack of coughing. Allergic rhinitis was defined by 170 the self reported history of 'nasal allergy'. 171In a second phase (the GA²LEN Survey Follow-Up), each center invited 120 randomly selected subjects with 172 asthma, 120 with CRS, 40 with asthma and CRS and 120 with neither asthma or CRS for a clinical study visit 173with further investigations among which a questionnaire including the same questions as those describ...

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.

BackgroundSCF (stem cell factor) is a pleiotropic cytokine exerting its role at different stages of bone marrow development and affecting eosinophil activation, mast cells and basophil chemotaxis and survival. The aim of the study was to assess concentration of SCF and its soluble receptor c-kit (sc-kit) in peripheral blood of patients with asthma referring it to asthma severity and phenotype.MethodsThe study involved 107 patients with bronchial asthma, well characterized with respect to severity and 21 healthy controls. Concentration of SCF and sc-kit in the patients serum were measured by ELISA method.ResultsMean serum SCF level in the group of asthmatics (n = 88) was significantly higher as compared to healthy controls (1010 pg/ml ± 37 vs 799 ± 33; p < 0,001). The level of SCF was higher in patients with severe asthma as compared to patients with non-severe asthma (1054 +/- 41 pg/ml vs 819 +/- 50; p < 0,01) and correlated with dose of inhaled glucocorticosteroids taken by the patients to achieve asthma control (R = 0,28; p < 0,01). The mean sc-kit serum level did not differ between asthmatic patients and healthy controls, however the level of sc-kit in non-severe asthmatics was significantly higher as compared to patients with severe asthma and healthy controls. In asthmatic patients (n = 63) the level of sc-kit correlated positively with FEV1% predicted value (R = 0,45; p < 0,001) and MEF25% predicted value (R = 0,33; p < 0,01). The level of sc-kit inversely correlated with the dose of inhaled glucocorticosteroids taken by the patients (R = -0,26; p < 0,01).ConclusionSerum levels of SCF and its soluble receptor c-kit seem to be reflect asthma severity suggesting a role for these molecules in asthmatic inflammation.

RationaleThere is conflicting evidence on whether patients with asthma experience an accelerated decline in lung function with age. We examined the association between postbronchodilator lung function, asthma, chronic rhinosinusitis (CRS), and atopy with age using a large European sample.MethodsIn 17 centers in 11 European countries, case–control studies were nested within representative cross-sectional surveys of adults aged less than 75 years. Representative samples of participants with asthma, CRS or both and controls were assessed for postbronchodilator ventilatory function, smoking history, atopy, and treatment. Multiple regression was used to assess the interactive effects of age and diagnostic group on decline in postbronchodilator ventilatory function.ResultsA total of 3337 participants provided adequate data (778 with asthma, 399 with CRS, 244 with both asthma and CRS and 1916 controls who had neither asthma nor CRS). Participants with asthma had lower FEV1/FVC (−4.09% (95%CI: −5.02, −3.15, P < 0.001) and a steeper slope of FEV1/FVC against age (−0.14%/annum [95%CI: −0.19, −0.08]) equivalent to smoking 1–2 packs of cigarettes per day. Those with atopy had a slope equivalent to controls.ConclusionsPeople with asthma have a steeper decline in postbronchodilator lung function with age, but neither CRS nor atopy alone were associated with such decline.

This article provides information on the pathogenesis of aspirin hypersensitivity, cross-sensitivity, and cross-tolerance of different NSAIDs in patients with respiratory types of reactions. Hypersensitivity to aspirin may affect 5-20% of patients with chronic asthma and an unknown fraction of patients with chronic urticaria-angioedema. These patients develop cross-reactions to other, chemically non-related, NSAIDs with strong inhibitory activity towards cyclo-oxygenase (COX)-1 (e.g. indomethacin, naproxen, ketoprofen). Avoidance of aspirin and all cross-reacting NSAIDs as well as education of patients are crucial. As an alternative antipyretic or analgesic drug, aspirin-sensitive asthmatic patients may take acetaminophen (paracetamol) in low or moderate doses (<1000mg). Preferential COX-2 inhibitors (nimesulide, meloxicam) are tolerated by the majority but not all hypersensitive patients. Selective COX-2 inhibitors (celecoxib and rofecoxib [withdrawn from the market]) are well tolerated by almost all aspirin-sensitive asthmatic patients. In patients with coronary artery disease requiring treatment with aspirin, desensitization to aspirin may be an alternative approach. Thus, for the majority of patients with asthma and hypersensitivity to aspirin or other NSAIDs, an alternative anti-inflammatory drug can be found. However, in each individual case physicians must consider the choice of an alternative NSAID carefully.