mini-review Allergo J Int (2018) 27:114–121 https://doi.org/10.1007/s40629-018-0064-0 NSAID hypersensitivity – recommendations for diagnostic work up and patient management Stefan Wöhrl Received: 21 February 2017 / Accepted: 30 November 2017 / Published online: 25 May 2018 © The Author(s) 2018 Abstract can only be confirmed by provocation testing, when Background Adverse drug reactions (ADR) to anal- required. Although cross-reactivity is usually present, gesics (i.e., non-steroidal anti-inflammatory drug hy- provocation testing is often able to find an alterna- persensitivity, NSAID-HS) are one of the most com- tive, tolerable analgesic. Individual patient manage- mon ADR, affecting approximately 1.6% of all patients. ment usually enables a solution to be found for most Despite the fact that they are common, they still pose patients. a diagnostic challenge. Methods This article is an overview of selected sci- Keywords Allergy · NSAID hypersensitivity · Aspirin entific articles and is based on research in PubMed, intolerance · Analgesic intolerance · Aspirin-sensitive specialist databases, and guidelines. asthma Results Approximately 80% of side effects are pharma- cologically predictable and are classified as type A re- Abbreviations actions, such as abdominal pain and bleeding events. ADR Adverse drug reaction More advanced diagnostic investigations are not use- AERD Aspirin-exacerbated respiratory disease ful in such cases. Type B reactions, which account for AGEP Acute generalized exanthematous pustu- the remaining 20%, are subdivided into the far more losis frequent cross-reactive, non-immunological NSAID- AMG Medicinal Products Act (Arzneimittelge- HS (acronyms NERD [NSAID exacerbated respiratory setz) disease],NECD[NSAIDexacerbatedcutaneousdis- ASA Acetylsalicylic acid ease], NIUA [NSAID-induced urticaria/angioedema]) BAT Basophil activation test and the much rarer true drug allergies of type I and COX Cyclooxygenase IV (acronyms SNIUAA [single NSAID-induced ur- DRESS Drug reaction with eosinophilia and sys- ticara/angioedema or anaphylaxis] and SNIDR [single temic symptoms NSAID-induced delayed reaction]). The two latter are EAACI European Academy of Allergy and Clinical not cross-reactive and all other NSAIDs are generally Immunology well tolerated. ENDA European Network on Drug Allergy Conclusion The diagnostic work-up begins with a de- LTT Lymphocyte transformation test tailed patient’s history. Skin tests are only useful in NECD NSAID exacerbated cutaneous disease SNIDR and SNIUAA, while in vitro tests are helpful NERD NSAID exacerbated respiratory disease merely in exceptional cases. In general, the diagnosis NIUA NSAID-induced urticaria/angioedema NSAID Non-steroidal anti-inflammatory drug SJS Stevens–Johnson syndrome PD Mag. Dr. S. Wöhrl ( ) SNIDR Single NSAID-induced delayed reaction Floridsdorf Allergy Center (FAZ), Pius-Parsch-Platz 1/3, 1210 Vienna, Austria SNIUAA Single NSAID-induced urticaria/angioedema [email protected] or anaphylaxis TEN Toxic epidermal necrolysis PD Mag. Dr. S. Wöhrl Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria 114 NSAID hypersensitivity – recommendations for diagnostic work up and patient management K mini-review Introduction zyme. Thus, this class of drug acts on the arachidonic acid metabolism, thereby influencing the balance be- “Non-steroidal anti-inflammatory drug (NSAID) intol- tween leukotrienes and prostaglandins by inhibiting erance” is known by many synonyms, e.g., aspirin the production of prostanoids (Fig. 2). The definitive intolerance/aspirin hypersensitivity, NSAID idiosyn- mechanism of NSAID hypersensitivity has not been crasy/NSAID hypersensitivity, as well as Widal’s dis- conclusively elucidated as yet, but it is likely that ease/Samter’s triad. NSAID-induced COX blockade results in excessive NSAIDs comprise a group of chemically diverse prostaglandin E2 production in affected individuals substances (Table 1,Fig.1)thathaveonethingin [1]. common, i.e., that they inhibit the enzyme cyclooxy- Acetylsalicylic acid (ASA; Aspirin®, Bayer and nu- genase-1 (COX) and, to a lesser extent, the COX-2 en- merous generic drugs) is the best known, strongest, Table 1 Pharmacological classification of antipyretic non-opioid analgesics with typical examples (from Beubler E [6])a Antipyretics Class Typical example Non-steroidal anti-inflammatory drug Salicylic acid derivatives – Acetylsalicylic acid Sulfasalazine Acetic acid derivatives – Diclofenac Acemetacin Indomethacin Propionic acid derivatives – Dexibuprofen Ibuprofen Naproxen Ketoprofen Flurbiprofen Enolic acid derivatives Oxicams Meloxicam Lornoxicam Piroxicam Pyrazolones Phenylbutazone Propyphenazone (historically) Metamizole= dipyrone Fenamates Mefenamic acid Selective COX-2 inhibitors Celecoxib Para-aminophenol Paracetamol= acetaminophen aNote: Most COX-2 inhibitors were withdrawn from the market because of a major pharmaceutical scandal at the beginning of this millennium in which class-specific cardiovascular side effects were downplayed in licensing trials [28]. Hence, celecoxib remains the only widely available COX-2 inhibitor Fig. 1 There are few chemical and structural similarities between the NSAID groups and the sim- ilarly acting paracetamol, which is also known as acetaminophen. Cross- reactivity in NERD, NECD, and NIUA (Fig. )isme- 3 Acetylsalicylic acid Ibuprofen diated via the common blockage of the COX enzyme (Fig. 2). The mech- anism differs from the truly Paracetamol = allergic SNIDR and SNIUAA Acetaminophen where cross-reactivity is unlikely (Fig. 3) Diclofenac Lornoxicam K NSAID hypersensitivity – recommendations for diagnostic work up and patient management 115 mini-review Membrane at high doses [6]. Type A ADR should not be submit- phospholipids ted to any further testing because all tests will yield a predictable negative outcome. Glucocorticoids Phospholipase In contrast, NSAID-HS is an unpredictable “bizarre” ADR (type B) caused by individual factors and is re- Arachidonic acid sponsible for around 20% of ADR to NSAID [7, 8]. The rest of this manuscript will exclusively address type B Cyclooxygenase NSAID 5-Lipoxygenase (COX-I, COX-II) reactions. Leukotrienes PGH 5-HPETE 2 Clinical symptoms In its original sense, “NSAID hypersensitivity” referred PGG LTA 2 4 to the triad of the symptoms nasal polyps, bronchial Prostaglandins asthma, and NSAID hypersensitivity, which is also LTC known as Widal’s disease Samter triad. According PGI2 PGE2 TXA2 LTB4 4 LTD 4 to the more recent nomenclature, five different enti- LTE 4 ties fall under “NSAID hypersensitivity” [9, 10]. The PGA TXB 2 2 three true NSAID hypersensitivity reactions are non- immunologically mediated, cross-reactive hypersen- PGH 2 sitivities caused by changes in the arachidonic acid metabolism. It is important for clinical understand- Fig. 2 NSAIDs divert the normal arachidonic acid metabolism ing that marked cross-reactivities between structurally by blocking cyclooxygenase-1 (COX-1), which is constitutively widely differing NSAIDs should be expected in these expressed in all cells. In the case of inflammatory reactions, three intolerances (Fig. 1), since the common basis COX-2 may also be induced in leukocytes. Blocking COX is the blockade of the COX-1 enzyme. Some authors (red) blocks prostaglandin synthesis (blue) and increases refertothistypeofreactionasa“pseudo-allergy”[8]. leukotriene production (purple), which can cause the intol- erance reactions NERD (NSAID exacerbated respiratory dis- There are three entities: ease), NECD (NSAID induced cutaneous disease), and NIUA ● Patients with skin reactions such as urticaria and/or (NSAID-induced urticaria/angioedema) in affected individuals angioedema are classified into two subgroups (see (Fig. 3). (Modified from Rozsasi A and Keck22 T[ ]) also Fig. 3): – Affected individuals with underlying chronic ur- and only irreversible COX-1 inhibitor. Aspirin, the ticaria and/or angioedema where NSAID use brand name used by Bayer, lent its name in the clin- causes an exacerbation of the underlying disease ical setting in English-speaking countries for many are classified as suffering from NSAID-exacer- decades and has only been replaced in recent years bated cutaneous disease (NECD). by NSAID (Table 1). Paracetamol, known in the An- – Affected individuals without underlying chronic glo-Saxon world as acetaminophen, is not a classic urticaria/angioedema are referred to as suffer- NSAID and its mode of action is still not completely ing from NSAID-induced urticaria/angioedema understood. However, its side effects profile is ex- (NIUA). What is interesting here is that many of tremely similar to that of NSAID; hence, its inclusion these patients to develop chronic urticaria later in this review article [2]. In addition, paracetamol is on; thus, NSAID use can “unmask” the subse- an alternative drug in NSAID hypersensitivity (NSAID- quent onset of urticaria somewhere in the future. HS) that is frequently well tolerated and, in contrast This resembles gestational diabetes, which often to many NSAIDs, can also be used intravenously. precedes true type II diabetes in the expecting Adverse drug reactions (ADR) occur in 1.6% of mother by many years and will still be reversible all users following NSAID administration [3]. Most following pregnancy. NSAIDs are not subject to medical prescription, ex- ● Patients with respiratory symptoms fall into one plaining why often substantial amounts of NSAID are group: used, sometimes without medical monitoring. The – This symptom is