The differential diagnosis of adverse reactions to non-steroidal anti-inflammatory drugs In vitro and in vivo methods

Introduction: According to the present knowledge, the effect of non-steroidal anti-inflammatory drugs (NSAIDs) depends on the inhibitory ratio of cyclooxigenase (COX)-1 to COX-2 in the plasma membranes. In addition to cardiovascular and gastrointestinal side effects, there are adverse symptoms which can be divided into cross-intolerance (non-immune mediated) and single or multiple hypersensitive (immune mediated) reactions. Due to clinical phenotypes and to in vivo aspirin reactivity, adverse effects could be further classified. Aim: The aim of these studies was a comparison of hit ratios obtained by a humoral serum test measuring specific immunglobulin E (IgE) against a rapid cellular test measuring interleukin (IL)-6 release from sensitized mononuclear cells due to various suspect NSAID after symptoms within one year. Retrospective case studies were performed in in- and out-patients of our teaching hospital in Budapest, between 2003 and 2013. Method: Specific anti-NSAID IgE levels were determined by ELISA in 55 cases. The other matching group of patients consisted of 51 patients and 9 tolerant persons. Their separated cells' supernatants were checked for IL-6 release incubated for 20 minutes by NSAID dilutions including intraassay controls by two-step ELISA assay. Both groups have been stratified according to "new" clinical classification. Results: Results have disclosed no significant differences among the distribution of clinical symptoms between the two groups. In both groups, 9 non-steroidal anti-inflammatory drugs were tested representing all frequently used compounds with COX-1 inhibitory potential. The overall positivity rate was nearly double (65.4% against 36.9%) within the group using IL-6 release assay against that with specific IgE as the diagnostic tool. In certain cases, non-drug components of commercial preparations prompted IL-6 release as well which was paralleled by in vivo test results. Positive in vitro tests were obtained in both groups with clinically cross-intolerant as well as single or multiple sensitized cases. Conclusion: The rates of single or multiple sensitized cases exceeded in both groups that of cross-intolerant patients. In some phenotypes belonging to the latter categories, IgE type antibodies against acetylsalicylic acid could be detected as well. IL-6 release assay was the more sensitive test. In addition to pure drugs, other ingredients of medicines could also be responsible for adverse events.