Genetic Risk Factors and Immunopathogenesis of Antimicrobial-Induced Severe Cutaneous Adverse Reactions

Abstract

Adverse reactions to drugs are a threat to individual safety and quality of life. Two of the severest reactions, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), are the consequences of aberrant immune responses. Patients with SJS/TEN develop a painful, blistering rash that results in separation and death of the upper skin layer often leading to serious infections and long-term effects such as blindness. DRESS presents with rash, fever, white blood cell abnormalities, organ failure and long-term immune abnormalities. Nevirapine and vancomycin are commonly used to treat life-threatening infections due to HIV and bacteria, respectively, and are known to cause both DRESS and SJS/TEN. A targeted approach examined variation in HLA genes that encode proteins that present foreign peptides on the surface of cells to stimulate an immune response. HLA-C*04:01 was identified as a necessary risk factor for nevirapine-induced SJS/TEN in a South African patient cohort and HLA-A*32:01 was strongly associated with the development of vancomycin-induced DRESS in a population of predominately European ancestry. For nevirapine and vancomycin SJS/TEN, cutting-edge techniques were used to profile the specific molecular and cellular signatures of individual cells at the site of tissue damage. These discoveries have the potential for direct translation to both scientific and clinical practice to understand, predict and prevent serious immune-mediated adverse drug reactions and to improve drug safety and patient outcomes.