Alpha-gal syndrome: challenges to understanding sensitization and clinical reactions to alpha-gal

Introduction The alpha-Gal syndrome (AGS) is a type of allergy characterized by an IgE antibody response against the carbohydrate Gal alpha 1-3Gal beta 1-4GlcNAc-R (alpha-Gal). Tick bites are recognized as the most important cause of anti-alpha-Gal IgE antibody increase in humans. Several risk factors have been associated with the development of AGS, but their integration into a standardized disease diagnosis has proven challenging. Areas covered Herein we discuss the current AGS diagnosis based on anti-alpha-Gal IgE titers and propose an algorithm that considers all co-factors in the clinical history of alpha-Gal-sensitized patients to be incorporated into the AGS diagnosis. The need for identification of host-derived gene markers and tick-derived proteins for the diagnosis of the AGS is also discussed. Expert opinion The current AGS diagnosis based on anti-alpha-Gal IgE titers has limitations because not all patients sensitized to alpha-Gal and with anti-alpha-Gal IgE antibodies higher than the cutoff (0.35 IU/ml) develop anaphylaxis to mammalian meat and AGS. The basophil activation test proposed to differentiate between patients with AGS and asymptomatic alpha-Gal sensitization cannot be easily implemented as a generalized clinical test. In coming years, the algorithm proposed here could be used in a mobile application for easier AGS diagnosis in the clinical practice.