Risk factors for systemic reactions in typical cold urticaria: Results from the COLD-CE study.

BACKGROUND: Cold urticaria (ColdU), that is, the occurrence of wheals or angioedema in response to cold exposure, is classified into typical and atypical forms. The diagnosis of typical ColdU relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). We aimed to determine risk factors for ColdA in typical ColdU. METHODS: An international, cross-sectional study COLD-CE was carried out at 32 urticaria centers of reference and excellence (UCAREs). Detailed history was taken and CST with an ice cube and/or TempTest® performed. ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms. RESULTS: Of 551 ColdU patients, 75% (n = 412) had a positive CST and ColdA occurred in 37% (n = 151) of the latter. Cold-induced generalized wheals, angioedema, acral swelling, oropharyngeal/laryngeal symptoms, and itch of earlobes were identified as signs/symptoms of severe disease. ColdA was most commonly provoked by complete cold water immersion and ColdA caused by cold air was more common in countries with a warmer climate. Ten percent (n = 40) of typical ColdU patients had a concomitant chronic spontaneous urticaria (CSU). They had a lower frequency of ColdA than those without CSU (4% vs. 39%, p = .003). We identified the following risk factors for cardiovascular manifestations: previous systemic reaction to a Hymenoptera sting, angioedema, oropharyngeal/laryngeal symptoms, and itchy earlobes. CONCLUSION: ColdA is common in typical ColdU. High-risk patients require education about their condition and how to use an adrenaline autoinjector.

Adrenaline autoinjector is under-prescribed in typical cold urticaria patients living in tropical climate countries.

Background: The diagnosis of typical cold urticaria (ColdU) relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). Till date, it is largely unclear how often patients with ColdU receive adrenaline treatment and are provided with an adrenaline autoinjector (AAI). Methods: An international, cross-sectional study, COLD-CE (i.e., comprehensive evaluation of ColdU and other cold-induced reactions), was carried out at 32 UCAREs. Detailed histories were taken and CST with an ice cube and/or TempTest® performed. ColdA was defined as an acute cold-induced (i.e., by cold water, air, or surfaces) involvement of the skin and/or visible mucosal tissue and at least one of the symptoms (cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms). Results: Of the 551 ColdU patients, 75% (n = 412) had a positive CST. Of them, concomitant chronic spontaneous urticaria was diagnosed in 10%. Of 372 patients with stand-alone ColdU, 69% were women and 91% adults. Their median age was 36 (IQR 26 - 48) years. Patients were also categorized into residents of countries with a tropical (n = 33), temperate (n = 264), or cold (n = 75) climate (Table 1: R13C1, R17C1, R21C1). AAI was more often prescribed to residents of temperate than tropical countries (30% vs. 12%, p = .038; Table 1: R31C1), although the frequency of ColdA did not significantly differ between these countries (44% vs. 42%, p = 1.000; R29C2). Residents of tropical countries had a higher frequency of ColdA induced by cold air than residents of temperate (36% vs. 12%, p = .001; R29C4) or cold (36% vs. 12%, p = .007; R25C4) countries. Cardiovascular manifestations induced by cold air were diagnosed in 33% (n = 11) of residents of tropical countries, but only 18% (n = 2) and 36% (n = 4) of them had received adrenaline and AAI, respectively (R13 - 15C7). Furthermore, hypotension and/or loss of consciousness induced by cold air occurred in 18% (n = 6) of patients, but only 17% (n = 1) received adrenaline (R13 - 14C10). ColdA was induced by complete cold water immersion in 9% (n = 3) of patients, and none of them received adrenaline treatment nor AAI (R13 - 15C3). Conclusion: Our findings suggest that ColdA is undertreated and call for changes in ColdU management.

Cold urticaria - What we know and what we do not know.

Cold urticaria (ColdU) is a common form of chronic inducible urticaria characterized by the development of wheals, angioedema or both in response to cold exposure. Recent research and guideline updates have advanced our understanding and management of ColdU. Today, its pathophysiology is thought to involve the cold-induced formation of autoallergens and IgE to these autoallergens, which provoke a release of proinflammatory mediators from skin mast cells. The classification of ColdU includes typical and atypical subtypes. We know that cold-induced wheals usually develop on rewarming and resolve within an hour and that anaphylaxis can occur. The diagnosis relies on the patient's history and cold stimulation testing. Additional diagnostic work-up, including a search for underlying infections, should only be done if indicated by the patient's history. The management of ColdU includes cold avoidance, the regular use of nonsedating antihistamines and the off-label use of omalizumab. However, many questions regarding ColdU remain unanswered. Here, we review what is known about ColdU, and we present important unanswered questions on the epidemiology, underlying pathomechanisms, clinical heterogeneity and treatment outcomes. Our aim is to guide future efforts that will close these knowledge gaps and advance the management of ColdU.

A Rat Model of Post-Traumatic Stress Syndrome Causes Phenotype-Associated Morphological Changes and Hypofunction of the Adrenal Gland.

BACKGROUND: Rats exposed to chronic predator scent stress mimic the phenotype of complex post-traumatic stress disorder (PTSD) in humans, including altered adrenal morphology and function. High- and low-anxiety phenotypes have been described in rats exposed to predator scent stress (PSS). This study aimed to determine whether these high- and low-anxiety phenotypes correlate with changes in adrenal histomorphology and corticosteroid production. METHODS: Rats were exposed to PSS for ten days. Thirty days later, the rats' anxiety index (AI) was assessed with an elevated plus-maze test. Based on differences in AI, the rats were segregated into low- (AI ≤ 0.8, n = 9) and high- (AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone (CORT) concentrations were measured by ELISA. Adrenal CORT, desoxyCORT, and 11-dehydroCORT were measured by high-performance liquid chromatography. After staining with hematoxylin and eosin, adrenal histomorphometric changes were evaluated by measuring the thickness of the functional zones of the adrenal cortex. RESULTS: Decreased plasma CORT concentrations, as well as decreased adrenal CORT, desoxyCORT and 11-dehydroCORT concentrations, were observed in high- but not in low-anxiety phenotypes. These decreases were associated with increases in AI. PSS led to a significant decrease in the thickness of the zona fasciculata and an increase in the thickness of the zona intermedia. The increase in the thickness of the zona intermedia was more pronounced in low-anxiety than in high-anxiety rats. A decrease in the adrenal capsule thickness was observed only in low-anxiety rats. The nucleus diameter of cells in the zona fasciculata of high-anxiety rats was significantly smaller than that of control or low-anxiety rats. CONCLUSION: Phenotype-associated changes in adrenal function and histomorphology were observed in a rat model of complex post-traumatic stress disorder.

Comorbid Inducible Urticaria Is Linked to Non-Autoimmune Chronic Spontaneous Urticaria: CURE Insights.

BACKGROUND: Patients with chronic spontaneous urticaria (CSU) can have comorbid inducible urticaria (CIndU). How comorbid CIndU affects patients and their CSU is largely unclear. OBJECTIVE: To compare patients with CSU with and without comorbid CIndUs for differences in demographic features, clinical characteristics, and laboratory markers. METHODS: We analyzed 708 patients with CSU of our Urticaria Center of Reference and Excellence enrolled in CURE, the chronic urticaria registry. CURE data collected until October 2022 were used to compare patients with and without comorbid CIndU for their demographic characteristics, disease onset, activity, impact, and control, as well as concomitant allergic and autoimmune diseases and laboratory parameters associated with autoimmune CSU. RESULTS: Of 708 patients with CSU, 247 (35%) had comorbid CIndU. Compared with patients with standalone CSU, patients with CSU with comorbid CIndU were significantly younger, had earlier disease onset, longer disease duration, higher impact on quality of life, and a higher rate of concomitant allergic diseases. Moreover, patients with CSU with comorbid CIndU less often had features linked to autoimmune CSU such as angioedema, concomitant autoimmune diseases, eosinopenia, low levels of total IgE, and low total IgE combined with elevated anti-thyroid peroxidase IgG. CONCLUSIONS: Autoimmune CSU may be less common in patients with comorbid CIndU than without, and comorbid CIndU may point to autoallergic CSU.