Gülfem Çelik

Hypersensitivity to nonsteroidal anti‐inflammatory drugs (NSAIDs) – classification, diagnosis and management: review of the EAACI/ENDA# and GA2LEN/HANNA*

To cite this article: Kowalski ML, Makowska JS, Blanca M, Bavbek S, Bochenek G, Bousquet J, Bousquet P, Celik G, Demoly P, Gomes ER, Niżankowska‐Mogilnicka E, Romano A, Sanchez‐Borges M, Sanz M, Torres MJ, De Weck A, Szczeklik A, Brockow K. Hypersensitivity to nonsteroidal anti‐inflammatory drugs (NSAIDs) – classification, diagnosis and management: Review of the EAACI/ENDA and GA2LEN/HANNA. Allergy 2011; 66: 818–829.

Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs.

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.

Formoterol and salmeterol in partially reversible chronic obstructive pulmonary disease: A crossover, placebo-controlled comparison of onset and duration of action.

Background: In contrast to the well-known activity profile in asthma, the precise efficacy and optimum dose schedules of long-acting β2-agonists in chronic obstructive pulmonary disease (COPD) are not clear. Objective: In this study, we aimed to compare the onset and the duration of action of a single inhalation of formoterol and salmeterol in COPD patients having partially reversible airway obstruction. Methods: In a double-blind, randomized, crossover and placebo-controlled study design, the respiratory functions of 22 patients (mean age 57.3 ± 5.4 years) having mild to severe COPD (5 mild, 8 moderate and 9 severe) and partially reversible airway obstruction [mean baseline reversibility of forced expiratory volume in 1 s (FEV1) 19.3 ± 3.1%] were evaluated after inhalation of 12 μg formoterol and 50 μg salmeterol. Results: Regarding the onset of bronchodilator action, the mean absolute increase of 0.20 liters in FEV1 10 min after inhalation of formoterol was significantly higher than baseline and that of placebo (0.04 liters), whereas that of salmeterol (0.11 liters) did not reach statistical significance. At 20 min, both formoterol (0.25 liters) and salmeterol (0.20 liters) produced a significant increase in FEV1 compared with baseline and with that of placebo (0.04 liters). The peak bronchodilator effects occurring at 60 and 120 min following formoterol (0.39 liters) and salmeterol (0.40 liters) inhalation, respectively, were significantly higher than the corresponding levels of placebo (0.02 and –0.12 liters, respectively). Concerning the duration of action, the 12-hour values of both formoterol (0.25 liters) and salmeterol (0.22 liters) were significantly higher than that of placebo (–0.12 liters). The area under the curve values of FEV1 of formoterol (3.5 ± 1.3 l·h) and salmeterol (3.2 ± 1.2 l·h) averaged over 12 h were comparable and higher than placebo values (1.2 ± 0.5 l·h). After formoterol inhalation 2 patients experienced tremor and 1 had palpitation; 1 tremor and 1 headache attack were noted after salmeterol. For the pharmacologically predictable side effects, there was no difference between the drugs. Conclusions: In conclusion, this study revealed that a single dose of 12 μg formoterol and 50 μg salmeterol provided comparable bronchodilation within 12 h and had tolerable side effects in patients with mild to severe COPD having partially reversible airway obstruction.

Release of cysteinyl leukotrienes with aspirin stimulation and the effect of prostaglandin E2 on this release from peripheral blood leucocytes in aspirin-induced asthmatic patients

Background The decrease in prostaglandin E2 (PGE2) release due to aspirin (ASA)‐induced cyclooxygenase inhibition and the increment in cysteinyl leukotriene (Cys‐LT) release secondary to the removal of the inhibitory effect of PGE2 on Cys‐LT release have been suggested in the pathogenesis of aspirin‐induced asthma (AIA).

Safety of Selective COX‐2 Inhibitors in Aspirin/Nonsteroidal Anti‐inflammatory Drug‐Intolerant Patients: Comparison of Nimesulide, Meloxicam, and Rofecoxib

Background. Intolerance to acetylsalicylic acid (ASA) and other nonsteroidal anti‐inflammatory drugs (NSAIDs) is a crucial problem in clinical practice. There is, therefore, a need for safer NSAIDs in patients with analgesic intolerance. Objective. To assess the safety of nimesulide, meloxicam, and rofecoxib, selective COX‐2 inhibitors, in a group of ASA/NSAIDs‐intolerant patients. Method. Tolerances to nimesulide, meloxicam, and rofecoxib were assessed by single‐blind placebo‐controlled oral challenges. One hundred twenty‐seven subjects with history of adverse reaction to ASA/NSAIDs received oral challenges with nimesulide, 61 subjects were challenged with meloxicam, 51 subjects were challenged with rofecoxib, and 37 subjects were challenged with all three drugs. Placebos were given to all patients on the first day of the study. On the second day, one‐fourth and three‐fourths of the therapeutic doses of the active drugs (nimesulide 100 mg, meloxicam 7.5 mg, or rofecoxib 25 mg) were given at 60‐minute intervals. There was at least a 3‐day interval between challenge tests. Erythema, pruritus accompanied by erythema, urticaria/angioedema, rhinorrhea, nasal obstruction, sneezing, dyspnea, or cough associated with a decrease of at least 20% in the forced expiratory volume (FEV1) and hypotension were considered as positive reactions. Results. Positive reactions to the nimesulide, meloxicam, and rofecoxib challenges were observed in 18/127 (14.3%), 5/61 (8.1%), and 1/51 (2.0%) patients, respectively. In each group of nine patients, there were two patients with asthma and four who developed skin type reactions and asthmatic reactions, respectively, to the nimesulide challenge. Among five patients who reacted to the meloxicam challenge, asthmatic type reactions were detected in two asthmatics. Only one urticarial type reaction was observed with rofecoxib challenge in one patient who presented with anaphylaxis to ASA/NSAIDs. All patients with asthma tolerated rofecoxib without any adverse effects. None of the patients reacted to the placebo. Among 37 patients challenged with all three drugs, 11 reacted to nimesulide, and one patient reacted only to meloxicam. Three patients reacted to more than one of the drugs tested, and one of them reacted to all drugs. Conclusion. This is the first placebo‐controlled report comparing these three drugs. The results indicate that among these alternative drugs for ASA/NSAIDs‐intolerant patients, rofecoxib seems to have the most favorable tolerability.

The use of nimesulide in patients with acetylsalicylic acid and nonsteroidal anti-inflammatory drug intolerance

Intolerance or idiosyncrasy to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) is a crucial problem because these drugs are frequently used in medical treatment. In this study, we tested whether nimesulide, a selective cyclooxygenase-2 (COX-2) inhibitor, might be a valid alternative for patients with histories of adverse reaction to ASA or NSAIDs. A single-blind, placebo-controlled oral challenge procedure was applied to 60 adult patients (19 male, 41 female; with a mean age of 40.31 +/- 10.44 years, range 20-68 years) with a reliable history of ASA/NSAIDs-intolerance. According to history, the clinical presentations of intolerance were urticaria/angioedema in 32 patients, anaphylactoid reaction in 2 patients, respiratory reaction in 19 patients, and respiratory and cutaneous reaction in 7 patients. Atopy was confirmed by means of skin prick test with inhalant allergens. Oral challenge protocol was started with 25 mg of nimesulide and the remaining 75 mg was given 1 hr later. During the challenge procedure, blood pressure, pulse, nasoocular, pulmonary, and cutaneous symptoms were monitored. Of the 60 patients tested, 55 (91.7%) tolerated the drug with no adverse reaction. Only five (8.3%) patients demonstrated a positive response to oral challenge. The clinical presentations of intolerance to nimesulide were urticaria/angioedema in three patients, mild rhinitis in one patient, and mild dyspnea in one patient. The atopy prevalence was higher, with a ratio of 41.7%, in patients with ASA/NSAIDs intolerance than that of the healthy adult population in Turkey (p < 0.05). We believe that nimesulide can be used as an alternative drug for patients with ASA/NSAIDs intolerance.

Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity

Background Lipoxin (LX) A4, an endogenous anti‐inflammatory eicosanoid, has been found to be low in patients with severe asthma. However, few studies also suggested more diminished LX A4 levels in aspirin‐exacerbated respiratory disease (AERD) when compared with aspirin‐tolerant asthma (ATA). It is, therefore, currently not clear whether the asthma severity or the presence of AERD has a primary role in the disturbed LX metabolism.

In vitro tests for drug hypersensitivity reactions : an ENDA/EAACI Drug Allergy Interest Group position paper

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.

Effect of in vitro aspirin stimulation on basophils in patients with aspirin-exacerbated respiratory disease.

Background Basophil activation has been implicated in the pathogenesis of aspirin‐exacerbated respiratory disease (AERD). However, a comprehensive analysis of basophil responses to aspirin in terms of mediator release, cytokine secretion and increased expression of surface activation markers has not been performed.

The prevalence of allergic diseases and atopy in Ankara, Turkey: a two-step population-based epidemiological study.

To assess the prevalence of allergic diseases and atopy in adults, a two-step population-based epidemiological study was undertaken in Ankara, the capital city of Turkey. In step 1, a screening questionnaire adapted from the European Community Respiratory Health Survey (ECRHS) was applied in a cross-sectional manner. In step 2, a nested case-controlled design study was conducted and subjects were evaluated in the clinical setting for history, physical examination, skin prick tests (SPTs), and serum total IgE and phadiotop measurements. According to the results, self-reported current asthma prevalence in step 1 was lower compared with that in step 2 (3% vs. 7%, p < 0.05). The prevalences of food and drug allergy were 6.2% and 3.9%, respectively, in step 1, but were not demonstrated in any of the subjects in step 2. The overall prevalence of atopy was 25% after step 2 evaluation. In conclusion, allergic disorders are not uncommon in our adult population; however, sole application of a screening questionnaire appeared to be ineffective in revealing the accurate figures of asthma, and food or drug allergy.