NSAIDs-hypersensitivity often induces a blended reaction pattern involving multiple organs

Inmaculada Doña,José Julio Laguna,Esther Barrionuevo,José Antonio Cornejo-García,James Richard Perkins,Gádor Bogas,Elena García-Martín,José Agúndez,María José Torres,María Salas

doi:10.1038/s41598-018-34668-1

Abstract

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.

Highlights

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequent triggers of drug hypersensitivity reactions (DHRs
Exclusion criteria included the following: patients with delayed DHRs such as fixed drug eruption, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis complex or acute generalised exanthematic pustulosis; pregnant or breastfeeding patients; patients taking beta-blockers or ACE inhibitors or with contraindications for epinephrine administration; patients with acute infections and/or underlying cardiac, hepatic or renal diseases that contraindicated drug provocation test (DPT); patients with chronic spontaneous urticaria (CSU) that was exacerbated by NSAIDs (NECD); patients with psychosomatic disorders; patients reporting throat tightness not associated with dysphonia, difficulty breathing and swallowing and glottis oedema was not observed by fiberscope; and patients reporting gastrointestinal symptoms such as epigastric burning and hemorrhage related to alterations in the gastroduodenal mucosa secondary to the pharmacology action of NSAIDs
Diagnosis could not be achieved for 1662 patients (1230 could not undergo DPT to acetylsalicylic acid (ASA) due to age or comorbidities, 376 refused to perform the study, and 56 were excluded due to pregnancy), and 267 individuals were diagnosed with selective reactions

Summary

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequent triggers of drug hypersensitivity reactions (DHRs). Several classifications have been proposed, including a recently published and heavily cited publication from the European Network on Drug Allergy (ENDA) group from the European Academy of Allergy and Clinical Immunology (EAACI)9 They classify hypersensitivity reactions to NSAIDs according to the clinical symptoms induced, the number of NSAIDs involved, and the presence or absence of underlying www.nature.com/scientificreports/. Patients with cross-reactive hypersensitivity to multiple NSAIDs may simultaneously develop a combination of skin and respiratory symptoms independently of the presence of underlying CSU, asthma or rhinosinusitis. They often experience angioedema and/ or urticaria alongside rhinoconjunctivitis and/or bronchial asthma after NSAIDs intake. In our clinical experience and in the literature, blended reactions are almost never found in patients with NECD, as a result we excluded them from this study

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