Ice Cube Test Research Articles

Cold urticaria associated with acute serologic toxoplasmosis

Cold urticaria is defined as a urticarial and/or angioedematous reaction of the skin to contact with cold objects, water or air. Types of urticaria associated with infectious diseases, such as mononucleosis, rubeola, varicella, syphilis, hepatitis, and HIV infection have been reported. We present the case of a patient who developed cold urticaria associated with acute serologic toxoplasmosis. The patient was a 34-year-old man who for the previous 2 months had presented cutaneous pruritus accompanied by several papular lesions in parts of the skin exposed to cold as well as those in contact with cold water. The result of an “ice-cube test” was positive. Serologic tests for Toxoplasma gondii showed an IgG level of 68 UI/ml and were positive for IgM, while a test for cryoglobulins was positive. One month later cryoglobulins were negative and a serologic test for T. gondii showed an IgG concentration of 75 UI/ml and positive IgM. Three months later cryoglobulins were still negative, IgG for T. gondii was 84 UI/ml, and IgM was positive. After 6 months cryoglobulins were still negative, IgG level was 68 UI/ml and IgM was still slightly positive. In the final evaluation, 14 months later, IgG level was 32 UI/ml and IgM was negative. The patient continues to present clinical manifestations of cold urticaria, although he has experienced some improvement and his tolerance to cold has increased after treatment with cetirizine.

Urticaire et angio-oedème au froid avec cryofibrinogène chez un enfant

Chronic cold-induced urticaria is rare in children and most often idiopathic. We report a case of chronic cold urticaria with cryofibrinogenaemia in a 3-year-old girl. Since she was 18 months old she had urticaria and angioedema on cold-exposed skin beginning about 20 min after cold stimuli such as aquatic activities and cold drinks. Simultaneously, she had systemic reactions (dizziness, pallor and dyspnoea) that spontaneously resolved after a few minutes. A test for cryofibrinogen was positive. The diagnosis of cold urticaria is usually based on the medical history and confirmed with an ice cube test. Some laboratory tests, such as tests for ANA, cryoglobulin and cryofibrinogen, should be done to rule out secondary cold urticaria. It is imperative that all patients with cold urticaria syndromes be fully informed of the risks associated with cold exposure to prevent potentially severe systemic reactions.

Cold urticaria and infectious mononucleosis in children

Physical urticaria includes a heterogeneous group of disorders characterized by the development of urticarial lesions and/or angioedema after exposure to certain physical stimuli. The authors present the case of a child with severe acquired cold urticaria secondary to infectious mononucleosis. Avoidance of exposure to cold was recommended; prophylactic treatment with ketotifen and cetirizine was begun and a self-administered epinephrine kit was prescribed. The results of ice cube test and symptoms significantly improved. Physical urticaria, which involves complex pathogenesis, clinical course and therapy, may be potentially life threatening. Evaluation and diagnosis are especially important in children. To our knowledge this is the first description of persistent severe cold-induced urticaria associated with infectious mononucleosis in a child

Treatment of acquired cold urticaria with cetirizine and zafirlukast in combination

Acquired cold urticaria is an infrequent physical urticaria that can provoke severe systemic reactions. Histamine is the primary mediator, but leukotrienes are also involved in the pathogenesis. H 1 antihistamines are recommended as first-choice treatment, but their efficacy is sometimes unsatisfactory. On the basis of pathogenic knowledge, it can be hypothesized that a combination therapy with antihistamines and leukotriene receptor antagonists is more effective than each drug given alone. We tested this hypothesis in 2 patients with severe systemic cold urticaria poorly responsive to conventional therapy. The patients underwent 3 consecutive treatment regimens (each of 2 weeks): cetirizine (10 mg once a day); zafirlukast (20 mg twice a day); and their combination. They were clinically evaluated, after each regimen, by means of a visual analog scale and ice-cube test. The combination therapy was superior to the 2 drugs given alone, as testified by subjective and objective evaluations.

Mizolastine in primary acquired cold urticaria

Background: Treatment of primary acquired cold urticaria (CU) is quite difficult because of variable clinical effectiveness and side effects of classic antihistamines. Objective: The objective of the study was to assess the efficacy and safety of mizolastine, an antihistaminic with antiallergic properties, versus placebo in primary acquired CU. Methods: This study was a phase II, multicenter, randomized, double-blind, crossover, placebo-controlled study of mizolastine (10 mg, once daily) versus placebo in 28 patients with primary acquired CU. Efficacy was measured by the cold-stimulation time test, the wheal response, and pruritus intensity after an ice-cube test. Results: Mizolastine delayed the cold-induced wheal reaction, reduced wheal response at 3 and 10 minutes, and reduced pruritus intensity. Statistically significant differences were observed versus placebo for the cold-stimulation time test, wheal response at 3 and 10 minutes, and pruritus intensity ( P = .006, .015, .009, and .005, respectively). No clinically relevant adverse events were reported. Conclusions: Mizolastine (10 mg, once daily) was shown to be superior to placebo for both delaying and reducing the cold-induced wheal reaction without significant adverse events. Results suggest that mizolastine may be effective in the treatment of CU. (J Am Acad Dermatol 2003;48:578-83.)

Cold urticaria.

Cold urticaria is one form of urticaria that may be associated with other forms of physical urticarias. Frequency is generally estimated at two or three per 100. The triggering effect of cold is found at history taking in most of the cases. The urticaria is usually superficial, and more rarely associated with deep and/or mucosal urticaria. The diagnosis is based on history taking and the ice cube test. An exhaustive search for an etiologic factor is often unfruitful, and the presence of a cryopathy should lead to a complete work-up. Therapy of cold urticaria may prove to be difficult. In patients with secondary cold urticaria, underlying disease must be treated in order to resolve the skin symptoms. H1-antihistamines can be used but the clinical responses are highly variable. Short-time treatment with low concentration corticosteroids suppresses the symptoms only partially and temporarily. In patients who do not respond to previous treatments, induction of cold tolerance may be proposed but the procedure is difficult to carry out in daily life over an extended period. Key word: cryoglobulins.

731 Predictive relationship between the severity of cold urticaria and the area of the ice-cube test

731 Predictive relationship between the severity of cold urticaria and the area of the ice-cube test

Tumor necrosis factor-α release during systemic reaction in cold urticaria

Primary cold urticaria (PCU) characterized by the association of urticaria, angioedema, and sometimes a shock-like reaction after cold exposure, is usually considered to be linked with histamine and prostaglandin D 2 release by mast cells. To determine the involvement of cytokines, we studied the release of tumor necrosis factor-α (TNF-α) in the blood of the efferent vein after immersion of the hand in chilled water. Five patients with PCU were compared with a control population (three patients with nonphysical urticaria and three healthy subjects). Among patients with PCU who underwent the cold immersion test, two exhibited a shock-like reaction with a large urticarial plaque (patients 1 and 2), one had only a mild cutaneous reaction, and two had no reaction. Patient 1 was reevaluated after 6 months of treatment with H 1 and H 2 antihistamines: he did not respond to this challenge. All controls were strictly negative. Histamine was released within the first minute after the challenge in the three patients with PCU, but at a higher level for the two patients who had a systemic reaction. TNF-α was undetectable in the blood of the patient with only a mild cutaneous reaction, whereas TNF-α release was observed for the two patients with a systemic reaction, 2 and 6 minutes after the end of the cold immersion test. The two other patients and the control subjects released neither histamine nor TNF-α. In parallel, pathologic and immunohistochemical (with a rabbit anti-TNF-α antibody) studies were performed on skin biopsy specimens collected 10 minutes after ice-cube test. Four patients with PCU who had positive ice-cube test results were studied, as well as patient 1 after treatment, who did not respond to the ice-cube test. The pathologic study revealed that mast cells were the only cells infiltrating the dermis in PCU and that most of mast cells were degranulated but only in the four patients with positive ice-cube test results. Immunohistochemical study revealed that only mast cells were stained by anti-TNF antibody (90% ± 2.5%). In conclusion, besides histamine release, cold exposure in PCU induces a concomittent TNF-α release by mast cells. Its detection in blood suggests that in addition to histamine, TNF-α may be implicated in the shock-like reaction in cold urticaria.

Regional expression of cold urticaria

Idiopathic cold urticaria is associated with pruritus, erythema, and swelling after exposure to a cold stimulus. In the typical case it is confined to portions of the body that have contacted the cold, such as when cold objects are touched, exposed to the wind, or in swimming. Any part of the body can react, given a suitable stimulus. In this article, we report an unusual patient with cold urticaria in which cold exposure causes hives in a localized region of the body and the ice-cube test is posit ive only in that area.

Alpha-fluoromethylhistidine in the treatment of idiopathic cold urticaria.

Alpha-fluoromethylhistidine (alpha-FMH), a new irreversible inhibitor of mammalian histidine decarboxylase, was tested in the treatment of idiopathic cold urticaria in 11 patients. In the initial trial with 50 mg b.i.d., a significant decrease (about 30%) in the total blood histamine level was found after 3 weeks of treatment but clinically there was no improvement in the symptoms of ten cold urticaria patients nor in the responses to the ice-cube test. In the second trial with three patients suffering from severe idiopathic cold urticaria, a higher dose of up to 500 mg b.i.d. of alpha-FMH for 3 weeks resulted in a marked decrease in the total blood histamine level as well as in an apparent inhibition of histamine synthesis in the skin previously exposed several times to cold water. The symptoms of cold urticaria and the responses in the ice-cube tests also decreased simultaneously. No clinical side effects nor changes in laboratory analysis were seen during the treatment with alpha-FMH. These results suggest that alpha-FMH may be useful in the treatment of severe cold urticaria especially in combination with histamine exhaustion of mast cells using cold water.

Cold urticaria in association with cholinergic urticaria

The coexistence of two or more varieties of physical urticaria is well recognized but is frequently diagnostically confusing. We now report 13 patients with concurrent cold and cholinergic urticaria in whom heterogeneity in clinical presentation was a striking feature. Four patients showed a hitherto unreported local reaction to cold which bore the clinical appearance of the rash of cholinergic urticaria, but which could not be inhibited by blockade of cholinergic receptors. In two patients the ice-cube test was negative, but exposure of the whole body to cold induced a generalized rash resembling classical heat-or exercise-induced cholinergic urticaria as described by Kaplan.1 Cold and cholinergic urticaria coexisted in their classical form in the remainder. Systemic symptoms occurred following severe cold exposure in three patients and following exercise in six patients. Of the nine patients we were able to review, three had spontaneously cleared of both types of urticaria after intervals of 5,6 and 26 years, respectively, following onset. Treatment was often unsatisfactory and showed marked variability between patients. Both types of urticaria were helped by terfenadine in four out of seven, by hydroxyzine in three out of three, by chlorpheniramine in three out of six, by ketotifen in two out of three and by cyproheptadine in one out of five. The combination of cimetidine with an H1 antagonist was helpful in three patients. Desensitization to cold was attempted in three and achieved in two, whilst desensitization to exercise was ineffective in a single patient. Severe cholinergic urticaria responded well to danazol in two patients. Previous reports have suggested that this clinical association is rare,2 but we believe it to be quite common, possibly suggesting some common aetiological factor in both types of urticaria.

Cold urticaria: Clinical findings in 220 patients

Patients with cold urticaria, a total of 220, were studied in Finland. Sixty-three percent of the patients were female. The diagnosis was based on a positive ice cube test in 90% of cases, and the other cold tests were needed to certify the diagnosis for the remainder of patients. The mean age at the onset of the disease was 25.1 years (range, 1-74), and the mean duration of symptoms was 6.3 years (range, 3 weeks to 37 years). Cold urticaria symptoms had disappeared in fifty-three patients (24%), but there was a recurrence of the disease in twelve. Idiopathic (primary acquired) cold urticaria was present in 96% of the patients. Only two patients had a secondary acquired cold urticaria. Two patients had cold-induced, "cholinergic" urticaria, and four patients had a delayed type of cold urticaria. Twenty-one percent of the patients had dermatographism, 8% had cholinergic urticaria, and two patients (1%) had heat urticaria concurrently with cold urticaria.

Comparison of cinnarizine, cyproheptadine, doxepin, and hydroxyzine in treatment of idiopathic cold urticaria: Usefulness of doxepin

Randomized double-blind trials using doxepin and several conventional antihistamines were carried out for treatment of patients with idiopathic cold urticaria. In the first double-blind trial, eight of nine patients preferred doxepin (10 mg three times daily) to cinnarizine (10 mg three times daily). In the second double-blind trial, the results of ice cube tests suppressing the effect of cyproheptadine (4 mg three times daily), doxepin (10 mg three times daily), and hydroxyzine (10 mg three times daily) did not statistically differ. However, doxepin was subjectively the most effective and it had fewer side effects than other treatments that were compared. Doxepin effectively suppressed the wheal and itching responses and shortened the duration of the wheal response in the ice cube test in all patients with cold urticaria who were studied.

Infectious Mononucleosis and Cold Urticaria

To the Editor.— The recent article by Lemanske and Bush (1982;247:1604) reported a case of cold urticaria associated with infectious mononucleosis. We would like to support their findings by presenting a similar case. Report of a Case.— A 26-year-old man had a week-long history of pruritus, erythema, and urticaria that first appeared after ingesting cold foods and then progressed to occurring after exposure to cold air or after contact with cold surfaces. No respiratory distress was noted. He had a nonproductive cough with myalgias in the week preceding the onset of urticaria. There was no personal or family history of allergies or urticaria. Physical examination disclosed urticaria on forearms, buttocks, and calves. Submaxillary, axillary, and anterior cervical adenopathy were present, but without hepatosplenomegaly. The presence of urticaria was confirmed by a positive response to an ice cube test. Other laboratory data were as follows: WBC count, 10,000/cu mm, with 79%

Identification of a new physically induced urticaria: cold-induced cholinergic urticaria

Four patients with symptoms suggestive of either cold urticaria or a combination of cold and cholinergic urticaria were studied. However, all patients were negative to an ice-cube test or cold-immersion test and had no urticaria after exercise in a warm environment. When each patient was seated in a cold room (4° C) for 5 to 15 min, generalized urticaria appeared, consisting of punctate wheals and surrounding erythema as seen in cholinergic urticaria. Two patients had weakly positive methacholine skin tests and the other two had completely negative tests. When serial venous blood samples were obtained to test for mediator release, three of four patients had evidence of histamine release and the time course was similar to that previously reported for patients with cholinergic urticaria. These four cases represent a new syndrome with features suggestive of cold and/or cholinergic urticaria, but the results of all the tests usually utilized to diagnose these conditions were negative. We have called this disorder cold-induced cholinergic urticaria to indicate that it is cold dependent and visually indistinguishable from cholinergic urticaria.

Treatment of acquired cold urticaria with azatadine.

Summary Acquired cold urticaria is a clinical entity in which wheals appear on exposure to cold, rive patients with cold urticaria were treated with 0,1 mg of azatadine four times a day. Followed for 15–36 months (mean 22 months), the patients were under good control. No significant side effects were noted. Drowsiness was initial and transitory. Ice cube test was positive in four and negative in one patient. This preliminary study suggests that azatadine may be a useful drug in treatment of cold urticaria.

The role of cyproheptadine in the treatment of cold urticaria

Histamine release in cold urticaria was studied before and after therapy with cyproheptadine to determine whether any effect upon histamine release could be distinguished from end-organ receptor-site blockade. Patients were asymptomatic while taking cyproheptadine, their ice cube test reverted to normal, and only one of six patients had any swelling upon ice-water submersion of one hand for 5 min. Histamine-release curves were obtained following ice-water submersion before and after cyproheptadine therapy. All patients had significant histamine release and in five of six patients there was no evident difference in the magnitude of histamine release before or after therapy. A single patient did have diminished histamine release after therapy, but could not be restudied to be sure this was not a spurious result. Our data demonstrated that cyproheptadine is extremely effective in ameliorating the symptoms and signs of cold urticaria and that its principal effect is that of an H 1 receptor antagonist, thereby blocking the effects of histamine. These data further suggest that a sufficient dose of any standard antihistamine should be similarly effective and that patients who do not tolerate cyproheptadine or do not appear to respond to it should be tried on other antihistamines of the h 1 type.

Evaluation of a patient with cold and cholinergic urticaria

A-20-year-old male Army paratrooper presented with a history of inducible urticaria associated with exercise as well as cold exposure. Upon evaluation, he not only had a positive ice cube test, but also had a positive mecholyl skin test with numerous satellite lesions and generalized punctate urticaria following exercise challenge. Thus, he appeared to have combined cold and cholinergic urticaria. When mediator release was examined during cold and exercise challenge, histamine release was observed in each instance; a rapid rise and fall of plasma histamine was seen after cold challenge, while a lag phase followed by sustained elevation of plasma histamine was associated with exercise challenge. This represents the fourth reported case of combined cold and cholinergic urticaria and is the first in whom mediator release was assessed. The time-course of histamine release was characteristic of each disorder.