Novel insights into molecular and cellular aspects of delayed drug hypersensitivity reactions

ABSTRACT

Introduction

Delayed drug hypersensitivity reactions (DDHRs) represent a major health problem. They are unpredictable and can cause life-long disability or even death. The pathophysiology of DDHRs is complicated, multifactorial, and not well understood mainly due to the lack of validated animal models or in vitro systems. The role of the immune system is well demonstrated but its exact pathophysiology still a matter of debate.

Area covered

This review summarizes the current understanding of DDHRs pathophysiology and abridges the available new evidence supporting each hypothesis. A comprehensive literature search for relevant publications was performed using PubMed, Google Scholar, and Medline databases with no date restrictions and focusing on the most recent 10 years.

Expert opinion

Although multiple milestones have been achieved in our understanding of DDHRs pathophysiology as a result of the development of useful experimental models, many questions are yet to be fully answered. A deeper understanding of the mechanistic basis of DDHRs would not only facilitate the development of robust and reliable diagnostic assays for diagnosis, but would also inform therapy by providing specific target(s) for immunomodulation and potentially permit pre-therapeutic risk assessment to pursue the common goal of safe and effective drug therapy.

KEYWORDS:

• Drug hypersensitivity reaction
• drug allergy
• adverse drug reactions
• idiosyncratic drug reaction
• drug safety
• pathophysiology

Article highlights

• Delayed drug hypersensitivity reactions (DDHRs) are type of adverse drug reactions that are unpredictable and can be severe or even fatal.

• These reactions are known to be mediated by the immune system, but their exact pathophysiology is not well elucidated.

• Understanding their pathophysiology is essential for prediction, diagnosis, and better management of these reactions.

• It is now evident that DDHRs are multifactorial events with complicated and overlapping underlying pathophysiology pathways.

• This review discusses different hypotheses and the most recent findings in the pathophysiology of DDHRs.

• A novel hypothesis, ‘the cross-reactivity model’ is introduced and relevant available evidence is discussed.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.