Severe cold urticaria can point to an underlying clonal mast cell disorder

Gain-of-function mutations of KIT, most frequently D816V, cause clonal mast cell disorders (CMCD) and drive severe anaphylaxis in patients with systemic mastocytosis (SM). The connection between CMCD and chronic inducible urticaria (CIndU) has not been investigated before. Cold urticaria (ColdU) is characterized by the appearance of wheals and/or angioedema in response to body cooling and rewarming. In cold-induced anaphylaxis (ColdA), there is a sudden cold-induced onset of at least two of the following: (a) involvement of the skin and/or mucosal tissue, (b) respiratory involvement, (c) reduced blood pressure or associated symptoms, or (d) gastrointestinal symptoms. Clinical presentations of ColdU depend on the potency and duration of exposure to different cold triggers (air, fluids, surfaces), individual cold sensitivity thresholds and other yet to be defined factors. The diagnosis of ColdU relies on the patient's history and positive cold stimulation testing (CST) with an ice cube and/or TempTest® or other less commonly used methods. Critical temperature threshold (CTT) is the highest TempTest® temperature, and the critical stimulation time threshold (CSTT) is the shortest time required to induce a wheal in CST.1 Here, we describe detailed characteristics of a 65-year-old female patient who presented with a 19-year history of ColdU with increasing severity two years before evaluation and compare them to characteristics of 35 other subsequent ColdU patients comprehensively evaluated at the Urticaria Center of Reference and Excellence (UCARE) at the University Clinic Golnik.2 The following data indicated a severe ColdU (Table 1): (a) wheals induced by air temperatures of 24°C or lower, (b) an unusual 5-minute episode of dyspnea after drinking cold water, and (c) high disease activity with a 30-second CSTT and a 28°C CTT, with ice cube- and TempTest®-induced pseudopodial whealing, and whealing beyond the TempTest®-stimulated skin area (Figure 1A,B). Because these findings pointed to unusually severe ColdU as compared to 35 control ColdU patients (Table 1), we determined the patient's basal serum tryptase levels, which were elevated twice in a four-month period (17.3, 23.0 ng/mL). An underlying CMCD was suspected and confirmed by a positive KIT D816 V mutation test in circulating blood leukocytes (1.0% mutational burden) and in the bone marrow. No cytomorphological features of SM were found in the bone marrow. The diagnosis of SM is established if: (a) at least a major and one minor or (b) three minor criteria defined by the World Health Organization are fulfilled.3 Our patient did not meet these criteria. Since she presented with symptoms of mast cell activation, the KIT D816V mutation and lacked signs of cutaneous mastocytosis, she was diagnosed with a monoclonal mast cell activation syndrome (MMAS).4 MMAS has not been previously described in patients with ColdU, probably because they are hardly ever assessed for a CMCD. Our findings suggest that severe reactivity to cold triggers, in patients with ColdU, can point to comorbid MMAS and the possibility that MMAS is a risk factor for severe reactions. Our patient's reaction to drinking cold water, a single, short-lived episode of dyspnea with spontaneous resolution, may have been ColdA or, more likely, a severe local response. Screening CIndU patients with severe disease for an elevated tryptase and the presence of the KIT D816V mutation could help to clarify the rates and role of activating KIT mutations as a potential driver for severe reactions. It could also improve our approach to the management and treatment of patients with severe KIT D816V-positive ColdU, for example, by the use of selective tyrosine-kinase inhibitors, such as avapritinib or other KIT-targeting therapies, and of omalizumab, which has been shown to benefit patients with CIndU and effectively prevent anaphylaxis in patients with MMAS and SM.5, 6 The authors thank Dr. Matija Rijavec and other members of the Clinic Golnik Laboratory for Clinical Immunology and Molecular Genetics for their kind cooperation in performing laboratory tests. Open access funding enabled and organized by Projekt DEAL. [Correction added on 04 August 2021, after first online and print publication, the Funding statement line has been added] MB has been a speaker and an advisor for Novartis. MM is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, MSD, Novartis, Roche, Sanofi/Regeneron, Third HarmonicBio, UCB, and Uriach. MK, DTM, SZ, and TB have nothing to disclose. FS reports non-financial support from Allakos, grants and personal fees from Bluprint, grants and personal fees from Novartis, personal fees from Sanofi-Aventis, outside the submitted work. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.