D1.308 - Severe Chronic Spontaneous Urticaria with Recurrent Anaphylaxis and Extreme IgE Elevation Associated with Innate Immune Dysregulation

Chronic spontaneous urticaria (CSU) associated with recurrent anaphylaxis and extreme IgE elevation represents a significant diagnostic challenge, particularly when mast cell disorders and monogenic autoinflammatory diseases are excluded. Increasing evidence suggests that alterations in innate immune pathways may modify allergic disease phenotypes and contribute to severe, complex clinical presentations.

We report a 29-year-old female with a five-year history of severe CSU refractory to high-dose antihistamines, complicated by recurrent angioedema, laryngeal edema and confirmed food-induced anaphylaxis. An extensive immunological and genetic evaluation was undertaken, including autoimmune screening, complement assessment, serum tryptase measurement, and whole-exome sequencing, to exclude mast cell disorders and monogenic autoinflammatory diseases.

The patient demonstrated markedly elevated total IgE levels (>2500 kU/L), positive antinuclear antibodies, and normal IgG, IgM, CH50 and serum tryptase levels. Whole-exome sequencing excluded mastocytosis and monogenic autoinflammatory conditions. Genetic analysis identified a heterozygous MBL2 variant (p.Arg52Cys), previously associated with reduced mannose-binding lectin functional activity and increased susceptibility to infections. Clinically, the phenotype was characterized by asthma, recurrent food-induced anaphylaxis, and recurrent fungal vaginitis, supporting an underlying innate immune dysfunction. Treatment with omalizumab resulted in significant improvement in urticaria activity and a reduction in anaphylactic episodes.

This case describes a complex immuno-allergic phenotype in which severe CSU with recurrent anaphylaxis and extreme IgE elevation reflects broader immune dysregulation rather than isolated mast cell pathology. A functionally relevant MBL2 variant may act as a disease modifier, contributing to infection susceptibility and amplification of allergic manifestations. Recognition of innate immune modifiers in similar clinical presentations may refine diagnostic evaluation and support individualized biologic treatment strategies.