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.