Nonsteroidal anti‐inflammatory drugs (NSAIDs), the medications most commonly used for treating pain and inflammation, are the main triggers of drug hypersensitivity reactions. The latest classification of NSAIDs‐hypersensitivity by the European Academy of Allergy and Clinical Immunology (EAACI) differentiates between cross‐hypersensitivity reactions (CRs), associated with COX‐1 inhibition, and selective reactions, associated with immunological mechanisms. Three phenotypes fill into the first group: NSAIDs‐exacerbated respiratory disease, NSAIDs‐exacerbated cutaneous disease, and NSAIDs‐induced urticaria/angioedema. Two phenotypes fill into the second one: single‐NSAID‐induced urticaria/angioedema/anaphylaxis, and single‐NSAID‐induced delayed reactions. Diagnosis of NSAIDs‐hypersensitivity is hampered by different factors, including the lack of validated in vitro biomarkers and the uselessness of skin tests. The advances achieved over recent years recommend a re‐evaluation of the EAACI classification, as it does not consider other phenotypes such as blended reactions (coexistence of cutaneous and respiratory symptoms) or food‐dependent NSAID‐induced anaphylaxis. In addition, it does not regard the natural evolution of phenotypes and their potential interconversion, the development of tolerance over time or the role of atopy. Here we address these topics. A state of the art on the underlying mechanisms and on the approaches for biomarkers discovery is also provided, including genetic studies and available information on transcriptomics and metabolomics.

Background: Anaphylaxis, which is rare, has been reported after COVID‐19 vaccination, but its management is not standardized.Method: Members of the European Network for Drug Allergy and the European Academy of Allergy and Clinical Immunology interested in drug allergy participated in an online questionnaire on pre‐vaccination screening and management of allergic reactions to COVID‐19 vaccines, and literature was analysed.Results: No death due to anaphylaxis to COVID‐19 vaccines has been confirmed in scientific literature. Potential allergens, polyethylene glycol (PEG), polysorbate and tromethamine are excipients. The authors propose allergy evaluation of persons with the following histories: 1—anaphylaxis to injectable drug or vaccine containing PEG or derivatives; 2—anaphylaxis to oral/topical PEG containing products; 3—recurrent anaphylaxis of unknown cause; 4—suspected or confirmed allergy to any mRNA vaccine; and 5—confirmed allergy to PEG or derivatives. We recommend a prick‐to‐prick skin test with the left‐over solution in the suspected vaccine vial to avoid waste. Prick test panel should include PEG 4000 or 3500, PEG 2000 and polysorbate 80. The value of in vitro test is arguable.Conclusions: These recommendations will lead to a better knowledge of the management and mechanisms involved in anaphylaxis to COVID‐19 vaccines and enable more people with history of allergy to be vaccinated.

Drug hypersensitivity reactions have multiple implications for patient safety and health system costs, thus it is important to perform an accurate diagnosis. The diagnostic procedure includes a detailed clinical history, often unreliable; followed by skin tests, sometimes with low sensitivity or unavailable; and drug provocation testing, which is not risk-free for the patient, especially in severe reactions. In vitro tests could help to identify correctly the responsible agent, thus improving the diagnosis of these reactions, helping the physician to find safe alternatives, and reducing the need to perform drug provocation testing. However, it is necessary to confirm the sensitivity, specificity, negative and positive predictive values for these in vitro tests to enable their implementation in clinical practice. In this review, we have analyzed these parameters from different studies that have used in vitro test for evaluating drug hypersensitivity reactions and estimated the added value of these tests to the in vivo diagnosis.

Non-steroidal anti-inflammatory drugs (NSAIDs)-induced hypersensitivity reactions are classified by the European Network on Drug Allergy (ENDA) as either cross-reactive or selective. The former is the most frequent type and includes patients with exclusively respiratory symptoms (NSAIDs-exacerbated respiratory disease, NERD) or exclusively cutaneous symptoms: NSAIDs-induced urticaria/angioedema (NIUA); and NSAIDs-exacerbated cutaneous disease (NECD). However, although not reflected in the current classification scheme (ENDA), in clinical practice a combination of both skin and respiratory symptoms or even other organs such as gastrointestinal tract symptoms (mixed or blended reactions) is frequently observed. This entity has not been sufficiently characterised. Our aim was to clinically characterize blended reactions to NSAIDs, comparing their clinical features with NERD and NIUA. We evaluated patients with symptoms suggestive of hypersensitivity to NSAIDs who attended the Allergy Unit of the Regional University Hospital of Malaga (Malaga, Spain) between 2008 and 2015. We included 880 patients confirmed as cross-reactive based on clinical history, positive nasal provocation test with lysine acetylsalicylate (NPT-LASA), and/or positive drug provocation test (DPT) with acetylsalicylic acid (ASA), who were classified as blended (261; 29.6%), NERD (108; 12.3%) or NIUA (511; 58.1%). We compared symptoms, drugs, underlying diseases and diagnostic methods within and between groups. Among blended patients the most common sub-group comprised those developing urticaria/angioedema plus rhinitis/asthma (n = 138), who had a higher percentage of underlying rhinitis (p < 0.0001) and asthma (p < 0.0001) than NIUA patients, showing similarities to NERD. These differences were not found in the sub-group of blended patients who developed such respiratory symptoms as glottis oedema; these were more similar to NIUA. The percentage of positive NPT-LASA was similar for blended (77%) and NERD groups (78.7%). We conclude that blended reactions are hypersensitivity reactions to NSAIDs affecting at least two organs. In addition to classical skin and respiratory involvement, in our population a number of patients also develop gastrointestinal symptoms. Given the high rate of positive responses to NPT-LASA in NERD as well as blended reactions, we suggest that all patients reporting respiratory symptoms, regardless of whether they have other associated symptoms, should be initially evaluated using NPT-LASA, which poses less risk than DPT.