Hypersensitivity Reactions Caused by Nonsteroidal Anti-Inflammatory Drugs
Introduction
The frequent and widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs) is inevitably associated with a high incidence of adverse reactions. This group of medications is one of the most common causes of adverse drug reactions. The spectrum of these reactions is extremely broad, ranging from localized skin rashes and stomach pain to severe anaphylactic reactions. Although these reactions are well known and the mechanisms underlying most of them are understood or presumed, challenges related to diagnosis and patient management remain. This article presents the classification of NSAID-induced hypersensitivity reactions and the principles of diagnosis and patient management.
Approximately 80% of adverse reactions result from the pharmacological effects of the drug, are predictable, and are classified as type A reactions. They may occur in any patient treated with NSAIDs, particularly when high or higher-than-recommended cumulative doses are used. Such NSAID-induced adverse reactions are most commonly associated with the gastrointestinal tract, including gastric and abdominal pain. Patients receiving regular aspirin therapy may experience bleeding and hearing impairment. NSAIDs are also associated with drug-induced renal dysfunction resulting from afferent arteriolar vasoconstriction and a reduced glomerular filtration rate (1, 3).
Type B reactions are hypersensitivity reactions that, unlike type A reactions, occur only in certain susceptible individuals. These patients repeatedly react to a drug dose that is normally tolerated by other people. Moreover, even a small dose may be sufficient to trigger an adverse reaction. The mechanism underlying most NSAID-induced reactions is non-immunological and is associated with cyclooxygenase-1 (COX-1) inhibition, which causes activation of inflammatory cells and the release of mediators. Non-allergic hypersensitivity reactions were previously referred to as pseudoallergic or idiosyncratic reactions, but these terms should no longer be used. Among outpatients referred for an allergist consultation because of suspected drug allergy, NSAIDs account for approximately 29% of cases and are second only to antibiotics in frequency (4). When an immunological mechanism has been demonstrated, the reactions are classified as allergic.
The current classification of NSAID-induced adverse reactions recommended by the European Academy of Allergy and Clinical Immunology is presented in Figure 1 (2, 5). Applying this classification in clinical practice makes it possible to identify the mechanism of hypersensitivity and may determine recommendations for an individual patient. Hypersensitivity reactions may present with various symptoms, including respiratory, cutaneous, anaphylactic, or organ-specific manifestations, and may occur at different times after drug administration. They are divided into cross-reactive reactions, which are induced by several chemically unrelated NSAIDs, and selective reactions, in which the patient reacts to only one drug. In the latter case, a reaction may also occur to another drug with a very similar chemical structure. Cross-reactive reactions are associated with COX-1 inhibition, whereas selective reactions are immunological. Selective reactions may be immediate and IgE-dependent or delayed and mediated by drug-specific T lymphocytes. This article focuses primarily on immediate type B reactions (5).
Clinical assessment, diagnosis, and recommendations for the patient are possible only after understanding the pathophysiological mechanism responsible for the previous reaction.
Pharmacological Mechanism of NSAID-Induced Hypersensitivity Reactions
The mechanism of action of NSAIDs was discovered by J. Vane in 1971, when it was demonstrated that these drugs share the ability to inhibit prostaglandin synthesis (6). It was later established that NSAIDs inhibit COX, which exists in two forms: COX-1 and COX-2. COX-1 is continuously expressed by most cells and is responsible for the synthesis, from arachidonic acid, of prostanoids such as prostacyclin, which maintain normal renal function, platelet aggregation, and the integrity of the gastric mucosa (7). COX-2 activity is normally low but increases substantially during inflammation or cellular activation.
In 1975, Szczeklik and colleagues described that some NSAID-induced respiratory or cutaneous reactions are specifically associated with this pharmacological effect of the drug, which also explains the high frequency of cross-reactive reactions (8). NSAIDs differ in their ability to inhibit COX-1 and/or COX-2, which explains not only differences in their clinical efficacy but also their differing potential to cause adverse reactions, including hypersensitivity reactions (9). Aspirin and most conventional NSAIDs, such as indomethacin, naproxen, and diclofenac, inhibit both COX-1 and COX-2. This non-selective effect disrupts the production of protective prostaglandins and results in frequent gastrointestinal adverse effects.
Products of the COX-1 enzyme stimulate platelet aggregation and activation and the activity of thromboxane and prostaglandin E2. When the COX-1 pathway is blocked, prostaglandin E2 no longer inhibits 5-lipoxygenase and the lipoxygenase-activating peptide, resulting in uncontrolled synthesis of leukotrienes B4, C4, and E4. This altered arachidonic acid metabolism is responsible for NSAID-induced hypersensitivity reactions, including urticaria, angioedema, and respiratory symptoms. Newer agents preferentially inhibit COX-2, such as nimesulide or meloxicam, or act selectively, such as celecoxib, thereby strongly suppressing inflammatory processes while having only a limited effect on the production of protective prostanoids.
Cross-Reactive Hypersensitivity Reactions
NSAID-Exacerbated Respiratory Disease
NSAID-exacerbated respiratory disease (NERD) is the most common form of NSAID hypersensitivity. This condition was previously referred to as aspirin-induced bronchial asthma, Vidal syndrome, or Samter’s triad. It is a distinct inflammatory syndrome affecting both the upper and lower respiratory tract. It is characterized by bronchial asthma, recurrent polypoid ethmoiditis, and exacerbation of respiratory symptoms following the use of aspirin or other COX-1 inhibitors.
This condition is usually diagnosed in the third or fourth decade of life. Patients often experience symptoms of chronic rhinosinusitis for 1–5 years before the development of asthma. This condition occurs in approximately 10–20% of patients with asthma (10). Symptoms develop within 30–180 minutes after taking the drug. They usually begin with nasal congestion and/or rhinorrhea, followed by wheezing, coughing, and dyspnea. In patients with unstable asthma, symptoms may develop much more rapidly, and the resulting reaction may be fatal (11). Some patients also experience flushing, urticaria, and/or gastrointestinal symptoms (12). The timing and severity of the reaction are dose-dependent, and the provocative dose ranges from 10 to 300 mg of aspirin, although 60 mg is usually sufficient to provoke symptoms (13).
Alcohol has also been observed to provoke respiratory symptoms (15).
Symptoms of bronchial asthma or chronic rhinosinusitis occur in these patients even before an NSAID-induced reaction; however, in some patients, NSAID use may trigger the first asthma attack of their life and may mark the onset of the disease. Most patients with NERD have moderate or severe asthma. Severe asthma is diagnosed twice as frequently as in the general population, occurring in 15% of patients (16). NSAID hypersensitivity in patients with asthma is a risk factor for hospitalization and for very severe or even fatal exacerbations.
Chronic rhinosinusitis in NERD is often severe and complicated by the formation of polyps, which tend to recur rapidly after surgical treatment (17). The predominant symptoms are nasal congestion, facial pain, rhinorrhea, and postnasal drip. Partial or complete loss of smell is very common and may be considered a clinical marker that helps identify patients with NERD (18).
It should be noted that NSAID use is not the cause of this chronic disease but triggers its exacerbation, and the disease persists even when these medications are not used (14).
NERD is a non-immunological, cross-reactive hypersensitivity reaction; therefore, weak COX-1 inhibitors or selective COX-2 inhibitors are usually well tolerated (10).
Diagnosis. NERD is often diagnosed clinically, and an attentive physician can identify it relatively easily. In a patient with bronchial asthma and recurrent nasal polyps, at least 2 episodes of NSAID-induced respiratory symptoms, at least one of which occurred within the previous 5 years, are sufficient to establish a diagnosis of NERD. In clear cases, no tests are required to confirm the diagnosis. Additional but non-specific findings include eosinophilia in the blood and tissues, identified on histological examination of polyps, and rapid regrowth of nasal polyps after their removal (1).
In some cases, the patient’s medical history is insufficient. An oral aspirin challenge is considered the gold standard for diagnosing NSAID hypersensitivity because it reproduces natural exposure to the drug. At least 15% of patients with NERD are unaware of their NSAID intolerance until it is demonstrated by a provocation test (19). Bronchial asthma and polyps are relatively easy to diagnose, but identifying the third component may require more than simply asking whether the patient is allergic to NSAIDs. There may be several reasons for this:
- The patient has not used NSAIDs since the onset of respiratory disease.
- The patient has asthma and nasal polyps and has occasionally used NSAIDs but has not noticed any adverse reactions because:
- the reaction is pharmacologically blocked, for example, by the use of leukotriene receptor antagonists. These medications may reduce the severity of the reaction and should therefore be discontinued 7 days before the provocation test;
- some patients, particularly those with severe asthma and complete nasal obstruction, may simply fail to notice worsening symptoms and attribute them to the natural course of the disease.
- The patient has bronchial asthma and nasal polyps but takes a low dose of aspirin daily for the prevention of cardiovascular disease and tolerates it. In such patients, aspirin should be discontinued for at least 10 days before the provocation test. These patients generally have milder bronchial asthma (1).
