Introduction
Serum sickness (SS) is a type III immune-complex mediated reaction first described by von Pirquet and Schick in 1951 when they recognized reactions developed in susceptible individuals 8-12 days after receiving heterologous antisera for the treatment of diphtheria and scarlet fever1. It was later found that circulating immune complexes and complement activation is important in the pathophysiology of these immune-mediated reactions2,3. SS is characterized by fever, cutaneous eruptions, arthralgia and lymphadenopathy. Serum sickness-like reaction (SSLR) is clinically similar reaction associated with commonly used drugs including beta-lactam antibiotics (especially cefaclor), sulfonamides, fluoroquinolones, aromatic anticonvulsants, tetracyclines, metronidazole, bupropion and others 2,4-6. It is defined by rash (usually urticaria) and arthritis usually manifested 1-3 weeks after drug exposure, which can be accompanied by lymphadenopathy, eosinophilia and rarely renal involvement7. It is uncommonly seen in clinical practice, but its incidence appears to be on the rise since the introduction of biologic drugs8-10. It has been estimated that the incidence of SSLR associated with cefaclor was between 0.024% and 0.2% per course7.
The precise pathophysiology of drug-induced SSLR is not well understood. However, in delayed onset drug hypersensitivity the generation of cytotoxic reactive metabolites from drug molecules in vivo is believed to be the first step in a cascade of events leading to the immune-mediated reaction 11. These reactive metabolites are capable of adducting (hapenating) endogenous macromolecules produced an antigen recognized by the immune system as non-self. They may also cause local or systemic cell damage resulting in releasing ‘danger signals’, which prime immune cells to mount the reaction 12,13. Diagnosis of drug-induced SSLR is mainly based on clinical presentation and medication history and no reliable and safe diagnostic test is available to date. The lymphocyte toxicity assay (LTA) is an in vitro test that has been proven to have a significant value in the diagnosis of drug-induced hypersensitivity reactions (DHRs) but most of the validation work has been focused on type IV T-cell-mediated delayed DHRs. In this study we set to explore the potential role(s) of reactive drug metabolites in β-lactam antibiotic induced SSLR using a cohort of patients and healthy control volunteers.