Introduction
Cold urticaria is a form of physical urticaria characterized by the appearance of hives and/or angioedema following direct skin contact with cold air, liquids, or objects. Cold urticaria is second only to symptomatic dermographism among all types of physical urticaria. The urticarial rash usually appears within 2–5 min of exposure to cold and lasts for 1–2 h [1–3]. Symptoms are confined to the area that was exposed to cold. However, when a large area of skin is exposed to cold, generalized urticarial lesions and even anaphylactic shock may occur. Anaphylaxis can be life-threatening and may include symptoms such as headache, difficulty breathing, rapid heartbeat, low blood pressure, and loss of consciousness. Swimming in cold water is the most frequent trigger for a severe reaction of cold urticaria. Patients with cold urticaria should be particularly warned about the risk of fatal anaphylaxis triggered by swimming in cold water. Edema of the lips, pharynx and uvula may develop due to consumption of cold food or drink [1, 4–6].
Among physical urticarias, the prevalence of cold urticaria has been reported to range between 5.2% and 33.8%, depending on the geographical region, with higher rates observed in colder climates [7]. The pathophysiology of cold urticaria has not yet been fully elucidated, but immunoglobulin E (IgE)-mediated mast cell activation has been suggested as a possible cause. Cold urticaria is thought to occur as a result of the release of histamine, platelet activating factor, leukotrienes and other proinflammatory mediators from mast cells following skin contact with cold [1–3, 7].
The diagnosis of cold urticaria is made using the ice cube test. An ice cube is placed on the forearm for 5 min, followed by a 10-minute warming period. If redness and swelling occur at the site of ice application, the test result is considered positive. If no reaction occurs, the test is repeated on the other forearm. If the result remains negative, the test is considered negative [1, 8, 9].
Step therapy is recommended in the treatment of cold urticaria. The treatment begins with a non-sedating H1 antihistamine at its standard dosage. If symptoms are not controlled, the dose of the current antihistamine may be increased up to 4-fold before switching to a different antihistamine. Emergency kits containing adrenaline autoinjectors, oral corticosteroids, and antihistamines should be given to patients with a history of anaphylaxis or systemic reactions [10].
Material and methods
We analyzed electronic and record-based medical data from 45 patients with urticaria and/or anaphylaxis associated with cold exposure who were admitted to our Allergy and Clinical Immunology Outpatient Clinic between January 2021 and November 2024. Exclusion criteria included: being under 18 years of age, isolated chronic inducible urticaria (CIndU) other than cold urticaria, atopic dermatitis, and pregnancy. The diagnosis of typical cold urticaria was based on a history of urticaria and/or angioedema after natural cold exposure and a positive ice cube test. The ice cube test was performed as a cold stimulation test in all cases. In our center, the stimulation time during the standard ice cube test was 5 min and if the test was negative, the stimulation time was first increased to 10 min. Antihistamines were discontinued for at least 7 days before the test and no patient had used systemic corticosteroids, montelukast or omalizumab in the last 15 days before the test.
Clinical parameters, including age, gender, the presence of angioedema, drug allergy, and laboratory tests such as eosinophil count, IgE level, cryoglobulin testing, tryptase level, and mean platelet volume (MPV), were collected from patient files. The cases were divided into three groups according to the severity of symptoms, similar to the classification proposed by Wanderer et al.: Type 1, urticaria and/or angioedema at contact sites; Type 2, generalized urticaria and/or angioedema without other systemic symptoms; Type 3, other systemic reactions compatible with anaphylaxis [11]. In contrast to the classification proposed by Wanderer et al., the Type 3 cold urticaria group included all cases of anaphylaxis and not only cases accompanied by hypotension [11].
This study protocol was reviewed and approved by Van Training and Research Hospital ethical committee, approval number GOKAEK/2025-02-19. The study was conducted in accordance with the Declaration of Helsinki. Written informed consent form was obtained from the patients who participated in the study.
Statistical analysis
Statistical analysis was done using SPSS software (version 21.0 for Windows; SPSS Inc., Chicago, IL, USA). Parametric variables are presented as means with standard deviations, while categorical variables are expressed as frequencies and percentages. Confidence intervals were reported at 95%. P-values less than or equal to 0.05 were considered statistically significant.
Results
This study consisted of 36 (80%) females and 9 (20%) males and the mean ± standard deviation age was 35 ±14 years. Baseline demographic characteristics and median values for laboratory outcomes are presented in Table 1. A 5-minute ice cube test was performed in all patients. Since 6 (13.3%) patients had negative results, the test was repeated with a duration of 10 min.
Table 1
Baseline demographic, clinical, and laboratory features of patients with cold urticaria (n = 45)
[i] Data were displayed as median (IQR). Type 1, urticaria and/or angioedema at contact sites; type 2, generalized urticaria and/or angioedema without other systemic symptoms; type 3, other systemic reactions consistent with anaphylaxis [11]. SD – standard deviation, MPV – mean platelet volume, ESR – erythrocyte sedimentation rate, CRP – C- reactive protein, TSH – thyroid-stimulating hormone.
Regarding the severity of symptoms, type 1 was observed in 23 (51.2%) patients, type 2 in 20 (44.4%) patients, and type 3 in 2 (4.4%) patients. Systemic total frequency of reactions (type 2 and type 3) was detected in 48.8% (22/45) of the patients. Ferritin levels were < 30 ng/ml in 10 patients, and 1 (0.02%) patient showed elevated thyroid-stimulating hormone (TSH) levels, suggestive of hypothyroidism.
Due to the lack of laboratory equipment in our hospital, cryoglobulin levels were tested in 6 patients only and were negative. The baseline tryptase level was 4.6 ±3.8 µg/l. The total IgE level was 271 ±267 IU/ml. Regarding the treatments received by the patients, 34 (75.5%) patients received antihistamines, 3 (6.7%) patients received antihistamines plus montelukast, and 8 (17.8%) patients received omalizumab. In addition, 2 (4.4%) patients with anaphylaxis symptoms were prescribed adrenaline auto-injectors.
Discussion
This study was conducted in the Van province, which is located in the eastern Anatolia region of Turkey, and it was noticed that cold-induced urticaria is common in patients due to cold climate conditions. In this study, the data of patients diagnosed with cold urticaria confirmed by the ice cube test were analyzed in the last 3 years. When the recommended diagnostic ice cube test was applied for 5 min, 6 out of 45 patients tested negative; however, when repeated with a 10-minute duration, the results turned positive. Localized urticaria on the hands, feet and face was frequently observed, while 2 (4.4%) patients had anaphylaxis symptoms after water activity in Lake Van. Patients experienced symptoms of anaphylaxis even though basal tryptase levels were within the normal range.
Most other studies report that cold urticaria begins in young adults aged 18–27 years [11–14]. The mean age of the patients in our study was 35 years. The reason for the higher mean age compared to other studies may be related to the fact that the majority of the patients sought medical attention later due to localized symptoms.
Some studies have reported gender-related differences, with female predominance reaching up to 66% [4, 6, 12, 15]. In our study, similar to the literature, the majority of patients (80%) were female and 2 patients with a history of anaphylaxis were also female [5].
Rates of systemic cold-induced reactions reported in other studies range from 29% to 40% [4, 11, 12, 16]. Although more than half of our patients had localized reactions (51.2%), only 4.4% had anaphylaxis. This may be due to the fact that in this region, they engage in fewer activities in cold weather to protect themselves from the cold and activities such as swimming are less common. In the literature, localized cold urticaria has mostly been reported through case reports, with the majority of cases affecting the face and neck region. However, involvement has also been reported in areas of allergen-specific immunotherapy, allergen skin testing sites, and even the larynx [17–20]. The cause of localized cold urticaria is unknown. Various mechanisms such as cold-induced mast cell activation, IgE-mediated autoimmune responses, neurogenic inflammation and cold-related autoantigen formation are thought to play a role in the development of the disease [18, 19].
The most common method to confirm the diagnosis of cold urticaria is the ice cube test, as used in our patients. The sensitivity of this method is 71.6–90% and the specificity is 100% [4, 12]. However, the application time of the ice cube is not standardized. Various studies in the literature have used different maximum time intervals including 4, 5, 10, 15 or 20 min [11, 12, 20, 21]. The sensitivity of the ice cube test was reported to be 71.6-72.0% when the stimulation time was 5 min [4, 11]. If the stimulation time was 10 min, the sensitivity of the ice cube test was found to be 80.0–83.6% [11, 22]. Reliable wheal formation occurs after 10 min of rewarming. In this study, all patients initially underwent a 5-minute ice cube test. Since it yielded negative results in 6 patients, the test was repeated using a 10-minute application, which produced positive results. Consistent with the literature, we think that increasing the duration of the ice cube test will increase the sensitivity of the test [23].
Some studies have reported cases of cold urticaria secondary to the presence of serum cryoproteins [24]. Therefore, cryoglobulin levels can be measured to exclude cryoglobulinemia as an underlying cause [25]. The main clinical manifestation of cryoglobulinemia is purpura and patients usually present with cutaneous and systemic vasculitis symptoms and other organ involvement [26]. Cold urticaria has been reported in 3% of cryoglobulinemia cases [27]. In our study, cryoglobulin levels were evaluated in 6 patients, and no positivity was detected.
When the characteristics of the 2 patients with cold-induced anaphylaxis symptoms were analyzed, it was observed that both were women and MPV levels were increased. Several studies report a correlation between high MPV values and increased disease activity and inflammatory markers [28]. The pathophysiology of cold urticaria and anaphylaxis still remains inadequately understood because of its complex underlying mechanisms. In the future, comprehensive studies with a larger number of cases on MPV elevation in cold urticaria and anaphylaxis are needed.
The main treatment of acquired cold urticaria consists of patient education to avoid situations that may trigger a reaction. Warm clothing should be used in cold weather. Cold food and beverages should be avoided. Patients should be advised to avoid cold baths and refrain from swimming in cold water. If engaging in water activities such as swimming or surfing, patients should be closely supervised at all times. Severe reactions may occur if the patient is exposed to a cold environment while under general anesthesia during surgery. Therefore, it should be recommended to give prophylactic steroids and antihistamines before surgery, to give warm intravenous fluids, not to perform surgery in a cold environment and to avoid opiate group drugs [22, 29]. The use of antihistamines in the medical treatment of cold urticaria is the most common and effective treatment. When cold exposure is anticipated and cannot be avoided, prophylactic treatment with high dose antihistamines may be recommended. There are reports of successful treatment with leukotriene antagonists, cyclosporine, systemic corticosteroids, dapsone, oral antibiotics (doxycycline, penicillin), cyproheptadine, doxepin, ketotifen and danazol. In refractory patients, anti-IgE monoclonal antibody (omalizumab), etanercept (antitumor necrosis factor), anakinra (anti interleukin-1) may be preferred [5, 9, 22, 29]. Patients with a history of anaphylaxis or systemic reactions should be given emergency kits containing adrenaline autoinjectors, oral corticosteroids and antihistamines [5, 9, 29]. While antihistamine treatment was sufficient in most of the patients, antihistamine and montelukast treatment was given to 3 patients, and antihistamine treatment was switched to omalizumab treatment in 8 patients because of persistent symptoms.
Our findings are limited by the retrospective design of the study, the absence of a survey to assess disease progression or resolution and to evaluate patient behaviors, and the reliance on clinician-reported data. Larger multicenter prospective studies are needed to further evaluate the natural history and progression of cold urticaria, response to therapy, and rate of anaphylaxis.
Conclusions
We think that increasing the awareness of physicians about cold urticaria will help in the diagnosis and treatment of this group of diseases. Special attention should be paid to prevent anaphylaxis. Further studies are needed to standardize the diagnostic measures, uncover the pathophysiology, and improve therapy.
