Seafood allergy comprises IgE-defined molecular sensitization endotypes associated with distinct clinical severity profiles

Seafood allergy is characterized by heterogeneous IgE sensitization to distinct molecular components, but the clinical relevance of these profiles remains incompletely defined. Multiplex molecular diagnostics may help identify molecular endotypes and refine risk stratification.

This study aimed to characterize IgE-defined molecular sensitization patterns to major seafood allergens and assess their associations with clinical reaction severity.

In this multicenter prospective study (January 2021 to December 2025), 8,040 consecutive patients screened with the ALEX² multiplex immunoassay were evaluated; 787 (9.8%) were sensitized to ≥1 seafood-derived molecule. Sensitization to parvalbumin, tropomyosin, Ani s 1, arginine kinase, and other muscle-related proteins was analyzed in relation to prospectively collected clinical phenotypes (mild, moderate, and severe). Venn analysis, principal component analysis, and unsupervised hierarchical clustering explored molecular patterns. Multivariable binary logistic regression models were fitted for each severity category versus all others, adjusting for age and sex. Associations are reported as odds ratios (ORs) with 95% CIs.

Tropomyosin (45%), arginine kinase (37%), parvalbumin (24%), and Ani s 1 (12%) were the most prevalent sensitizations and showed limited overlap, delineating largely distinct molecular profiles. Hierarchical clustering and 3-dimensional principal component analysis confirmed the separation of major components in multivariate space, with distinct loading patterns. In adjusted analyses, parvalbumin (adjusted odds ratio [OR_adj], 3.7) and Ani s 1 (OR_adj, 2.7) were associated with severe reactions, tropomyosin with moderate reactions (OR_adj, 2.0), and arginine kinase with mild phenotypes (OR_adj, 5.3).

Major seafood allergens define largely distinct and minimally overlapping sensitization patterns that are statistically associated with specific clinical phenotypes.