D2.232 - Aquagenic Urticaria: High Atopic Comorbidity, Familial Aggregation, and Differential Water Reactivity

Aquagenic urticaria (AU) is a rare chronic inducible urticaria characterized by wheals following water contact irrespective of temperature . 

Approximately100 cases have been documented worldwide, and the contribution of atopy and genetic factors  remains poorly understood. This case series characterizes the clinical spectrum, familial aggregation, and biomarker profiles of five well-documented AU patients.

Five adults (3 females, 2 males; aged 21–48 years) underwent standardized water provocation using tap water and 3.5% saline at 35 °C for 30 minutes. Laboratory studies included complete blood count, serum IgE, tryptase, complement, and inflammatory markers during symptomatic phases and disease control. Treatments involved second-generation antihistamines (standard or up-dosed) or omalizumab 300 mg every four weeks.

All patients developed wheals within 5 minutes of water exposure without angioedema or systemic symptoms. Atopic comorbidity was 80% (4/5): allergic rhinitis 80%, asthma 60%, atopic dermatitis 60%. Concomitant physical urticarias occurred in 60%: cholinergic 40%, dermographism 40%, cold 20%; one patient had quadruple physical urticaria clustering. Familial cholinergic urticaria history was present in 40%, with all developing both conditions. Age of onset ranged 19-47 years. Water testing revealed three patterns: tap-only 40%, saline-only 20%, both-positive 40%. Mean IgE was 153.2±112.4 kU/L (range 22.1-307); 40% had eosinophilia >500/μL. Laboratory parameters remained stable between symptom onset and disease control. The patient failing antihistamines lacked atopy with eosinophils 20/μL, responding rapidly to omalizumab. Antihistamine responders (80%) achieved 30-minute water tolerance (Table 1).

This serie demonstrates high atopic comorbidity (80%), exceeding reported ranges and suggesting greater pathogenic significance than previously recognized. Familial aggregation wherein 40% had cholinergic urticaria-affected relatives with all developing both conditions could indicate shared genetic susceptibility warranting familial screening. Differential water reactivity patterns support distinct AU subtypes with different mechanisms. Absence of atopy with eosinophils <100/μL might predict antihistamine resistance, identifying early omalizumab candidates. Late-onset presentation (age 47) challenges traditional paradigms. Importantly, biomarker stability (IgE, eosinophils, tryptase) between onset and control represents constitutional trait markers reflecting predisposition rather than inflammatory activity. Antihistamines achieved 80% effectiveness; omalizumab controlled refractory disease. Our findings establish AU as heterogeneous, requiring individualized approaches based on atopic status, familial patterns, water reactivity subtypes, and biomarker profiles.