Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: from phenotyping to genotyping.After beta lactam antibiotics, hypersensitivity reactions to nonsteroidal anti-inflammatory drugs are the second cause of hypersensitivity to drugs. Acute manifestations affect the respiratory tract aspirin exacerbated respiratory diseasethe skin urticaria and angioedemaor are generalized anaphylaxis. Correct diagnosis and treatment in order to prevent unnecessary morbidity and the potential risk hypersensitivity reactions to nonsteroidal anti inflammatory drugs death from these severe reactions, and to provide proper medical advice on future drug use frequently requires the participation of allergology specialists familiar with these clinical conditions. Soon after horario trenes cercanias fuengirola malaga acid was introduced into medical use the first adverse reaction to aspirin was reported by Hirschberg in [ 1 ]. A number of pharmaceutical compounds with anti-inflammatory and analgesic properties, designated nonsteroidal anti-inflammatory drugs NSAIDsshare the inhibition of cyclooxygenase enzymes COX as hypersensitivity reactions to nonsteroidal anti inflammatory drugs main mechanism of action.
Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs. - PubMed - NCBI
After beta lactam antibiotics, hypersensitivity reactions to nonsteroidal anti-inflammatory drugs are the second cause of hypersensitivity to drugs. Acute manifestations affect the respiratory tract aspirin exacerbated respiratory disease , the skin urticaria and angioedema , or are generalized anaphylaxis. Correct diagnosis and treatment in order to prevent unnecessary morbidity and the potential risk of death from these severe reactions, and to provide proper medical advice on future drug use frequently requires the participation of allergology specialists familiar with these clinical conditions.
Soon after acetylsalicylic acid was introduced into medical use the first adverse reaction to aspirin was reported by Hirschberg in [ 1 ]. A number of pharmaceutical compounds with anti-inflammatory and analgesic properties, designated nonsteroidal anti-inflammatory drugs NSAIDs , share the inhibition of cyclooxygenase enzymes COX as their main mechanism of action. These enzymes participate in the metabolism of arachidonic acid, resulting in the production of potent inflammatory mediators such as prostaglandins and thromboxanes.
The classical NSAIDs inhibit both isoenzymes and their use is often accompanied by gastrointestinal intolerance due to a decreased production of protective prostaglandin E 2 in the stomach. New drugs that inhibit selectively COX-2 exhibit a better gastric tolerance profile, although their introduction into clinical practice has been associated with severe cardiovascular adverse events that led to the recommendation for careful utilization in patients with previous vascular diseases [ 2 , 3 ].
The preferential COX-2 inhibitors meloxicam and nimesulide are also available in some countries Table 1. This article is an update of the present knowledge on the diverse hypersensitivity reactions that can be induced by NSAIDs, including immediate and delayed reactions. The nomenclature for reactions to NSAIDs in the medical literature is somewhat confusing because authors have employed diverse terms in their reports, for example, pseudoallergy, idiosincrasia, or intolerance.
We will use the terminology proposed by the Nomenclature Committee of the World Allergy Organization that defines drug hypersensitivity as the symptoms or signs initiated by exposure to a drug at a dose normally tolerated by non-hypersensitive persons. Analgesic and anti-inflammatory medications are widely used in all age groups for the treatment of pain, inflammation and fevers of diverse etiologies. A large proportion of the population is exposed to these drugs, making them the second cause of untoward reactions, after beta lactam antibiotics.
In adult asthmatics aspirin intolerance occurs in 4. Aspirin intolerance is present with increased frequency in patients with chronic idiopathic urticaria CIU [ 5 , 6 ], and NSAIDs are among the leading causes of anaphylaxis [ 7 ]. Hypersensitivity to NSAIDs can be classified according to the time of onset and the clinical manifestations into acute and delayed. Acute reactions start immediately to several hours after drug administration and include:. Delayed reactions begin after 24 hours of NSAID exposure, can be induced by a single or multiple cross-reacting NSAIDs, and are clinically expressed either as organ specific or as multisystemic diseases [ 15 ].
Examples of organ specific diseases are:. Since NSAID hypersensitivity has multiple clinical manifestations, the mechanisms incriminated in each of them are different. Reactions to aspirin and NSAIDs observed in patients with AERD are mediated by inhibition of COX-1, leading to a shunting of arachidonic acid metabolism towards the 5-lipoxygenase pathway and increased production of cysteinyl leukotrienes [ 24 ].
A decreased production of PGE 2 , a modulator of mediator release from mast cells and other inflammatory cells, also plays a role [ 25 ]. They observed increased levels of urinary LTE 4 uLTE 4 in patients with chronic urticaria that showed symptom exacerbations during challenges with aspirin, as compared with CIU patients that did not respond to the aspirin provocation. The mechanisms of induction of acute urticaria, angioedema and anaphylaxis by multiple NSAIDs in patients who do not have chronic urticaria have not been defined.
Nevertheless, it is provocative to hypothesize that, since these drugs have as their major mean of action the inhibition of COX-1, this mechanism could also be involved in the production of these clinical manifestations.
Reactions to a single NSAID are mediated by drug-specific IgE antibodies, as can be demonstrated by means of immediate-type skin tests or in vitro measurement of specific IgE [ 27 , 28 ].
The information on symptoms and exposure to NSAIDs is of paramount importance to determine the temporal relationship between the initiation of the clinical picture and the probability of a drug etiology. In general, in patients who show repeated episodes of urticaria, angioedema or asthma after receiving one or various cross-reacting NSAIDs, the medical history is reliable.
Confirmation is generally obtained by oral provocation tests, single- or double-blinded, according to the protocols shown in Table 2. These tests are better performed in the hospital by trained specialists, with easily available drugs and equipment to treat reactions if they occur. In Europe, inhalation or nasal challenges with lysine-aspirin are also being used routinely for the diagnosis of AERD [ 30 ]. This is a promising method for those patients in whom a drug provocation is not possible due to ethical or clinical reasons [ 31 , 32 ], but is not available in most centers since it requires alive blood cells less than 24 hours of sample drawing and a fluorescence-activated cell sorter FACS.
Prick and intradermal skin tests with pyrazolone, paracetamol and diclofenac have been used in patients with single-drug hypersensitivity, but at this time these tests have not been standardized for general use [ 35 , 36 , 37 ]. Patch and photopatch tests are a simple and fast method for the diagnosis of delayed reactions to NSAIDs [ 38 , 39 ], and concentrations of NSAIDs for patch testing have been previously published [ 40 ].
Intradermal and scratch tests with reading at 48 hours are also useful [ 41 ]. The lymphocyte transformation test measures the in vitro proliferative response of T cells to the drug.
The test is available in few centers, is costly and laborious. Rechallenges with the drug are considered the gold standard for the diagnosis of delayed reactions to NSAIDs although they are contraindicated in patients with previous severe reactions. Patients with AERD must avoid all COX-1 inhibitors, including aspirin, in order to avoid the occurrence of serious asthma exacerbations. For the treatment of pain and inflammation NSAIDs that do not inhibit COX-1, such as acetaminophen in doses below 1, mg and COX-2 inhibitors are recommended after challenge in the office or medical facility.
Aspirin desensitization is indicated for patients who require continuous anti-inflammatory or anti-thrombotic therapy, such as those with ischemic heart disease or chronic arthritis [ 42 ].
Persistent asthma and rhinosinusitis are to be treated according to the recommendations given by international guidelines such as GINA and EPOS [ 43 , 44 ]. The treatment of chronic urticaria has been recently updated and is based on the use of non sedating antihistamines alone or in combination with other drugs [ 47 ].
Acetaminophen and COX-2 inhibitors are alternative drugs suitable for analgesia and treatment of pain and inflammation in these subjects.
COX-2 inhibitors are not recommended for chronic use because of the increased risk of cardiovascular side effects, especially in patients with previous history of coronary or cerebrovascular disease. For patients with reactions to a single drug, avoidance of the drug and other NSAIDs chemically related should be recommended.
NSAIDs constitute a frequent cause of adverse reactions to drugs that can be clinically manifested in multiple forms. Acute reactions may be systemic anaphylaxis , respiratory aspirin- exacerbated respiratory disease , and cutaneous urticaria and angioedema.
Delayed reactions include various types of skin conditions, or the involvement of various organs such as the lungs, central nervous system or the kidneys.
Diagnosis of NSAID hypersensitivity generally requires the performance of confirmatory tests in patients with a suggestive clinical picture. In selected patients with AERD desensitization is indicated. National Center for Biotechnology Information , U. Journal List Pharmaceuticals Basel v. Published online Jan 5. Received Dec 17; Accepted Dec This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license http: This article has been cited by other articles in PMC.
Abstract After beta lactam antibiotics, hypersensitivity reactions to nonsteroidal anti-inflammatory drugs are the second cause of hypersensitivity to drugs. Introduction Soon after acetylsalicylic acid was introduced into medical use the first adverse reaction to aspirin was reported by Hirschberg in [ 1 ].
Open in a separate window. Hypersensitivity Reactions to NSAIDs The nomenclature for reactions to NSAIDs in the medical literature is somewhat confusing because authors have employed diverse terms in their reports, for example, pseudoallergy, idiosincrasia, or intolerance. Clinical Picture Hypersensitivity to NSAIDs can be classified according to the time of onset and the clinical manifestations into acute and delayed. Acute reactions start immediately to several hours after drug administration and include: These individuals experience a chronic disease characterized by chronic rhinosinusitis, severe persistent and steroid-dependent asthma, with or without nasal polyposis.
These asthma attacks are severe and may be life-threatening. Various genetic polymorphisms have been associated with this condition [ 10 ].
Cross reacting urticaria and angioedema: Various genetic polymorphisms, including genes coding for HLA antigens, LTC 4 synthase, 5-lipooxygenase, and the high affinity receptor for IgE have been observed in these patients [ 10 ].
In patients who do not suffer other morbid conditions NSAIDs can precipitate acute urticaria, angioedema or systemic reactions. This variant of hypersensitivity is more prevalent in atopic individuals [ 8 , 12 ] and facial angioedema is the most frequent clinical manifestation [ 13 ].
More frequently triggered by pyrazolones, but also reported for aspirin, paracetamol, ibuprofen, diclofenac and naproxen. The clinical manifestations include urticaria, angioedema, laryngeal edema, anaphylaxis, generalized pruritus, rhinitis or bronchospasm.
Maculopapular exanthemas, Fixed drug eruptions [ 16 ], Bullous reactions erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis [ 17 ], acute generalized exanthematous pustulosis [ 18 ], contact and photocontact dermatitis [ 19 , 20 ].
Pneumonitis [ 21 ]. Aseptic meningitis [ 22 ]. Nephritis [ 23 ]. Pathogenesis Since NSAID hypersensitivity has multiple clinical manifestations, the mechanisms incriminated in each of them are different. Diagnosis The information on symptoms and exposure to NSAIDs is of paramount importance to determine the temporal relationship between the initiation of the clinical picture and the probability of a drug etiology.
Table 2 Oral provocation tests with acetylsalicylic acid ASA. Group Drugs Salicylic acid derivatives Aspirin, sodium salicylate, choline magnesium trysalicylate, salsalate, diflunisal, salicilsalicylic acid, sulfasalazine, olsalazine Para-aminophenol derivatives Acetaminophen Indol and indene acetic acids Indomethacin, sulindac, etodolac Heteroaryl acetic acid Tolmetin, diclofenac, ketorolac Arilpropionic acid Ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin Antranilic acid fenamates Mefenamic acid, meclofenamic acid Enolic acid Oxicams piroxicam, tenoxicam , pyrazoledinediones fenilbutazone, oxyfentathrazone Alkanones Nabumetone Pyrazolic derivatives Antipyrin, aminopyrin, dipyrone.
Conclusions NSAIDs constitute a frequent cause of adverse reactions to drugs that can be clinically manifested in multiple forms. Do cyclooxygenase-2 inhibitors provide benefits similar to those of traditional nonsteroidal antiinflammatory drugs, with less gastrointestinal toxicity? Coxibs and cardiovascular disease. Revised nomenclature for allergy for global use: Multiple NSAID intolerance in chronic idiopathic urticaria is correlated with delayed, pronounced and prolonged autoreactivity.
Reactions to aspirin and food additives in patients with chronic urticaria, including the physical urticarias. A review of cases. Atopy is a risk factor for nonsteroidal anti-inflammatory drug sensitivity. The effect of indication on hypersensitivity reactions associated with zomepirac sodium and other nonsteroidal anti-inflammatory drugs. Genetic markers for differentiating aspirin-hypersensitivity.
Challenge-based clinical patterns of Spanish patients with nonsteroidal anti-inflammatory-drug-induced-reactions. Intolerance to nonsteroidal antiinflammatory drugs: The AC polymorphism in the leukotriene C4 synthase gene is associated with aspirin-induced urticaria. Risk of skin reactions when using ibuprofen-based medicines. Current causes of fixed drug eruption in the UK.
The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with nonsteroidal anti-inflammatory drugs: Acute generalized exanthematous pustulosis. Analysis of 63 cases.