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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 . 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 · entific articles and is based on research in PubMed, intolerance · Analgesic intolerance · Aspirin-sensitive specialist databases, and guidelines. 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 IV (acronyms SNIUAA [single NSAID-induced ur- DRESS Drug reaction with eosinophilia and sys- ticara/angioedema or ] 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 metabolism, thereby influencing the balance be- “Non-steroidal anti-inflammatory drug (NSAID) intol- tween leukotrienes and by inhibiting erance” is known by many synonyms, e.g., aspirin the production of (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 E2 production in affected individuals substances (Table 1,Fig.1)thathaveonethingin [1]. common, i.e., that they inhibit the 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 non- with typical examples (from Beubler E [6])a Class Typical example Non-steroidal anti-inflammatory drug derivatives – Acetylsalicylic acid Sulfasalazine derivatives – Indomethacin derivatives – Enolic acid derivatives (historically) = dipyrone Fenamates Selective COX-2 inhibitors Para-aminophenol = 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 referred to as NSAID-exacer- majority (around 80%) of ADR to NSAID are phar- bated respiratory disease (NERD), formerly also macological and predictable (type A), which does known as aspirin-exacerbated respiratory disease not necessarily imply that all of these reactions are (AERD). Clinical symptoms include rhinorrhea, harmless, i.e., gastrointestinal bleeding and NSAID- blocked nose, and bronchial asthma. Many of induced nephrotoxicity are the most frequent causes these patients exhibit nasal polyps, chronic rhi- of death due to ADR to drugs [4].Inthecaseof nosinusitis, and/or bronchial asthma as underly- chronic use, all NSAID, with the exception of salicylic ing diseases. acid derivatives, may pose a cardiovascular risk, most particularly COX-2 inhibitors [5]. Although hepatox- In contrast to the earlier understanding of the term, icity is feared with paracetamol use, this only occurs and probably confusingly for most non-experts, the

116 NSAID hypersensitivity – recommendations for diagnostic work up and patient management K mini-review

new nomenclature also embraces the much rarer, true drug allergies to NSAID for the first time ([10]; Figs. 3 and 4). Since these are true immunological reactions,

and immunological cross-reactions with other NSAIDs are unlikely, in contrast to the true NSAID hypersensitivity Common Very common Very common Common Rare Very rare reactions (NECD/NIUA/NERD; see above) ● In rare cases, true T-cell-mediated, delayed type IV allergic drug eruptions may occur (single NSAID- induced delayed reactions, SNIDR). As with all NIUA, and NECD)

Cross reacons Cross type IV-mediated drug allergies, disease patterns vary widely. The clinical pictures most frequently Are cross reacons to other expected? be to NSAID No No seen include clinically mild maculopapular drug eruptions (MDE), in particular to systemically ad- ministered diclofenac and metamizole, as well as mild contact allergies, again mild, to topical NSAIDs 15 Min—8 h 15 Min—8 to onset inhibition (NERD, such as diclofenac and , the latter having since withdrawn from the market for this reason [11]. Fixed MDE, in particular to oral mefenamic acid [12], are also observed, as are rare cases of life- threatening severe cutaneous drug reactions, par- ticularly to systemically administered oxicams ([13]; Stevens-Johnson syndrome, SJS; toxic epidermal necrolysis,TEN;acutegeneralized exanthematous pustulosis, AGEP; and drug rash with eosinophilia and systemic symptoms, DRESS).

Underlying disease angioedemaChronic spontaneous urcaria and/or Up to 30 min NoneOponal underlying disease: bronchial asthma or chronic nasal polyps NoneNone Typical me Up to 30 min Within days Up to 10 min ● True IgE-mediated type I allergic reactions (sin- gle NSAID-induced urticaria/angioedema or ana-

D hypersensitivities caused by COX-1 phylaxis, SNIUAA) are the rarest reactions. Propy- , a phenazone derivative, used to be no- torious in this regard [14]and,asaresult,hasvirtu- ally disappeared from the market. Another known trigger is the metamizole [15], which is commonly used particularly in Austria. There have been extremely rare reports from Spain of individ- ual reactions to the acetic acid derivative diclofenac Urcaria, angioedema, Urcaria, angioedema, itch Urcaria, angioedema, severe cutaneous allergy, fixed drug erupon, drug reacon (SJS, TEN, AGEP, DRESS) hypotension, shock) and, in particular, to the propionic acid derivatives ibuprofen, ketoprofen, and naproxen (Table 1). Skin/mucosa Affected organAffected Symptoms Respiratory tract Bronchial asthma, rhinorrhoea SkinAnaphylaxis Maculopapular drug erupon, (photo)contact (urcaria, angioedema, asthma, Anaphylaxis Diagnostic allergy testing

Investigating ADR triggered by NSAIDs is often un- satisfactory for the allergist. This is due to the fact that both true NSAID hypersensitivity (NECD, NIUA, COX-I inhibion and NERD) and the most important differential diag- nosis of acute/chronic urticaria/angioedema are very IgE-mediated type I allergy IgE-mediated common. As such, the most important tool in allergy diagnosis, the patient history, is often non-specific. At the same time, NSAID is a class of drugs that are par- ticularly important in the primary care sector and for

reacons (SNIDR) T-cell-mediated type IV allergy which there are a multitude of indications. Therefore, they belong to the drugs, besides antibiotics and local ated respiratory disease) anesthetics, for which the international ADR consen- sus recommends diagnostic testing in all cases [16]. Due to the complexity of the task, testing should be The five reaction patterns of type B adverse drug reactions to NSAID: NSAI three performed at a center experienced in managing these Subgroup of NSAID intolerance Pathophysiology anaphylaxis (SNIUAA) types of patients [7]. V. Single NSAID-induced urcaria/angioedema or I.II. NECD (NSAID exacerbated cutaneous disease) (NSAIDs-induced urcaria/angioedema) NIUA III. NERD (NSAID exacerb IV. Single NSAID-induced delayed Fig. 3 two true allergic reaction patterns (SNIDR and SNIUAA) As always in allergology, taking the specific medical history is the most important diagnostic factor. Partic-

K NSAID hypersensitivity – recommendations for diagnostic work up and patient management 117 mini-review

ular attention should be paid to the following details ASA in NERD compared with 500mg in NECD/ (Figs. 3 and 4): NIUA) 1. Which type of reaction pattern? b.From a frequency of three or more episodes to dif- a.Skin-type (pruritus, flushing, urticaria, angioedema) ferent NSAIDs with the same symptoms, the like- b.Respiratory-type (cough, bronchial asthma, res- lihood of NSAID hypersensitivity increases to the piratory distress, rhinorrhea, sneezing, blocked extent that the diagnosis may be based solely on nose) the basis of patient history [10]. c. True anaphylaxis (severe drop in blood pressure, 3. Are there any characteristic underlying diseases? loss of consciousness, resuscitation, acute and se- a.Chronic urticaria/angioedema vere gastrointestinal symptoms (i.e., >5 times di- – Is there evidence that oral antihistamines are arrhea), other emergency medical measures) able to effectively suppress the reaction? 2. How many reported episodes? b.Bronchial asthma a.Is there evidence of cross-reactivity to other NSAID? – Existing asthma medication/current lung func- – What was the triggering dose? (Patients with tion? NERD react to significantly lower doses than c. Nasal polyps do patients with NECD/NIUA, e.g., 30mg oral i. Current nasal status? ii. Polypectomy in childhood? Recurrence? d.Chronic rhinosinusitis

Skin reacon History of clinical reacon paern ? to NSAID a er 24 h (lasng days to Acute reacons to NSAIDs <24 h (usually lasng 1-2 h) weeks)

• Bronchospasm • Urcaria • (Fixed) drug • Dyspnea • Angioedema erupon • Nasal discharge/blockage • Anaphylaxis • Contact • Flushing dermas • Severe History of underlying diseases ? cutaneous ADR

• Bronchial asthma • Urcaria • No history of chronic • No • Rhinosinusis • Angioedema urcaria/angioedema • Nasal polyps History of ADR to other NSAIDs ?

Cross-reacons No cross-reacons

NERD NECD NIUA SNIUAA SNIDR

Perform skin tesng with in vitro tests Skin tesng with triggering NSAID not recommended triggering NSAID

In vitro: BAT, CAST, ELISA with triggering NSAID * sIgE * LTT, ELISPOT * Intolerance Allergy

Fig. 4 Diagnostic and management algorithm for type B ad- tion, displayed on a light yellow background, while the IgE- verse drug reactions (ADR) to non-steroidal anti-inflammatory mediated type I allergy SNIUAA (single NSAID induced ur- drugs (NSAID); figure modified from Kowalski M et al. ([10]; ticaria/angioedema or anaphylaxis) and the type IV allergy also see Fig. 3. The NSAID hypersensitivity NERD (NSAID SNIDR (single NSAID induced delayed reaction) appear on exacerbated respiratory disease), NECD (NSAID exacerbated a purple background. *None of the in vitro tests for ADR to cutaneous disease), and NIUA (NSAID-induced urticaria/ NSAID are validated and are therefore not currently recom- angioedema), which are caused by cyclooxygenase-1 inhibi- mended for routine use [7, 10, 21]

118 NSAID hypersensitivity – recommendations for diagnostic work up and patient management K mini-review

4. Are there any differential diagnoses that could bet- However, although provocation tests are important ter explain the symptoms? in the diagnosis of ADR in general and NSAID hy- a.For instance, acute, infection-related urticaria persensitivity in particular, resources for provocation and angioedema? testing are limited. NSAID hypersensitivity is a com- mondiseasewithaprevalenceofupto2%inthe Classic NSAID hypersensitivity (NECD, NIUA, and general population, with a much higher prevalence in NERD) high-risk populations, e.g., asthma, nasal polyps, or urticaria [20]. If there are insufficient resources to per- Since COX-1 inhibition is the mechanism of the much form provocation tests in all patients, it is the task of more common NSAID hypersensitivity (NECD, NIUA, the allergist to define “high-need” patients and submit and NERD), classic skin allergy tests remain negative them to provocation testing in a selected manner. For and are thus not recommended ([10]; Fig. 4). example, the EAACI position paper offers the option Therefore, if it is not possible to unequivocally to clinically diagnose NSAID hypersensitivity without establish the diagnosis on the basis of patient his- the necessity of additional provocation testing in pa- tory, only provocation testing makes sense. At the tients with≥ three episodes to three different NSAIDs same time, this offers the possibility to test patients’ with similar reaction patterns (e.g., three independent toleranceofsafealternativedrugs(seethesection episodes of urticaria for 1h, each within 2h of oral in- “Safe alternative drugs”). This also enables—where gestion of 75mg diclofenac, 500mg ASA, and 400mg desired—the initiation of ASA desensitization, as has dexibuprofen; [10]). recently become fashionable, primarily as recurrence Some laboratories offer leukotriene measurement prevention in nasal polyps ([17]; see section “Miscel- following in vitro stimulation of leukocyte fractions laneous”). with NSAID (e.g., CAST-Elisa®, Bühlmann Laborato- The aim of provocation testing should be to un- ries, Schönenbuch, Switzerland). However, despite equivocally answer one question: Can the suspected decades of use and optimization, this method remains trigger really elicit the intolerance reaction? To insufficiently reliable to be recommended for routine achieve this, the suspected drug is administered (pref- use [7, 21, 22]. Similarly, the basophil activation test erentially) orally in increasing single doses over the (BAT; the determination of activation markers follow- course of a day until a normal daily dose is reached [7]. ing in vitro stimulation of leukocyte fractions of blood, Particularly in the case of ASA, this dose depends on e.g., CD63 and/or CD203c) is generally regarded as the indication. At 50–100mg, the cardiovascular target unsuitable for routine use, in contrast to IgE-medi- dose for the secondary prevention of thromboembolic ated drug allergies [21]. events is much lower compared with antipyretic or anti-inflammatory target doses of 1000–2000mg, e.g., NSAID allergy (SNIDR and SNIUAA) in or rheumatic disorders. The details involved in the planning of provoca- Classic diagnostic allergy testing using skin tests (skin tion tests go beyond the scope of this review article. prick test, intradermal test, and patch test) is only use- Numerous different provocation protocols (oral, more ful in the rare type IV (SNIDR) and type I (SNIUAA) rarely nasal, pulmonary, and intravenous) have been allergic reactions [10].Sincetheseareuncommon published. These often take into consideration dif- (in the author’s experience, around 3% of referrals for ferent clinical pictures and underlying diseases, but NSAID hypersensitivity to his institution, unpublished also include a generous measure of pragmatism (e.g., data), skin testing is only helpful if the patient history national availability of approved NSAID preparations points to SNIUAA (e.g., two episodes of urticaria and and accordingly selected dosages). The dosage for angioedema following 250mg of oral metamizole for the ASA oral provocation test published in the 2007 a maximum of 6h each without recurrence) or SNIDR position paper by the European Academy of Allergy (e.g., MDE on day 6 of 75-mg oral diclofenac twice and Clinical Immunology (EAACI; [18]) failed to be- daily, with a resolution after stopping diclofenac only come established in clinical routine—according to after weeks). Pyrazolones such as metamizole are the the author’s personal experience in German-speaking most frequent triggers of SNIUAA and, in the case of countries—due to the fact that different standard ASA a relevant patient history, should be tested on the skin. dosages are usual there compared with the rest of Testing with undiluted solutions (or crushed tablets Europe. For example, a possible dose increase in the when unavailable) is currently recommended for skin case of a reaction would be 50–250–500 (–1000) mg prick testing at a concentration of 0.1mg/ml in phys- ASA every 2h, for other NSAIDs 1/10, 1/2, and 1/1 of iological saline solution for intradermal testing and the normal single dose. In the case of severe reac- 10% in vaseline for patch testing. The reader is re- tions, lower initial and, where necessary, intermediate ferred to the position paper published by the Euro- doses need to be used. In this connection, the reader pean Network on Drug Allergy (ENDA) for detailed is referred to Bettina Wedi’s recent review article on information on performing skin tests with NSAID [23]. NSAID hypersensitivity in this journal [19]. Unfortunately, commercial, validated in vitro tests to determine IgE against NSAIDs are currently not

K NSAID hypersensitivity – recommendations for diagnostic work up and patient management 119 mini-review

available. From an historical perspective, the success- Although marked cross-reactions are to be ex- ful determination of IgE against propyphenazone us- pected, some patients tolerate NSAID that tend to- ing no-longer-available non-commercial ELISAs was wards stronger COX-2 inhibition, such as oxicams, arareexception[14]. Although BATs are offered by the COX-2 inhibitors that continue to be available, or, a handful of laboratories and can be helpful in some as an alternative, paracetamol. If the patient reports cases, they are not sufficiently standardized to be rec- good tolerance of one of these substances in their ommended for routine practice [7, 21, 22]. patient history, this tolerance can be noted in the al- In rare cases, suspected NSAID hypersensitivity lergy passport. Should the patient have high analgesic may be simulated by mastocytosis or mast cell ac- requirements, tolerance of alternative drugs should tivation syndrome [24]. In such cases, screening by be demonstrated in a clinically relevant dose. It is measuring serum basal tryptase may be useful, par- important that the tolerated dose ensures sufficient ticularly if the patient has a history of severe reactions. analgesia. For example, good tolerance of the weak analgesic paracetamol at a dose of 250mg is of no Management benefit in clinical practice if at least 1000–1500mg is required for a good analgesic effect. This needs to be Management should consider individual patient fac- taken into consideration in provocation testing. tors. In the rare cases of true drug allergy (SNIDR/ SNIUA), cross-reactions are not to be expected (Fig. 3), Miscellaneous and the approach is usually limited to issuing an al- lergy passport and avoiding the trigger. On the whole, In specific cases, ASA desensitization can be aimed other NSAIDs can continue to be used. for, e.g., as recurrence prevention in nasal polyps [17] or anticoagulation in the case of cardiovascular indi- Avoidance and an allergy passport cations where lower maintenance doses with a maxi- mum of 100mg ASA are adequate [26]. This is started The diagnosis should always be communicated to the with an extremely small single dose of ASA (gener- patient in written form. Issuing an allergy passport ally 1–10mg), which is then rapidly increased up to is a common, well established approach in German- the maintenance dose. In the respective, short refrac- speaking countries [25]. It makes the most important tory phase of around 30min, the next single dose is management strategy easier: avoidance of the eluci- administered, which explains tolerance and may ex- dating trigger. As a minimum requirement, the allergy ceed the initial triggering dose. It is important that the passport should include the generic name of the trig- achieved maintenance dose be continued daily and ger, together with the dose and the reaction pattern that a maximum pause of only 48h is permitted, oth- in generally understandable medical language, as well erwise the desensitization effect is lost. Interestingly, as the correct allergological classification (e.g., NSAID there is often cross-tolerance to other NSAID during hypersensitivity/NECD (symptom: urticaria); type IV this period. The gastrointestinal side effects of long- allergy to diclofenac [symptom: maculopapular drug term ASA use represent a limiting factor in ASA de- eruption] and how the diagnosis was established [e.g., sensitization (note: gastrointestinal side effects such “confirmed by provocation testing; confirmed by un- as ulcer, bleeding, and diarrhea are type A side effects; equivocal patient history”]). The ENDA/EAACI pub- see introduction); since these cause considerable suf- lication includes a practical and extremely useful En- fering on the patient’s part, there needs be a strict glish form for this purpose [25]. It is also essential that indication for interaction with other disciplines, such the date and issuer are easily identifiable on the al- as cardiology, neurology, or ENT, in order to consider lergy passport in the case of potential medical queries desensitization. later on. Another simpler and more pragmatic approach has In the usual case of NERD/NECD/NIUA, cross-in- recently been proposed. Similar to antihistamine pre- tolerance should be mentioned—to the extent that medication in allergen-specific immunotherapy, the this is known—due to the identical mechanism of ac- tolerated doses of NSAID in NECD and NIUA patients tion, e.g. “Trigger, acetylsalicylic acid 500mg, known in a small case series of 5mg desloratadine were sig- cross-reactions to all other NSAID.” nificantly increased [27]. However, this highly prac- tical approach still needs to be confirmed in further Safe alternative drugs investigations. Funding Open access funding provided by Medical Univer- The allergist needs to assess whether safe alternative sity of Vienna. drugs are needed. In principle, can be recom- mended as safe alternatives for analgesia even without Conflict of interest S. Wöhrl declares that he has no compet- testing, since their mode of action, i.e., blockade of the ing interests. µ-opioid receptor in the nervous system, is completely Open Access This article is distributed under the terms of different to that of NSAID. the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which per-

120 NSAID hypersensitivity – recommendations for diagnostic work up and patient management K mini-review

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