Drug Hypersensitivity reactions (DHRs) - either Immediate or Delayed – are among the most feared adverse effects of drug therapy. While DHRs are perhaps one-sixth of all ADRs, they are among the most problematic given that they are unpredictable, often severe and are major disruptors of therapy both currently and in the future. A key problem with addressing DHRs is the lack of a clear understanding of their pathophysiology, which appears quitomplex. The immune system in a clearly a key mediator of DHRs, but while IgE has been identified as a core element in the pathophysiology of immediate DHRs, much less is known for delayed DHRs. The classical hypotheses for the pathophysiology are the Hapten Hypothesis, the Pharmacologic Interference Hypothesis and the Danger Hypothesis. More recently the Altered Peptide Repertoire Hypothesis has been suggested. Recent work demonstrating the potential contributions of viral infection and inflammasome activation have led us to propose the Cross-Reactivity Hypothesis as a unifying platform bring the hypotheses together and to help understand potential role(s) other factors in the dysregulated immune activation resulting in delayed DHRs. Hence delayed DHRs may begin with metabolism of the drug to a reactive metabolite with haptenation and activation of the immune system not as a solitary players but rather as part of a proinflammatory milieu driven by pathogen or danger signals. There is an urgent need for research to better define the pathophysiology of delayed DHRs to inform best approaches to diagnose, treat and ideally prevent these serious ADRs.
