Immune mediation of hypersensitivity adverse drug reactions: implications for therapy

Adverse drug reactions are among the top causes of death in the developed world, and among the spectrum of adverse drug reactions, drug hypersensitivity is a principal contributor to serious adverse drug events. The pathophysiology of drug hypersensitivity remains incompletely understood, but seems to involve the initial recognition of a drug or metabolite by the immune system followed by an immune response that determines the clinical manifestations. At present, there are two competing theories for how immune recognition occurs: the Hapten Hypothesis in which drug hapten-carrier association is the key driver for immune recognition and the Pharmacological Interference Concept that postulates direct recognition of drugs by low affinity association with the T cell receptor. The Danger Hypothesis provides a potentially important addition to the Hapten Hypothesis. Therapy for drug hypersensitivity has traditionally involved excellent supportive care. Although corticosteroids and intravenous immunoglobulin have both been used as immunomodulatory therapy, there is no robust evidence supporting the efficacy of their therapy for drug hypersensitivity. Recent advances in molecular biology and genomic pharmacology offer previously unappreciated opportunities to clarify the controversies surrounding drug hypersensitivity and to better diagnose, treat and, it is hoped, prevent drug hypersensitivity in the future.