Non-steroidal anti-inflammatory drug hypersensitivity: association with elevated basal serum tryptase?

Anaphylaxis is defined as a systemic hypersensitivity reaction, which can be sub-classified as allergic anaphylaxis when the reaction is mediated by an immune mechanism, or non-allergic anaphylaxis induced by non-immunologic triggers (formerly called anaphylactoid reaction)[1]. Non-steroidal anti-inflammatory drugs (NSAID) are the most common causes of non-allergic drug-induced systemic hypersensitivity reactions[2]. In the pathogenesis of non-allergic anaphylactic reactions, mast cell activation, complement system activation, inhibition of cyclooxygenase 1, up-regulation of endothelial cell-active mediators, and specific enzyme defects are discussed[3, 4].

Mastocytosis comprises a heterogeneous disease spectrum with increased mast cell burden mainly in skin and bone marrow. Less frequently, involvement of the gastrointestinal tract, lymph nodes, spleen, and liver occur. Anaphylaxis symptoms may develop due to liberation of mast cell mediators whereas chronic organ dysfunction is caused by progressive tissue infiltration with mast cells. Known non-immunologic trigger factors for liberation of mast cell mediators are specific physical stimuli (such as skin rubbing, heat or physical exercise) and certain drugs[5]. While some observations suggest a possible increase of risk and severity for non-allergic systemic hypersensitivity induced by NSAID in mastocytosis patients, confirmatory data is sparse[6]. Nevertheless, NSAID are still considered as triggering anaphylactic reactions in patients with mast cell disease, probably because this group of compounds accounts for most non-allergic hypersensitivity reactions overall.

Aim of this retrospective analysis was to evaluate the relevance of basal serum tryptase measurement in patients with NSAID hypersensitivity reactions using a cohort of clinically and diagnostically well-defined patients. Basal serum tryptase values and grade of anaphylaxis were compared with a cohort of patients suffering from hymenoptera venom allergy.

In hymenoptera venom allergic subjects, raised baseline serum tryptase levels (obtained at least 1 week after resolution of the clinical signs) have been identified as a substantial risk factor for more severe anaphylaxis[5, 16‐18]. In accordance to these data, our group of hymenoptera venom allergic patients included a significant number with a history of severe anaphylactic reactions to hymenoptera stings and concomitantly elevated tryptase levels of > 20 ng/mL.

In contrast to immune-mediated allergy, the most important triggers of non-allergic drug-induced hypersensitivity are NSAID. The clinical symptoms of these reactions may closely mimic IgE-mediated mild to moderate anaphylaxis and mast cell degranulation has been demonstrated in IgE-mediated reactions as well as in non-allergic drug-induced hypersensitivity[3, 19]. Together with a generally increased risk for anaphylaxis in patients with mastocytosis[3, 4, 11], and because of individual cases reporting about severe non-allergic drug hypersensitivity reactions in these patients, it has been concluded that mastocytosis patients may be predisposed for NSAID-induced reactions[6]. In our clinically well-defined cohort of patients with non-allergic NSAID hypersensitivity, elevated basal serum tryptase levels were found only in a small number of cases and elevated tryptase levels seemed to be not associated with more severe reactions. In contrast to hymenoptera venom allergic patients, baseline serum tryptase levels in our NSAID hypersensitive subjects did not differ from those published in a general adult population (mean 5.6 ng/mL)[20].

Up to date there have been a limited number of studies focusing on the association of mastocytosis and non-allergic drug hypersensitivity. In an Italian study, 7 out of 86 patients (8.1%) were identified with an elevated baseline serum tryptase of > 11.4 ng/mL, ranging from 13.2 to 26.9 ng/mL[17]. The incriminated drugs included acetylsalicylic acid (2x), β-lactam antibiotics (2x), chloramphenicol, radio contrast medium, and chlorhexidine, respectively. In this study, only one patient was diagnosed with indolent systemic mastocytosis. Another study identified in a cohort of 83 mastocytosis patients 16 (19.3%) individuals with a history of drug-induced anaphylaxis. The incriminated drugs in this study were β-lactam antibiotics (4x), fosfomycin, NSAID (4x), codeine, mepivacaine, and rocuronium and in 4 patients hypersensitivity reactions could not be attributed to a single identifiable drug[21]. In our cohort of 284 NSAID hypersensitive patients we identified 26 who showed basal serum tryptase levels of > 10 ng/mL. It was hypothesized that systemic hypersensitivity reactions in patients with mastocytosis tend to be more severe. We were not able to confirm this hypothesis because only 2 of 6 patients with serum tryptase levels of > 20 ng/mL had moderate (grade 2) anaphylaxis not requiring adrenaline, while the remaining 4 patients experienced merely symptoms of urticaria and angioedema.

The pathogenesis of NSAID-induced non-allergic hypersensitivity is believed to be related to cyclooxgenase 1 inhibition resulting in activation of mediator release from inflammatory cells in the skin and not to an IgE-mediated allergy[22]. Although the exact role of mast cells and histamine is still not clear, a predisposition for drug-induced non-allergic hypersensitivity has been postulated for mastocytosis patients. This resulted in recommendations to avoid NSAID in patients with confirmed mastocytosis. In cases of medical necessity, pre-treatment with H₁-antihistamines and corticosteroids or graded challenges should be performed. However, our and the limited data in the literature failed to demonstrate a high risk for mast cell disease in patients with non-allergic NSAID hypersensitivity. Furthermore, the severity of hypersensitivity reactions was not increased in those patients with elevated basal tryptase levels with or without confirmed mastocytosis, suggesting that the recommendation to avoid NSAID may be not necessary.

While the association of mastocytosis and hymenoptera venom allergy has been confirmed in several studies, the role of drugs as triggers for anaphylaxis in patients with mast cell disease is still unclear. In our patients with non-allergic hypersensitivity reactions to NSAID basal tryptase levels appear not to be elevated and increased levels were not associated with a stronger severity of clinical reactions.