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Physical urticaria is often challenging to diagnose and manage. We present a case of both cholinergic and cold-induced urticaria and discuss the diagnosis and management strategies of these two important conditions., (2015 BMJ Publishing Group Ltd.)

Background: While a number of the consequences of mast cell degranulation within tissues have been documented including tissue-specific changes such as bronchospasm and the subsequent cellular infiltrate, there is little known about the immediate effects of mast cell degranulation on the associated vasculature, critical to understanding the evolution of mast cell dependent inflammation., Objective: To characterize the microcirculatory events that follow mast cell degranulation., Methodology/principal Findings: Perturbations in dermal blood flow, temperature and skin color were analyzed using laser-speckle contrast imaging, infrared and polarized-light colorimetry following cold-hand immersion (CHI) challenge in patients with cold-induced urticaria compared to the response in healthy controls. Evidence for mast cell degranulation was established by documentation of serum histamine levels and the localized release of tryptase in post-challenge urticarial biopsies. Laser-speckle contrast imaging quantified the attenuated response to cold challenge in patients on cetirizine. We found that the histamine-associated vascular response accompanying mast cell degranulation is rapid and extensive. At the tissue level, it is characterized by a uniform pattern of increased blood flow, thermal warming, vasodilation, and recruitment of collateral circulation. These vascular responses are modified by the administration of an antihistamine., Conclusions/significance: Monitoring the hemodynamic responses within tissues that are associated with mast cell degranulation provides additional insight into the evolution of the acute inflammatory response and offers a unique approach to assess the effectiveness of treatment intervention.

Cold urticaria is one of the five most common causes of chronic urticaria and is grouped as a physical urticaria. It can occur after exposure to cold, either through solid objects, air or liquids. Patients may have symptoms of urticaria, angioedema, respiratory distress and even anaphylaxis when the skin is exposed to a cold environment, such as handling refrigerated objects, swimming in cold water or entering an air-conditioned room. Five cases of cold urticaria are presented, followed by a brief literature review.

Background Acquired cold urticaria (ACU) is a physical urticaria characterized by local skin reactions after cold exposure. Objective markers of disease severity and activity would be helpful. Unfortunately, such markers are not yet available, even though stimulation time and temperature thresholds are promising candidates. Objectives We assessed and correlated critical temperature thresholds (CTTs) with disease severity and activity in patients with ACU. Methods CTTs were determined in 45 patients with ACU by TempTest-based cold contact stimulation tests (Emo Systems GmbH, Berlin, Germany), and ACU severity and activity were assessed using Likert scales. Results Patients with ACU exhibited mean +/- SEM CTTs of 17 +/- 6 degrees C (range 4-27 degrees C). These thresholds and their changes correlated with the severity (r = 0.53, P < 0.05) and activity of disease (r = 0.64, P < 0.05), respectively. Conclusions These findings indicate that temperature threshold measurements may be used for assessing disease severity and activity as well as the efficacy of therapeutic measures including novel treatment approaches for cold urticaria.

Background: Acquired cold urticaria (ACU) is a skin condition, in which exposure to cold results in wheals and itching and sometimes general systemic complications. It has a profound impact on patient quality of life. Second-generation antihistamines are recommended as the first-line treatment, but to date only a few have been scientifically tested for this condition., Aim: To assess the safety and efficacy of ebastine in preventing ACU symptoms., Methods: Twenty-two adult ACU patients participated in a double-blind crossover trial of 20 mg ebastine. The safety of ebastine was sensitively assessed with a psychometric battery testing cognitive performance and mood. After cold challenge, wheal and erythema were assessed by the investigator and the intensities of pruritus and burning were rated by the subject., Results: Ebastine had no negative impact on any of the parameters of cognitive performance or mood. It dramatically reduced the number of patients who experienced wheals, pruritus, and burning after challenge., Conclusion: Ebastine is safe and effective in preventing the symptoms of ACU.

Background: Cold-induced urticaria is a form of physical urticaria which is characterized by rapid onset of pruritus, erythema, and swelling after exposure to a cold stimulus. Familial cold autoinflammatory syndrome (FCAS) is a rare autosomal-dominant condition characterized by unremitting attacks of cold-induced urticaria, often accompanied by other systemic manifestations. The disorder was previously shown to be caused by mutations in CIAS1, encoding a pyrin-like protein also involved in the pathogenesis of Muckle-Wells syndrome (MWS), and chronic infantile neurological cutaneous and articular syndrome (CINCA)., Methods: In the present study, using direct sequencing, we assessed a two-generation family of Jewish Ethiopian origin, including 3 members affected with FCAS., Results: We identified a novel CIAS1 mutation, F525C. The mutation was shown to affect a highly conserved residue of the protein and to segregate with the disease throughout the extended family., Conclusions: Our results add to the expanding spectrum of mutations in CIAS1 and provide evidence for striking phenotypic heterogeneity in inherited autoinflammatory syndromes. This is the first report of inherited cold urticaria in a family of Ethiopian origin.

Objective: Familial cold autoinflammatory syndrome (FCAS) is a rare, hereditary disorder characterized by cold-induced inflammation. We describe the successful longterm treatment of a patient with FCAS with anakinra, an interleukin 1 receptor antagonist (IL-1Ra). The remarkable response of FCAS and associated Raynaud's disease in this patient suggests that IL-1 is an important mediator of these inflammatory diseases. Our report supports increasing evidence that anakinra plays an important role in the treatment of select chronic inflammatory diseases.

Acquired cold urticaria syndromes represent one of the more common forms of physical urticaria. The syndromes are heterogenous, and a diagnostic classification is presented to facilitate collation for future studies. Acquired cold urticaria represents an excellent reproducible in vivo model to investigate the mechanisms of urticaria. The discussion includes clinical manifestations, laboratory features, pathogenesis, and management of these disorders. A description of familial types, particularly familial cold auto-inflammatory syndrome (FCAS) that is manifested by cold-evoked signs and symptoms of chronic inflammation, is included. FCAS historically has been included with acquired cold urticaria, even though the exanthem of FCAS is maculopapular caused by leukocytic infiltration. FCAS has become an important investigative syndrome, as it represents a reproducible in vivo model of chronic inflammation.

Background: Familial cold autoinflammatory syndrome (FCAS), formerly known as familial cold urticaria, is a rare condition characterized by fever, rash, and arthralgias elicited by exposure to cold. Recently, mutations responsible for FCAS were identified in a novel gene (CIAS1), making it possible to confirm the diagnosis in most patients., Objective: We present a summary of clinical data from a large family with FCAS to further define the characteristics of the disorder and to validate previously proposed clinical criteria., Methods: A total of 73 participants were evaluated by interview and questionnaire, including 36 affected individuals. Responses from the questionnaire were analyzed and comparisons of proportions were made using the Z test. DNA was isolated and genotyping was performed on all subjects. Affected haplotypes (genotype patterns) were identified and used to confirm the diagnosis. Sequencing of the CIAS1 gene was performed in selected patients to confirm the mutation., Results: The prevalence of rash, fever/chills, joint complaints, nausea, headache, and thirst were not significantly different from previously reported proportions. There was statistically significant differences in conjunctivitis, sweating, and drowsiness with alpha = 0.01. The mean temperature required to produce symptoms was 22 degrees C, and the average earliest onset of symptoms after exposure was 1.5 hours., Conclusions: Applying the proposed clinical criteria, 41% of affected subjects met all six criteria, 90% met five criteria, and 100% met four criteria for FCAS. None of the unaffected subjects met more than two criteria. Using a threshold of 4 of 6 clinical criteria, the data support the diagnostic validity of the proposed clinical criteria.

Cold urticaria is characterized by the development of urticaria, usually superficial and/or angioedematous reaction after cold contact. It was found predominantly in young women. The diagnosis is based on the history and ice cube test. Patients with a negative ice cube test may have represented systemic cold urticaria (atypical acquired cold urticaria) induced by general body cooling. The pathogenesis is poorly understood. Cold urticaria can be classified into acquired and familial disorders, with an autosomal dominant inheritance. Idiopathic cold urticaria is most common type but the research of a cryopathy is necessary. Therapy is often difficult. It is essential that the patient be warned of the dangers of swimming in cold water because systemic hypotension can occur. H1 antihistamines can be used for treatment of cold urticaria but the clinical responses are highly variable. The combination with an H2 antagonists is more effective. Doxepin may be useful in the treatment. Leukotriene receptor antagonists may be a novel, promising drug entity. In patients who do not respond to previous treatments, induction of cold tolerance may be tried.

Familial cold urticaria (FCU) is a rare autosomal dominant inflammatory disorder characterized by intermittent episodes of rash with fever, arthralgias, conjunctivitis, and leukocytosis. These symptoms develop after generalized exposure to cold. Some individuals with FCU also develop late-onset reactive renal amyloidosis, which is consistent with Muckle-Wells syndrome. By analyzing individuals with FCU from five families, we identified linkage to chromosome 1q44. Two-point linkage analysis revealed a maximum LOD score (Zmax) of 8.13 (recombination fraction 0) for marker D1S2836; multipoint linkage analysis identified a Zmax of 10. 92 in the same region; and haplotype analysis defined a 10.5-cM region between markers D1S423 and D1S2682. Muckle-Wells syndrome was recently linked to chromosome 1q44, which suggests that the two disorders may be linked to the same locus.

Urtica is characterized by an erythematous wheal surrounded by a flare and is frequently caused by physical agents (e.g. cold). The exact mechanism and mediators involved in the mechanism of physical urticaria are not known. This study of the role of the neurogenic factors in cold urticaria showed, that local capsaicin treatment (desensitization) of the skin in patients with cold urticaria resulted in the abolition of whealing in response to cold. This result suggests that C-fibers might play an important role in the pathomechanism of idiopathic contact cold urticaria.

Recent advance about pathogenesis of Idiopathic acquired Cold-induced Urticaria underline the role of Neutrophils that, drawn by a specific mast-cell factor (HMW-NCF) might characterise precise stages of disease and presumably specific histologic "subset". This factor together with the chemotactic factor for eosinophils (ECF) can determine the so called neutrophils' "deactivation". In this study we have valued the role of neutrophils in six patients with idiopathic cold-induced urticaria and in a group of control including both patients with other forms of urticaria and healthy controls. The results of our research show the absence of alterations either in cellular neutrophilic chemotaxis or the serum one. Furthermore we have been able to determine that this "deactivation" is specific for idiopathic cold-induced urticaria and that it does not happen in the other forms of physical or non urticaria.

Six patients with acquired primary cold urticaria and six normal control subjects were challenged with a 5-minute immersion of an arm in cold water, at 10 degrees C, to induce cold urticaria. Venous blood draining the arm was sampled before and at 5 and 20 minutes after challenge. Prostaglandin D2 levels in the serum increased significantly after cold challenge but did not correlate with the severity of the urticaria. Significant elevations in histamine after cold challenge tended to be higher in the patients with a low threshold to cold reaction. Two markers of platelet activation, platelet factor 4 and beta-thromboglobulin, remained at basal levels 5 minutes and 20 minutes after challenge.

The physical conditions of challenge were investigated in a climatic chamber on 8 patients with cholinergic urticaria and 10 patients with generalized cold urticaria. The cholinergic urticaria was induced by passive or active (physical exercise) heating and psychological stimulation; the generalized cold urticaria was induced by general cooling at rest and during physical effort. The ambient temperature was varied, and the mean body temperature was recorded continuously at different measuring points. The experiments revealed that in both types of urticaria the physical trigger mechanism seems to be strictly related to thermoregulatory processes; the crucial point is neither the actual temperature of the skin surface, the average skin temperature, nor even the "core" temperature, but a rise or fall in the weighted average body temperature. In cholinergic urticaria it was not relevant whether skin lesions were provoked by passive heating of the body at rest (sauna-like conditions) or by active heating at low ambient temperature. A basically different challenge mechanism must be assumed therefore in the generalized type of heat and cold urticaria, in contrast to their localized contact types.

During an 8-year period we have seen two cases of cold-induced urticaria at the King Faisal Specialist Hospital and Research Centre, a major tertiary centre in Saudi Arabia. This indicates a lower prevalence in Saudi Arabia compared with other countries. One of our patients did not respond to cyproheptadine but she had an excellent response to ketotifen.

Histamine release from peripheral blood basophils challenged with C5a, f-met-peptides and calcium ionophore was studied in patients with cold urticaria before and after exposure to low environmental temperatures. Compared to healthy controls, stimulated mediator release before cold exposure was increased in 7 of 11 patients. When challenged by cold exposure mediator release from in vitro-stimulated basophils was decreased. This decrease was more pronounced after stimulation with receptor-mediated stimuli (e.g. C5a) as compared to receptor-unrelated stimuli, e.g. calcium ionophore. In 4 of 11 patients stimulated mediator release before cold exposure was moderately increased. Also after cold exposure only a weak decrease of stimulated histamine release was seen. Levels of activated complement components (C3a) before and after cold exposure failed to provide evidence for complement activation in vivo. Also the number of circulating basophils as well as their cellular histamine content remained normal after cold exposure. The results show that in these patients release of histamine is altered before and after cold exposure. These changes in basophil responsiveness are not due to complement activation in vivo.

The eosinophilic activity appearing in the venous effluent of the cold-induced angioedematous extremity of patients with cold urticaria has been resolved into three fractions by gel filtration and Dowex-1 chromatography. The low molecular weight activity, 300-700 mw, is highly acidic while the activity of 1000-3000 mw is composed of highly acidic and less acidic moieties. Each of the three activities has a different retention time on high pressure liquid chromatography, indicating that they represent distinct fractions which differ in size, charge, and hydrophobicity. Each fraction requires a gradient to attract eosinophils in a dose-response fashion and each deactivates eosinophils at subchemotactic concentrations. The more acidic 1000-3000 mw fractions also attract human monocytes in a chemotactic gradient at concentrations identical to those which attract human eosinophils. These three classes of eosinophil chemotactic activities and the activity for monocytes appear and disappear from the venous effluent with essentially the same time course as a distinct neutrophil chemotactic factor and histamine with cold induction of angioedema in patients with cold urticaria. The elaboration of these diverse chemoattractants in experimentally induced physical allergy provides potential pathways for mast cell-mediated infiltrative reactions.

Cold urticaria is probably the most common form of physical urticaria. It is usually a chronic idiopathic disorder but may be secondary to another disease characterized by abnormal serum proteins with a cold-dependent property. In delayed cold urticaria, hives appear 24 to 48 hours after cold challenge. In addition to challenge testing, the physician should obtain serologic tests to exclude the presence of associated cold agglutinins, Donath-Landsteiner antibody, cryoglobulins and cryofibrinogen.

Thirteen patients with both cold and cholinergic urticaria are reported. There was considerable variability, particularly in the cold urticaria which was of the common cold contact type in seven patients, of the generalized cold induced cholinergic type in two and in four patients the lesions induced by direct contact with ice were morphologically like cholinergic urticaria, but appeared despite prior application of an acetyl choline antagonist. The natural history, laboratory findings and the effects of therapy are discussed.