Subtypes of Atypical Cold Urticaria and Recommendations for Their Diagnostic Workup

Background: A substantial subset of patients suffering from cold urticaria (ColdU) have atypical disease presentations and develop cold-induced wheals and/or angioedema in a real-world setting but not in response to standard cold stimulation tests. How to diagnose atypical ColdU is largely unclear, and little is known about the clinical features and treatment responses. Objective: The aim of the study was to describe subtypes of atypical ColdU and provide recommendations for the diagnostic workup. Methods: We conducted a comprehensive literature search on subtypes of atypical ColdU and published testing procedures. We then developed and pilot-tested modified cold stimulation tests (mCSTs) for 8 subtypes of atypical ColdU. Results: Our systematic review identified 10 subtypes of atypical ColdU—delayed ColdU, ColdU with aberrant wheals, extended exposure ColdU, generalized exposure ColdU, localized ColdU, cold-induced cholinergic urticaria, cold-dependent dermographism, water-dependent ColdU, food-dependent ColdU, and ultra-freeze ColdU. Pilot-testing of protocols for diagnostic mCSTs was successful in 8 of 8 variants. Based on these results, we generated recommendations for the diagnostic workup of known subtypes of atypical ColdU. Conclusions: The mCSTs provide a more precise diagnostic confirmation in patients with suspected atypical ColdU and allow effective monitoring throughout the disease course, facilitating access to specific therapy options, and ultimately leading to improved care for this patient population.