Study Links Key Clinical Features, Biomarkers to Cold-Induced Anaphylaxis

A new study revealed a link between cold-induced anaphylaxis and new high-risk features, including typical cold urticaria, greater total immunoglobulin E (IgE) levels, and a greater prevalence of KIT p.D816V and hereditary α-tryptasemia (HαT).1

These data also confirmed a higher frequency of clinical features associated with cold-induced anaphylaxis previously reported by the large, multicenter COLD-CE study, including generalized wheals, skin angioedema, oropharyngeal/laryngeal manifestations, and itchy earlobes.

“To the best of our knowledge, this is the first study to systematically analyze [basal serum tryptase] levels, KIT p.D816V, HαT, and IgE levels in patients with [cold urticaria] and [cold-induced anaphylaxis],” wrote investigators, led by Mojca Bizjak, MD, PhD, from the University Clinic of Respiratory and Allergic Diseases Golnik in Slovenia. “Our findings provide new insights into the clinical and laboratory characteristics of these conditions.”

The mechanisms by which cold urticaria leads to cold-induced anaphylaxis remain unclear, as do the clinical features that could guide treatment. Investigators sought to assess basal serum tryptase and IgE levels in cold urticaria and cold-induced anaphylaxis, their associations with clinical features, and the utility of testing for the KIT p.D816V variant in blood leukocytes and heredity α-tryptasemia.2,3

The study included 92 adults with cold urticaria. Cold-induced anaphylaxis was defined as a reaction involving skin and/or mucosal tissue with ≥1 additional cardiovascular, respiratory, and gastrointestinal symptomatic manifestation. Investigators collected data on patient history, standard cold stimulation testing (sCST) using an ice cube and TempTest, and laboratory tests.1

Among the participants, 35.9% were diagnosed with cold-induced anaphylaxis. Based on sCST, approximately 52.2% cases of typical cold urticaria, 42.4% cases of cold urticaria with a negative test, and 5.4% cases of cold reflux urticaria were identified in the population.

Compared to typical cold urticaria, a negative sCST was linked to fewer instances of cold-induced anaphylaxis (P =.004), but more spontaneous wheals (P <.001). Patients with cold-induced anaphylaxis were more often to present generalized wheals (P =.047), skin angioedema (P =.007), oropharyngeal/laryngeal manifestations (P <.001), and itchy earlobes (P =.002) than patients with non-cold-induced anaphylaxis.

Increased basal serum tryptase (BST) levels (> 11.4 ng/mL) were attributed to KIT p.D816V or HαT in 9.8% of patients. Moreover, KIT p.D816V was detected in 6.6% of patients with cold urticaria and 6.3% of patients with cold-induced anaphylaxis.

Further analysis showed the prevalence of HαT was greater in patients with cold urticaria (10.9%; P =.041) and cold-induced anaphylaxis (15.2%; P =.038) than in the general population (estimated at 5.7%). Total IgE levels were significantly greater in patients with cold-induced anaphylaxis than those without cold-induced anaphylaxis (P = .021).

“Our findings demonstrate a higher prevalence of HαT and KIT p.D816V in cold urticaria and cold-induced anaphylaxis compared to the general population,” Bizjak and colleagues wrote. “These results raise the hypothesis that HαT and clonal MC disease may contribute to the pathogenesis of cold urticaria and cold-induced anaphylaxis in some patients. Additionally, elevated IgE levels could serve as a potential biomarker for cold-induced anaphylaxis.”

References

1. Bizjak M, Korošec P, Košnik M, et al. Cold-induced anaphylaxis: new insights into clinical and genetic characteristics. Front Immunol. 2025;16:1558284. Published 2025 Feb 21. doi:10.3389/fimmu.2025.1558284

2. Bizjak M, Košnik M, Dinevski D, et al. Risk factors for systemic reactions in typical cold urticaria: Results from the COLD-CE study. Allergy. 2022;77(7):2185-2199. doi:10.1111/all.15194

3. Prosty C, Gabrielli S, Le M, et al. Prevalence, Management, and Anaphylaxis Risk of Cold Urticaria: A Systematic Review and Meta-Analysis. J Allergy Clin Immunol Pract. 2022;10(2):586-596.e4. doi:10.1016/j.jaip.2021.10.012