Mucosal angioedema involving the oropharynx signals severe cold urticaria: COLD-CE study insights

Abstract

Dear Editor, Cold urticaria manifests with a wide range of reaction severity, from localized wheals and cutaneous angioedema to cardiovascular, respiratory and gastrointestinal symptoms.1,2 Interestingly, not all individuals react to the ingestion of cold food or drinks.3,4 This clinical variability remains poorly understood, highlighting the need for better phenotyping in ColdU. Typical ColdU (ColdUT ) is diagnosed by whealing within 10min on skin exposed to a melting ice cube or the TempTest? device (either version 4.0 [TT4] with a 4-44?C gradient, or the older version 3.0 [TT3] with 12 fixed 4-26?C probes). The critical stimulation time threshold (CSTT) and critical temperature threshold (CTT) indicate the shortest exposure time and highest temperature needed to elicit a wheal.5 These parameters vary substantially among patients,5,6 and their associations are not yet fully understood. Magerl et al. reported a correlation between CTTs obtained via TT4 and TT3.7 This analysis expands on our previous COLD-CE study report,5 which identified oropharyngeal and laryngeal symptoms as risk factors for systemic reactions. In the present analysis, we define these symptoms as mucosal angioedema involving the oropharynx (MAO), characterized by a sensation of swelling of the tongue, pharynx or larynx and examine this phenotype in depth. A total of 535 patients with ColdUT were recruited from 2019 to 2025, including 123 additional patients enrolled after the first phase of the study. All underwent cold stimulation testing (CST) with an ice cube and/or TempTest?. Patients receiving omalizumab (n=55) at enrolment were included based on CST results obtained prior to treatment, and only their clinical histories were analyzed. Statistical analyses were performed using IBM SPSS V25.0, with a significance level set at p(0.05. Numerical variables were non-normally distributed and expressed as medians and interquartile ranges (IQR), while categorical variables were presented as counts and percentages. The Mann-Whitney and Fisher's exact tests were used for continuous and categorical variables, respectively. Correlations were assessed with Spearman's rho (r), interpreted as weak (0.10-0.29), moderate (0.30-0.50) or strong ()0.50).8 MAO triggered by ingestion of cold food or drinks was reported by 32.1% of patients and was significantly associated with generalized wheals (p(0.001), cutaneous angioedema (p(0.001) and systemic symptoms (cardiovascular: p(0.001; respiratory: p(0.001; gastrointestinal: p=0.001). MAO was also linked to a higher number of relevant cold triggers (p(0.001), including weaker stimuli like localized contact with cold liquids or surfaces (both p(0.001). Moreover, MAO patients had shorter CSTTs and higher CTTs measured with TT4 (both p(0.001), and reported greater quality-of-life impairment per the Dermatology Life Quality Index (DLQI)9 (Table 1). To our knowledge, this is the first demonstration that shorter CSTTs correlate with higher CTTs and