In Vitro Diagnosis of Hypersensitivity to Nonsteroidal Anti-Inflammatory Drugs (NSAID) Comparison of Two Methods

Abstract

Objective: Current concept distinguishes between cross intolerance (non-immune) and single or multiple hypersensitivity based (immune) adverse reactions of non-steroidal anti-inflammatory drugs (NSAID) due to their potential to inhibit cyclooxygenase (COX) isoenzymes (COX-1, COX-2). Recently we described a rapid IL-6 release assay using blood mononuclear cells of patients with various clinical forms of drug hypersensitivity. Here we present data of a comprehensive analysis of the IL-6 release test and the classical IgE immuno-assay for their sensitivity in cases with adverse reactions to NSAIDs grouped according to the new clinical classification. Methods: Total and specific serum IgE against 9 different HSA coupled-NSAIDs were determined by manual ELISA tests (55 cases) and compared to drug-specific release from preformed IL-6 pool of PBMCs of patients sensitized to the same NSAIDs after short (20 ') incubation of 4 standardized concentrations (51 cases and 9 controls) and IL-6 measurement from their cell free supernatants including positive and negative intraassay controls. Results: The ratio of cross intolerant to specific hypersensitive (HS) cases was higher in the IgE group (and total IgE too,) than in the IL-6 release tested ones. There was no difference, however, in the overall ratio of early and accelerated plus late onset adverse events based on individual histories. Nine NSAIDs were tested in both groups which represented all major COX-1 inhibitors. The positivity of validated test results was double within the IL-6 tested group (65.4% vs. 36.9%). In some cases non-drug components of NSAID formulations were responsible for the observed (mainly) anaphylactic reactions. Positive results in both groups were scattered amongst cross intolerant and single to multiple hypersensitive (HS) subgroups. To our knowledge no comprehensive analysis had been performed before either on clinical phenotypes dependent IgE immunoassays or on NSAID-induced "early" Tcell activation after those specified adverse events. Conclusion: Specific HS and multiple non cross-reactive NSAID sensitizations exceeded non-immune reactions in both in vitro tested groups. Some intolerant patients revealed detectable ASA antibodies of IgE type. Preformed IL-6 release by PBMC was more sensitive than specific IgE immunoassays as an in vitro diagnostic tool. The results indicate that checking of non-drug components should be considered in allergy workups. ASA in vivo provocations need further standardization.