Cold Urticaria: From Wheals to Anaphylaxis

Abstract

Cold urticaria (ColdU) is characterized by wheals, angioedema, or both, which are triggered by exposure to cold. A subset of patients experiences cold-induced anaphylaxis (ColdA), a potentially life-threatening systemic reaction. The pathogenesis of ColdU remains incompletely understood, but mast cell activation plays a central role. Most hypotheses are decades old and require further investigations. ColdU and ColdA are clinically diagnosed and typically supported by cold stimulation testing (CST). However, standard CST methods may yield negative results despite a clear clinical history. ColdU is classified into typical and atypical forms based on CST responses. ColdA occurs more frequently in patients with mucosal angioedema involving the oropharynx. It is most commonly triggered by full-body cold exposure, such as swimming. Diagnostic workup should include a detailed history, CST, and evaluation for underlying conditions, particularly in patients with clinical signs and symptoms extending beyond the skin. First-line treatment involves second-generation H₁-antihistamines, often needed at increased doses for disease control. Omalizumab has shown efficacy in clinical trials and case reports for refractory cases. Adrenaline is the first-line therapy for ColdA; high-risk patients should be prescribed autoinjectors and receive proper training in their use. This review provides an overview of the pathophysiology, classification, diagnostic procedures, and management of ColdU and ColdA, emphasizing clinical variability and unmet research needs.

INTRODUCTION

Cold urticaria (ColdU), the second most prevalent subtype of chronic inducible urticaria (CIndU),¹ is characterized by localized or generalized wheals, cutaneous angioedema, and/or mucosal angioedema involving the oropharynx (MAO), triggered by exposure to cold.² Compared to chronic spontaneous urticaria (CSU), wheals and angioedema in ColdU are typically of shorter duration.³ A potentially life-threatening manifestation of ColdU is cold-induced anaphylaxis (ColdA).²,⁴ The primary aim of this review is to summarize current knowledge on ColdU and ColdA and to provide practical guidance for clinical management. Particular emphasis is placed on findings from the COLD-CE study, conducted within the UCARE GA²LEN network.

PATHOGENESIS

The mechanisms underlying ColdU are not fully understood, but strong evidence indicates that mast cells play a central role.⁵ Their mediators activate cutaneous nerves and lead to vasodilation and increased vascular permeability, which result in pruritus, erythema, wheals, and/or angioedema.⁶ The precise mechanism triggering mast cell degranulation in ColdU remains unclear. Fig. 1 provides a schematic overview of proposed mast cell activation pathways in ColdU.

Fig. 1. Skin mast cell activation pathways and therapeutic targets in ColdU.

This figure illustrates how cold exposure may trigger skin mast cell degranulation as described in the pathogenesis paragraph. Therapeutic agents acting at various targets are also displayed (created with BioRender.com).

IgG, immunoglobulin G; IgE, immunoglobulin E; IgM, immunoglobulin M; C5a, complement 5a; C5aR, complement 5a receptor; FcγR, cell-surface receptor for immunoglobulin G; KIT, stem cell factor receptor; FcεRI, high-affinity receptor for immunoglobulin E; IL4Rα, interleukin-4 receptor alpha subunit; BTK, Bruton's tyrosine kinase; MRGPRX2, Mas-related G protein-coupled receptor X2; TRPM8, transient receptor potential channel melastatin 8; TRPA1, transient receptor potential channel ankyrin 1; H₁R, H₁ receptor; sgAHs, second-generation H₁-antihistamines.

In vivo Prausnitz-Küstner studies (1970−1988), in which serum from ColdU patients was injected into healthy individuals, revealed that serum from some patients could induce ColdU. These experiments are no longer performed due to concerns about pathogen transmission. They provided insights into potential transfer factors, namely, immunoglobulin (Ig) E,⁷,⁸,⁹ IgM,¹⁰,¹¹ and IgG.⁹ Still, the exact role of each Ig in ColdU pathogenesis remains unclear.

Since passive transfer can trigger ColdU, it is assumed that mast cells function normally and require an additional skin factor that responds to temperature drops for activation.¹² Whealing typically peaks during rewarming.¹³ Asero et al. ¹⁴ proposed that reactive vasodilation following cold exposure increases local concentrations of circulating histamine-releasing factors, thereby amplifying the response.

The autoallergy hypothesis suggests that cold temperatures modify skin proteins, creating autoallergens that bind to IgE on mast cells, thereby triggering degranulation in a type I hypersensitivity-like manner.⁸ However, this remains speculative, as no cold-dependent antigens have yet been identified.

A second hypothesis, proposed by Wanderer, aligns with the observation that wheal formation mirrors the shape of the cold stimulus. It suggests that prior antigenic stimulation (e.g., by infections or insect stings) leads to the production of anti-IgE antibodies. These may form immune complexes with their antigen or remain unbound.¹⁵ These autoantibodies are hypothesized to act as cryoglobulins (i.e., proteins that precipitate upon cooling¹⁶), which are present at low levels and not routinely detectable.¹⁷ Upon cold exposure, cryoprecipitation in the subcutaneous tissue may activate mast cells. Immune complexes may induce mast cell degranulation either via the production of complement C5a, which binds to the C5a receptor,¹⁸ or through cross-activation of activating cell-surface receptors for IgG (FcγR).¹⁹ Unbound anti-IgE antibodies may cross-link IgE bound to high-affinity receptors for IgE (FcεRI).¹⁵ Rewarming may cause immune complexes to dissociate due to thermal disruption of their molecular bonds.⁹

Gruber et al. ⁹ found IgG anti-IgE antibodies in 5 of 9 (55%) and IgM anti-IgE antibodies in 2 of 9 (22%) patients with ColdU. Heating the sera enhanced antibody binding to IgE.⁹ Inganäs et al. ²⁰ reported IgG anti-IgE antibodies in 2 of 6 (33%) patients. Kaplan,¹² however, noted that ColdU is primarily associated with IgE antibodies, with IgM and IgG playing only exceptional roles.

A 2021 single-center study found high rates of cryoglobulin and cold agglutinin positivity among ColdU patients (46% and 27%, respectively). Importantly, samples were collected and processed by specialized laboratories to avoid false negative results from improper handling.²¹ Omalizumab, a monoclonal anti-IgE antibody that binds free IgE and consequently reduces the number of FcεRI receptors, has proven effective in patients unresponsive to H₁-antihistamines,²²,²³ supporting both the autoallergy and Wanderer hypotheses.

The involvement of transient receptor potential (TRP) cation channels and the Mas-related G protein-coupled receptor X2 (MRGPRX2) on mast cells remains speculative in ColdU and has not been confirmed in clinical studies. TRP cation channels, specifically TRPM8 (melastatin 8) and TRPA1 (ankyrin 1), which mediate cold sensing, have been proposed as potential contributors to mast cell activation in ColdU.²⁴,²⁵ MRGPRX2 mediates IgE-independent activation of mast cells. A selective antagonist of this receptor, EP262, is currently under investigation in ColdU.⁵

SUBTYPES OF ColdU

ColdU is classified into acquired and rare hereditary forms. The acquired form most commonly affects young adults but can occur at any age.²⁶ It has been linked to infections, including Helicobacter pylori,²⁷,²⁸ Toxoplasma gondii,²⁹ Epstein-Barr virus,³⁰,³¹ hepatitis C virus,³² and human immunodeficiency virus.³³ Other reported triggers include Hymenoptera stings,³⁴,³⁵,³⁶,³⁷ jellyfish stings,³⁸ vaccinations,³⁹ and malignancies,⁴⁰,⁴¹,⁴²,⁴³,⁴⁴ which are mostly described in case reports. This has led to the use of the confusing terms “primary” (for unknown causes) and “secondary” (linked to an underlying disease) acquired ColdU.⁴⁵ However, a direct causal link remains uncertain. Acquired ColdU is typically self-limiting in most patients, while hereditary forms are lifelong.⁴⁶ Among patients in the COLD-CE cohort, 5% reported a positive family history of ColdU.² ColdU is further subdivided into typical and atypical forms based on the results of standard CST using an ice cube or the TempTest^® device (see paragraph “Standard CST” below).⁴ In COLD-CE phase 1, 412 of 551 patients (75%) had typical ColdU.²⁶,⁴⁷ Key clinical terms used throughout this review are summarized in Table 1.

Table 1. Key clinical terms.

Term	Explanation
Acquired ColdU	ColdU that is not inherited.
Atypical ColdU	Standard CST produces non-classical responses (e.g., no wheal at the test site within 10 min), or modified CST is required to induce whealing.
CST	The patient is exposed to a cold stimulus and monitored for a response. A positive result is defined by the appearance of palpable, clearly visible wheals or angioedema, typically during rewarming.
CSTT	The shortest duration of ice cube contact that induces whealing.
CTT	The highest temperature at which whealing occurs during testing with the TempTest®.
MAO	Sensation of swelling in the oral cavity or throat, typically after consuming cold foods or drinks.
Standard CST	A 5-min application of an ice cube or the TempTest® to the volar forearm, followed by a 10-min observation period.
Typical ColdU	Characterized by palpable whealing at the site of standard CST, occurring within 10 min after a 5-min cold stimulation.

ColdU, cold urticaria; CST, cold stimulation testing; CSTT, critical stimulation time threshold; CTT, critical temperature threshold; MAO, mucosal angioedema involving the oropharynx.

ColdA

The diagnosis of ColdA is clinical, but a universally accepted definition is lacking.²⁵ Anaphylaxis is generally diagnosed on the basis of clinical criteria, which include the rapid onset of clinical signs and symptoms involving multiple organ systems.⁴⁸ Anaphylaxis is considered highly likely when at least 2 systems are involved (e.g., skin, lips-tongue-uvula; cardiovascular; respiratory; and gastrointestinal)⁴⁸; however, this may not always apply to ColdA. For instance, respiratory symptoms in a patient with asthma may reflect an asthma exacerbation, while gastrointestinal discomfort following cold food ingestion may result from direct mucosal cooling rather than ColdA.²⁵

In the COLD-CE study, ColdA was defined as an acute cold-induced reaction involving the skin and/or visible mucosa, accompanied by at least one systemic manifestation (e.g., cardiovascular, respiratory, or gastrointestinal). In phase 1, ColdA was diagnosed in 37% of patients with typical ColdU.²⁶ Phase 2 focused on analyzing MAO and individual systemic manifestations in patients with typical ColdU, without applying a ColdA definition. Cardiovascular symptoms, with or without loss of consciousness, were reported in 28% of patients; syncope or documented hypotension (<90/60 mmHg), considered the most severe and objective indicator of ColdA, occurred in 12%. Respiratory symptoms were reported in 20%, and gastrointestinal symptoms in 10%.² Other smaller studies have reported systemic reactions in 4%–51% of ColdU patients,²⁵ highlighting the variability across studies.

The pathophysiology of ColdA remains unclear, but histamine is thought to play a major role in its development.⁴⁹ A 2018 case report described a child with ColdU who experienced intraoperative ColdA; the reaction was associated with an elevated tryptase level and a normal baseline.⁵⁰ Juhlin and Shelley¹⁶ suggested that both ColdU and ColdA are triggered by histamine release from mast cells in the skin and basophils in the blood. Their study demonstrated that basophils from ColdU patients undergo degranulation when exposed to cold in vitro. ¹⁶

TRIGGERS

In the COLD-CE cohort, patients with typical ColdU reported the following triggers: cold air (88%), full-body cold-water immersion (68%), localized skin contact with cold liquids (65%), cold surfaces (59%), and ingestion of cold food or drinks (34%). Aggravating factors included wind (70%) and increased summer humidity (32%).

For ColdA, cold-water immersion was the most common trigger, reported by 27% of patients, while exposure to cold ambient air was reported by 13%.² This difference can be explained by physical principles: cold water conducts heat more efficiently than air, resulting in a more rapid drop in body temperature via convective heat loss. In contrast, air is a relatively poor conductor, causing slower cooling.

Other, less frequently reported but clinically relevant ColdA triggers included localized contact with cold liquids or ice and contact with cold solid surfaces.²⁶ These findings emphasize the importance of caution when performing CST in clinical settings.

ColdA may also be triggered by intraoperative exposure to low ambient temperatures or administration of cold intravenous or irrigation fluids.²⁵ Overall, the evidence suggests that ColdA is more likely to occur when larger surface areas are exposed to cold stimuli for extended periods.

DIAGNOSIS

The diagnosis of ColdU is clinical.⁵¹,⁵² A detailed patient history should be obtained (Table 2), followed by a physical examination. If available, real-life photographs documenting wheals or angioedema can support the diagnosis. CST should also be performed.⁵¹ Currently, no biomarkers are available for diagnosing ColdU.

Table 2. Proposed parameters for guided patient history²,⁴,²⁵,²⁶ .

Category	Parameters to be obtained
Baseline characteristics	Duration of disease, wheal duration, angioedema duration
Cutaneous reactions	Localized or generalized wheals, cutaneous angioedema (deeper swellings with imprecise borders), itch, flushing, earlobe itching
MAO	See Table 1.
Cardiovascular manifestations	Dizziness, lightheadedness, confusion, loss of consciousness (due to reduced blood flow), hypotonia, weakness (reduced muscle tone), collapse (involuntary falling), tachycardia, recorded hypotension (< 90/60 mmHg)
Respiratory manifestations	Dyspnea (breathing discomfort), wheeze (whistling sound, mainly during exhalation due to bronchoconstriction), stridor (high-pitched sound during inhalation due to airway obstruction), dysphonia (hoarseness from laryngeal edema), sneezing, cough, chest pain
Gastrointestinal manifestations	Persistent crampy abdominal pain, vomiting, diarrhea
Systemic inflammatory symptoms	Fever or malaise on days of cold exposure
Relevant cold triggers/aggravators	Cold air, full cold-water immersion, localized skin contact with cold liquids, contact with cold surfaces, consumption of cold foods or drinks, wind, increased summer humidity, surgical cold exposure
Comorbidities, family history	CSU, other CIndU subtypes, previous Hymenoptera venom-triggered anaphylaxis (may indicate clonal mast cell disease), other comorbidities, family history of ColdU

MAO, mucosal angioedema involving the oropharynx; CSU, chronic spontaneous urticaria; CIndU, chronic inducible urticaria; ColdU, cold urticaria.

Wheals are sharply circumscribed, superficial skin swellings that vary in size and shape, and are typically pruritic. They are often surrounded by erythematous flare. In contrast, cutaneous angioedema presents with deeper, erythematous, or skin-colored swellings with poorly defined borders. The diagnosis of ColdA is also clinical (see ColdA definition above).

According to the most recent international urticaria guidelines,⁶ routine laboratory testing is not required in typical ColdU. Testing should be considered when the clinical picture is atypical, when an associated systemic disease is suspected, or when a differential diagnosis must be excluded.

A study conducted in 2025 found that 7% of 92 ColdU patients tested positive for the KIT p.D816V missense variant (i.e., aspartic acid [D] is replaced by valine [V] at position 816), which is considered absent in the general population, but can occur in clonal mast cell disorders, including cutaneous mastocytosis, systemic mastocytosis, and monoclonal mast cell activation syndrome. Hereditary α-tryptasemia was identified in 11% of ColdU patients and in 15% of those with ColdA, compared to a general population prevalence of 5.7%. Moreover, individuals with ColdA had significantly higher total serum IgE levels than those without ColdA.⁴

STANDARD CST

Standard CST is typically performed using an ice cube and, if available, the TempTest^® device (Table 3, Fig. 2A-C). H₁-antihistamines and systemic glucocorticosteroids should be discontinued at least 3 days (allowing for 5 plasma half-lives) and 7 days, respectively, before CST.⁵³ In both methods, cold stimulation is applied to the volar (flexor) forearm for 5 minutes, followed by a 10-minute observation period.²⁶,⁵³ Typical ColdU is characterized by palpable whealing at the site of standard CST, appearing within this observation period (Fig. 2D). In atypical ColdU, 1) standard CST is negative at the contact site within 10 minutes or produces non-classical responses or 2) whealing is provoked only by modified CST (Table 4).

Table 3. Cold stimulation testing methods.

CST method		Explanation of procedure	Diagnosis if positive
(A) Standard CST
	Ice cube test	A 5-min ice cube application on the volar forearm, followed by a 10-min observation period.	Typical ColdU (wheal at test site ≤ 10 min)
	TempTest® device	A 5-min contact of the volar forearm with the TempTest®, followed by a 10-min observation period.	Typical ColdU (wheal at test site ≤ 10 min)
(B) Modified CST methods
	Natural exposure test	Patients are reexposed to conditions that previously triggered symptoms, if safe (e.g., cold weather challenge).	Inconclusive result
	Prolonged ice cube application test	Up to 10 min applied to the forearm.45	Likely typical ColdU requiring a stronger stimulus
	Cold pack test	A 4°C gel cold pack is applied to the forearm for 5 min.54	Likely typical ColdU requiring a stronger stimulus
	Hand immersion test	The hand, wrist and up to 5 cm of distal forearm are immersed in a tray filled with cold water and ice (≤ 10°C) for 5 min.45,55 Hypotension may occur.45,56	Likely typical ColdU requiring a stronger stimulus
	CST on atypical location	CST on body areas selected based on patient history. Usually an ice cube is used, though TempTest® has also been reported.57	Localized ColdU
	Cold room exposure test	Gradual cooling while seated in cold room wearing light clothing under medical supervision, as hypotension may occur.58,59	Presumably systemic ColdU
		Methods: air-conditioned room at 16°C−17°C (1 hr)60 or 4° (10−20 min).58,59
	Evaporative cooling test	A droplet of water or ethanol is applied to the skin and exposed to gentle airflow using a fan to promote cooling.55,61	Positive in ColdU triggered by combined cooling and moisture (e.g., sweating, swimming, rain). May also be positive in FACU or FCAS3/PLAID.
	Cold wet gauze test	Cold, wet gauze is applied to the skin and replaced every few min for 15 min.60	Unclear diagnosis
	Exercise in cold room	Exercise in air-conditioned room under medical supervision.	Cold-induced cholinergic urticaria

CST, cold stimulation testing; ColdU, cold urticaria; FACU, familial atypical cold urticaria; FCAS3, Familial cold autoinflammatory syndrome type 3; PLAID, PLCγ2-associated immune dysregulation.

Fig. 2. Standard CST methods.

For ice cube testing, an ice cube melting inside a non-latex glove is applied to the volar forearm for 30 seconds to 5 minutes (A). The TempTest^® 4.0 device, which generates a continuous temperature gradient from 4°C to 44°C (B), is applied to the volar forearm for 5 minutes (C). The results of both tests are assessed after 10 minutes; the skin is examined for palpable whealing (D). The CTT is determined using a transparent measurement template (E), and the wheal width can also be measured (F). (personal archive).

CST, cold stimulation testing; CTT, critical stimulation time threshold.

Table 4. Subtypes of cold urticaria.

Diagnosis	CST method (see also Table 3)	What is known
Typical ColdU26	Standard CST: ice cube test and/or TempTest® on the volar forearm	Whealing appears at the test site within 10 min.
Localized ColdU	Ice cube test or TempTest® on atypical location	Whealing only in specific areas has been reported: the face,62,63,64,65,66,67 hands,57 feet,57 vaccination site,68 and allergen immunotherapy sites.67,69,70
Localized cold-reflex urticaria71,72	Standard CST	Papular wheals appear near (but not at) the contact site. In real-life settings, wheals may be limited to the upper extremities.
Cholinergic-like contact urticaria73	Standard CST	Papular wheals appear at the contact site. It is unclear whether this represents a distinct subtype of ColdU.
Delayed ColdU74,75	Standard CST	Red, deep swelling appears 9–24 hours after the test. May be acquired74 or hereditary (due to an unknown genetic variant).75
Systemic ColdU58,76	Cold room exposure test	Triggered by systemic cold exposure with a drop in core and skin temperature.76
Food-dependent ColdU77	High-protein meal plus cold exposure	First described in 2018. Requires both food ingestion and cold exposure to trigger symptoms.
Cold-dependent dermographism59,78	Scratch test followed by cold exposure (e.g., immersion in cold water)	Wheals appear only when scratching is combined with cold exposure, not with scratching alone.
Familial atypical ColdU (FACU)61	Evaporative cooling test	Autosomal dominant inheritance. First reported in 2009. May be associated with ColdA. Lacks systemic inflammatory symptoms.
Cold-induced cholinergic urticaria79	Exercise in cold room	Wheals appear during exercise in a cold environment but not after warm showers, sweating, or exercise in a warm setting.

CST, cold stimulation testing; ColdU, cold urticaria; ColdA, cold-induced anaphylaxis.

The ice cube test can be performed by first tying the fingers of a non-latex (as latex may induce contact urticaria⁸⁰) glove together, then placing an ice cube with a small amount of water inside, and pressing it against the forearm. If a polyethylene bag is used instead, the ice may melt too quickly. If the test is positive, shorter predefined exposure times can be used to determine the critical stimulation time threshold (CSTT), which refers to the shortest duration of ice contact required to induce whealing. It typically ranges from 0.5 to 5 minutes. Using 2 ice cubes simultaneously (e.g., one for the 5-minute test and the other for shorter durations) can save time (Fig. 2A). To avoid cold-induced desensitization, testing should be done at separate skin sites.⁴⁵

The TempTest^® is a thermoelectric device. The earlier 3.0 version includes 12 circular metal elements with fixed temperatures ranging from 4°C to 26°C in 2°C increments. The updated 4.0 version features a U-shaped Peltier element that generates a continuous temperature gradient from 4°C to 44°C (Fig. 2B). The TempTest^® can be used to: 1) confirm a diagnosis of ColdU, 2) measure the critical temperature threshold (CTT), which is the highest temperature (≥ 4°C) at which whealing occurs (Fig. 2D and E), and 3) determine the maximum wheal diameter (Fig. 2F).²,²⁶

In COLD-CE phase 2, among patients tested with both the ice cube and TempTest^® (n = 318), 80.8% had positive results on both tests, 16.7% were positive only with the ice cube, and 2.5% only with the TempTest^®.² The ability of the ice cube test to detect reactivity in patients who tested negative with the TempTest^® suggests that it may capture cold sensitivity specific to lower temperatures.² Conversely, the TempTest^® identified responses in 2.5% of patients who were negative on the ice cube test. It has previously been reported that, in some patients, whealing occurs only in response to stimuli warmer than the temperature of ice.⁶⁰,⁸¹

Although discrepancies between the 2 tests are minor, performing both CST methods is valuable, particularly when one test yields a negative result despite a convincing clinical history. Moreover, the TempTest^® 4.0, with its constant 2-millimeter wide metal element (in contrast to the variable size and shape of the ice cube), enables quantitative assessment of wheal diameter and thus provides additional insights into individual cold sensitivity. It also offers standardized and reproducible results, which are essential for retesting patients, assessing therapy responses, or conducting multicenter studies. In contrast, the ice cube test, while simpler and more accessible, has limitations. Its temperature may vary depending on freezer conditions, even though adding water helps stabilize it at 4°C (the melting point of ice). Additionally, it may cause discomfort at the contact site.

Both CSTT and CTT vary significantly among patients. In COLD-CE, a strong correlation was observed between shorter CSTT, higher CTT, and larger wheal size.² Patients who required shorter cold exposure to elicit a reaction also reacted at higher temperatures (i.e., higher CTT) and tended to develop larger wheals.²

MODIFIED CST

A negative result on standard CST may suggest an atypical form of ColdU. In such cases, patients should be asked to describe specific situations that triggered whealing, which can guide the use of modified CST tailored to their history (Table 3). These methods are not standardized and should not be used as first-line tests. Caution is advised because hypotension may occur, particularly with the hand immersion test⁴⁵,⁵⁶ and the cold room exposure test.⁵⁸,⁵⁹

ATYPICAL ColdU

Various forms of atypical ColdU have been reported, mainly in case reports or case series (Table 4). These remain poorly defined with respect to their prevalence, diagnostic criteria, and clinical presentations.⁸² Diagnosis can be based on clinical presentations, atypical responses to standard CST, and/or positive results on modified CST methods (Table 4). Negative standard CST results have been associated with spontaneous wheals, suggesting that some patients may have cold-exacerbated CSU rather than true ColdU. They have also been linked to a lower frequency of ColdA.⁴

HIGH-RISK FEATURES

Although the fatality rate of ColdA remains unknown, early recognition of patients at risk is essential. The most important clinical predictor of ColdA is MAO.²,²⁶ The COLD-CE data revealed that approximately one-third of patients with typical ColdU experience MAO triggered by cold foods or beverages and provided evidence that MAO is a high-risk feature, as these patients showed greater cold sensitivity and a higher frequency of ColdA.² Additional features associated with a history of ColdA include longer disease duration, generalized wheals, earlobe itching, prior Hymenoptera venom–triggered anaphylaxis (which may indicate clonal mast cell disease), shorter CSTT, higher CTT, larger wheal diameter, and wheals extending beyond the stimulation site during CST (i.e., pseudopodia).²⁵,²⁶,⁸³

DIFFERENTIAL DIAGNOSIS

Acquired and hereditary forms of ColdU (Table 4) must be differentiated from monogenic familial cold autoinflammatory syndromes, which have been linked to pathogenic variants in 5 genes to date (familial cold autoinflammatory syndrome types 1–4 [FCAS1–4] and factor XII–associated cold autoinflammatory syndrome [FACAS]; Table 5).⁸⁴ These syndromes are mediated by interleukin-1 or factor XII and typically present in infancy.⁵ In addition to skin reactions after cold exposure, patients develop systemic inflammatory symptoms such as fever, chills, headache, fatigue, conjunctivitis, joint swelling, muscle pain, and joint pain. Standard CST results are negative.⁸⁴

Table 5. Differential diagnoses of cold urticaria: monogenic familial cold autoinflammatory syndromes and FCU.

Diagnosis	First described (yr)	Gene/locus
FCAS1	1940 (disease), 2001 (gene)	NLRP3 gene
FCAS2	2008	NLRP12 gene
FCAS3 or PLAID	2012	PLCG2 gene
FCAS4	2014	NLRC4 gene
FACAS	2020	F12 gene
FCU	2000	Locus on 1q44

FCU, familial cold “urticaria”; FCAS, Familial cold autoinflammatory syndrome (types 1–4); PLAID, PLCγ2-associated immune dysregulation; FACAS, factor XII–associated cold autoinflammatory syndrome.

ColdU must also be differentiated from familial cold “urticaria” (FCU), an autosomal dominant inflammatory disorder linked to a locus on chromosome 1q44 (Table 5). FCU presents with systemic inflammatory symptoms, a non-pruritic maculopapular exanthem, swelling of the extremities, and leukocytosis following generalized cold exposure.⁸⁵

MANAGEMENT

Key components of effective management include: 1) avoidance of cold triggers, 2) education regarding high-risk activities, 3) use of adrenaline (epinephrine) for ColdA, 4) regular monitoring of disease activity and control, and 5) pharmacologic treatment. The primary goals are to achieve disease control and prevent ColdA. Management should be individualized on the basis of disease severity, exposure risk, and treatment response.

Patients should be advised to avoid known cold triggers and educated about activities that pose a high risk for ColdA. Complete avoidance of all cold exposure is usually unnecessary; instead, patients should focus on avoiding specific triggers that have previously caused reactions. Cold foods and beverages should be avoided if they are not tolerated. Particular caution should be taken with cold water immersion, which increases the risk of ColdA.

Anesthesia and surgical teams should be informed about a patient's ColdU diagnosis and the potential risk of intraoperative ColdA. Preventive measures include maintaining normothermia with warming blankets, keeping the operating room temperature above 21°C, and pre-warming intravenous fluids. Caution is also needed with cold parenteral medications (e.g., vaccines and biologics).²⁵,⁸²,⁸⁶

Immediate intramuscular injection of adrenaline is the first-line treatment for ColdA. Antihistamines and glucocorticoids should not be used as substitutes for anaphylaxis.⁴⁸ Patients must be educated to recognize the clinical signs and symptoms of ColdA and respond appropriately. High-risk individuals (see section on “High-Risk Features” above), particularly those with a history of ColdA and/or MAO, should be prescribed an adrenaline autoinjector, instructed on when and how to use it, equipped with a medical alert bracelet, and followed up regularly. They should also be instructed to lie flat with their legs elevated during an episode.⁴⁸ COLD-CE data showed that only a minority of patients received adrenaline during ColdA or were prescribed an autoinjector.⁴⁷

Management should also include the use of patient-reported outcome measures (PROMs). The ColdU Activity Score is the first disease-specific PROM developed for daily assessment of ColdU disease activity. It includes 4 questions addressing the frequency and severity of wheals or angioedema, frequency and severity of symptoms, exposure to triggers, and avoidance behavior.⁸⁷,⁸⁸ The Urticaria Control Test is used to assess control of ColdU. It contains 4 questions, each scored from 0 to 4; a total score of ≥12 indicates controlled disease.⁶

Cold desensitization has been shown to reduce the CTT and cold-induced symptoms. This approach, performed under supervision, involves gradually increasing exposure to cold showers or baths by extending the area of skin exposed and progressively lowering the water temperature. However, it is rarely used in routine practice due to the risk of systemic reactions and the need for daily exposure to maintain efficacy.⁶,⁸⁹

Some patients may require only minimal therapy if they can avoid exposure. However, avoidance alone is often insufficient, and pharmacologic treatment is usually necessary. Second-generation H₁-antihistamines (sgAHs) are the first-line symptomatic treatment and should be continued until remission is achieved. For patients with seasonal disease patterns (e.g., winter-only symptoms), treatment may be confined to symptomatic periods. Desloratadine,⁹⁰,⁹¹ bilastine,⁹² and rupatadine⁹³ have demonstrated efficacy in randomized trials and case reports. As in other types of chronic urticaria, sgAHs can be increased up to 4 times the standard dose to achieve control.⁹⁰,⁹¹,⁹²,⁹³

Omalizumab, a monoclonal anti-IgE antibody, is not licensed for ColdU, but has shown efficacy in case reports and in one randomized, placebo-controlled trial.²²,⁹⁴ It may be considered off-label for patients with inadequate control on high-dose sgAHs. Some individuals may benefit from omalizumab only during the coldest months.

In severe and refractory cases, cyclosporine may be considered, but supporting evidence is limited to case reports.⁹⁵ Several other biologics approved for other indications have also shown benefit in ColdU in case reports, including anakinra (anti interleukin-1),⁹⁶ etanercept (anti tumor necrosis factor),⁹⁷ reslizumab (anti interleukin-5),⁹⁸ and dupilumab (anti interleukin-4 and -13).⁹⁹,¹⁰⁰

Several investigational therapies are currently being studied in ColdU, including biologics and small-molecule inhibitors. These include EP262, a previously mentioned MRGPRX2 receptor antagonist; YH35324, an IgE-trap protein; remibrutinib, a Bruton's tyrosine kinase inhibitor; and barzolvolimab, an anti-KIT monoclonal antibody.⁵ A schematic overview of current and investigational therapeutic targets in ColdU is shown in Fig. 1.

CONCLUSION

ColdU presents with a broad spectrum of clinical manifestations, ranging from localized wheals to potentially life-threatening ColdA. Diagnosis remains clinical and is primarily supported by CST, which may yield negative results despite a convincing patient history. This highlights the urgent need for improved and standardized CST methods. Importantly, not all types of cold exposure provoke symptoms equally across patients, reflecting significant clinical heterogeneity of ColdU.²¹

Most of the existing hypotheses regarding ColdU pathogenesis are based on studies conducted 4 to 6 decades ago, with little progress since.¹²,¹⁵ Retrospective measurement of tryptase levels could help support the diagnosis of ColdA. According to the EAACI anaphylaxis guideline, tryptase should be measured 30 minutes to 2 hours after symptom onset and again at least 24 hours after complete resolution.⁴⁸

Pharmacologic treatment is often required, but sgAHs frequently fail to achieve adequate disease control at standard doses. High-risk patients should be equipped with adrenaline autoinjectors and educated on avoiding known triggers and responding to emergencies.

Future research should aim to clarify the mechanisms underlying the marked clinical variability observed in ColdU. Differences in cold reactivity, ranging from isolated cutaneous symptoms to mucosal involvement, most likely determine whether reactions remain localized or escalate to ColdA. Ultimately, the development of more effective, targeted therapies is essential to improve outcomes for patients with ColdU and ColdA.