7/30/2019 Physical and Cold Urticarias
1/26
PHYSICAL URTICARIAS
INTRODUCTION Physical urticarias are disorders in which urticaria (ie, hives or wheals) are induced by
environmental stimuli, such as heat, cold, pressure applied to the skin, exercise, water, vibration, and
sunlight. These conditions probably result from heightened sensitivity by the mast cell to environmental
conditions, although the exact pathogenesis is unknown.
An urticarial lesion is an intensely pruritic, circumscribed, raised, erythematous plaque, which can range
in diameter from a few millimeters to many centimeters (picture 1 and picture 2). Urticaria may enlarge,
sometimes developing central pallor, and coalesce with other adjacent lesions. They usually appear in
crops and are typically short-lived, expanding and then resolving over a few hours without leaving
residual marks on the skin (unless there is trauma from scratching).
Physical urticarias will be discussed in this topic review. Other disorders of acute and chronic urticaria
are reviewed separately. (See "New onset urticaria: Epidemiology, clinical manifestations, and
etiologies" and "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history" and "Chronic
urticaria: Standard management and patient education".)
GENERAL POINTS ABOUT PHYSICAL URTICARIAS Before discussing individual syndromes, it is helpful
to review some observations about the physical urticaria disorders as a group.
Physical urticarias are considered subtypes of chronic urticaria (CU). In some patients, a specific physical
stimulus is the only trigger for hives, whereas in others, a physical stimulus is an identifiable factor in a
case of otherwise idiopathic urticaria. A minority of patients have hives triggered by multiple physical
stimuli.
Prevalence Considered together, the physical urticarias are present in approximately 20 to 30 percent
of adults with chronic urticaria, a disorder that afflicts approximately 1 percent of adults. Physical
urticarias may be more common in children [1]. The prevalence of these disorders in the generalpopulation is not well defined, and many cases may be mild and easily managed in the primary care
setting. In contrast, most published reports are based upon patient populations referred to specialty
centers, and so may overestimate the severity and persistence of these disorders.
Classification There are differences among experts concerning the best manner of classifying the
physical urticarias. Guidelines for classification and diagnosis have been published by a European expert
panel [2]; the material in this topic review is similar, although not identical.
Variations in clinical presentation and severity Physical urticarias vary widely in severity. The
symptoms of each syndrome can range from mild to disabling, with some patients experiencing
potentially dangerous systemic symptoms.
Testing Specific testing procedures are presented in the discussions of each disorder below and
summarized in the table (table 1) [3]. However, there are some general points to consider in performing
challenge procedures for physical urticarias.
Precautions Physical challenges are not always needed for diagnosis, although they are sometime
invaluable in clarifying or confirming the diagnosis. These challenges are usually performed by allergy
specialists with training in the management of the systemic allergic reactions that could conceivably
7/30/2019 Physical and Cold Urticarias
2/26
result in anaphylaxis. Proper access to the staff and equipment necessary to treat a potentially life-
threatening allergic reaction is essential. This is especially true if the patient has experienced systemic
symptoms in the past (eg, bronchospasm or hypotension).
During these challenges, physical stimuli are applied to the skin for a specified amount of time, usually a
few minutes, and then removed. Urticaria typically develops AFTER removal of the stimulus. Leaving the
stimulus in contact with the skin until hives actually appear can result in excessive exposure and
systemic symptoms. Similarly, exposure time may need to be reduced in patients who describe unusual
levels of sensitivity.
When to refer Patients suspected of having a syndrome of physical urticaria should be referred to an
allergy or dermatology specialist with experience in these disorders in the following situations:
The diagnosis is not apparent, orThe condition does not respond adequately to initial therapy
As mentioned previously, referral is usually appropriate if a challenge procedure is being considered.
Patients with past systemic reactions/anaphylaxis should be referred to allergists specifically, because of
the potential risk involved in challenging such patients.
OVERVIEW OF TREATMENT APPROACH The treatment of physical urticarias should be approached in
a stepwise manner. Avoidance of the physical stimuli that induce symptoms should always be
considered initially, although complete avoidance may not be possible or practical.
Pharmacologic therapy is often required but variably successful. Certain types of physical urticaria (eg,
dermographism) are responsive to antihistamines, while other forms (eg, local heat urticaria) are
typically resistant. However, therapy must be individualized in each case, often by trial and error. In
addition, most studies of therapy in these disorders were performed with first-generation, sedating H1
antihistamines, and the relative effectiveness of the newer second- and third-generation drugs has not
been evaluated.
In most patients with a physical urticaria disorder who cannot avoid the stimulus, a trial of
antihistamines is warranted. The approach outlined here is opinion-based, since trials comparing
different regimens are lacking.
We usually begin with a second or third generation H1 antihistamine at standard doses, but quickly
increase to double the standard dose (eg, cetirizine 10 mg twice daily, fexofenadine 180 mg twice daily,
or loratadine 10 mg twice daily) if needed.If symptoms are not controlled, we add an H2 antihistamine
at standard dose. If there is no detectable improvement, the H2 antihistamine can be discontinued.If the
response is still not adequate, we usually change the second generation H1 antihistamine to a first
generation agent, and increase the dose as tolerated (eg, hydroxyzine, beginning with 25 mg at bedtime,
and increasing gradually to an upper limit of 100 to 200 mg daily, divided among four doses).
When symptoms of physical urticaria cannot be controlled with combinations of antihistamines, oral
glucocorticoids may be used for short-term treatment and are usually very effective. We typically
continue antihistamines and begin glucocorticoid therapy with prednisone, 0.5 to 1.0 mg per kg daily.
Symptoms usually improve within days. The dose can then be tapered gradually over two to four weeks
to discontinuation, or at least to
7/30/2019 Physical and Cold Urticarias
3/26
sparing agent should be considered, as the long-term side effects of glucocorticoids make chronic
therapy undesirable. (See "Major side effects of systemic glucocorticoids".)
Agents that have been found to be useful for particular physical urticaria syndromes are discussed in the
sections below, as are alternate therapies for refractory disease. The treatment of chronic idiopathic
urticaria is reviewed in detail separately. (See "Chronic urticaria: Standard management and patient
education".)
DERMOGRAPHISM Dermographism (also called dermatographism) literally means to ''write on the
skin.'' Patients with this condition develop the rapid onset of a wheal and flare reaction after firm
stroking, scratching, or the application of pressure to the skin. Dermographism is the most common of
the physical urticarias and is often an incidental finding in the evaluation of other skin conditions, most
commonly atopic dermatitis, chronic idiopathic urticaria, and the other physical urticarias discussed in
this article.
There are several forms of dermographism. Most individuals have simple dermographism, which is
asymptomatic (non-pruritic) other than the raised urticarial welts that form on the skin with scratching,
etc. (picture 3 and picture 4). The other forms of dermographism are symptomatic and vary in theirclinical appearances.
Epidemiology Simple dermographism is the most common form and is thought to occur in
approximately 2 to 5 percent of the general population [4,5]. The symptomatic forms of dermographism
are much less common and usually occur sporadically, although there is a single case report of familial
dermographism [6].
Clinical features In simple dermographism, a wheal is provoked by stroking the skin with a firm
object. The wheal typically appears within 6 to 7 minutes and begins to fade 15 to 30 minutes later [4].
Symptomatic dermographism is only slightly different, with lesions appearing in less than 5 minutes andlasting 30 minutes [2]. In addition to classic wheals, variants of symptomatic dermographism have been
described in which the reactions are follicular [7] or inflamed and swollen (red dermographism) [8].
Although a purposeful stroking of the skin is the most common way to elicit symptoms, patients often
are unaware of the inciting action. Occasionally, idiopathic pruritus or pruritus caused by dry skin can be
the event that elicits scratching and subsequent dermographism. In this setting, the wheals are typically
linear. Simple actions such as scratching, leaning against a solid object, or irritation from clothes or bed
sheets may provoke whealing. In one case series, dermographism could be exacerbated by hot water,
emotion, exercise, or cold exposure [9].
Dermographism is typically idiopathic and begins without a clear inciting event. However, inflammatory
perturbations may occasionally precede onset, as cases have been described in which symptomatic
dermographism appeared to be triggered by infections with bacteria, fungi, and scabies [10,11] or after
receiving penicillin [12] or famotidine [13].
Pathogenesis The cause of dermographism is unknown. The release of vasoactive mediators from
cutaneous mast cells is assumed to be involved, and elevated levels of serum histamine have been
demonstrated after a whealing episode [14]. Experiments in which serum from a dermatographic
7/30/2019 Physical and Cold Urticarias
4/26
patient injected intradermally into a monkey transferred dermographism suggest that the reaction may
be IgE-mediated, although no allergen has been identified [14,15].
Diagnostic testing Patients with dermographism can be diagnosed in an office setting by stroking the
skin with a firm (clean) object, such as a tongue blade (table 1). This action provokes a typical wheal-
and-flare response within a few minutes, as described earlier. The patient should refrain from taking
antihistamines for several days before the test.
Treatment Simple dermographism that is non-pruritic requires no therapy, and treatment involves
avoidance of inciting triggers. If the skin appears dry, emollients (such as hydrated petrolatum applied
daily, immediately after bathing) can be helpful.
H1 antihistamines have been shown to be effective for treatment of pruritus and reduction of whealing,
and are the initial drug of choice. Both first-generation antihistamines, such as hydroxyzine, and second-
generation H1 antihistamines, such as cetirizine, have demonstrated benefit, although studies
comparing different antihistamine regimens are lacking [8,16-18].
It is our practice to initiate therapy for symptomatic dermographism with non-sedating second-generation H1 antihistamines, as described above. (See 'Overview of treatment approach' above.)The
addition of an H2 antihistamine was beneficial in several studies [17,19,20], although not all concluded
that there was an additive effect [14]. A trial of combination therapy with an H1 and H2 antihistamine is
warranted if the response to H1 antihistamines alone is inadequate.Some patients report that sun
exposure improves the condition, and one uncontrolled study of 43 patients reported that 39 improved
or cleared with ultraviolet B (UVB) light treatment [21]. Such aggressive therapy could be considered in a
patient refractory to standard medications and with a severe decrease in quality of life (eg, poor sleep,
poor performance at work or school, negative effect on social life).Case reports describe successful
treatment with omalizumab [22], although this application is not approved by the US Food and Drug
Administration.
DELAYED PRESSURE URTICARIA/ANGIOEDEMA Delayed-pressure urticaria/angioedema (which is
sometimes classified as a delayed form of symptomatic dermographism) presents most commonly as an
erythematous swelling of the skin that develops four to six hours after pressure has been applied to the
area.
Clinical manifestations The leading presentation is erythematous swelling of the skin four to six hours
after the application of pressure. Less often, patients develop urticaria with prominent swelling. The
amount of pressure that is needed to induce symptoms varies among different individuals. Patients
often describe burning and pain instead of or in addition to pruritus, and the swelling can last several
hours to several days [2]. There may be accompanying arthralgias [10].
Activities that typically induce symptoms in patients with delayed-pressure angioedema include wearing
tight clothing (affecting areas of constriction), sitting for prolonged periods of time on a hard surface
(affecting the buttocks), an extended period of walking (affecting the soles and feet), or carrying heavy
bags of groceries (affecting the palms and hands). Some patients will wake up with facial swelling on the
side of the face that was compressed against the pillow.
Diagnosis Delayed pressure urticaria/angioedema can often be accurately diagnosed based upon
historical features alone. Devices called dermographometers have been used in research protocols in
7/30/2019 Physical and Cold Urticarias
5/26
the past, but are not widely available [23,24]. Alternatively, a sling attached to a 10 pound weight may
be placed over the patient's arm for 20 minutes [25], after which the patient is instructed to observe the
compressed skin for symptoms over the next 24 hours (table 1). The patient should refrain from taking
antihistamines for several days before the test.
Treatment The approach to treatment of delayed-pressure urticaria/angioedema is similar to that of
symptomatic dermographism, although antileukotriene agents have also shown utility [26-28].
In a randomized trial of 36 patients with delayed pressure urticaria confirmed by challenge with a
dermographometer (18 of whom had concomitant chronic idiopathic urticaria), patients were assigned
to one of three treatment groups [28]:
Oral desloratadine (5 mg once daily) plus oral placeboOral desloratadine (5 mg once daily) plus
montelukast (10 mg once daily)Oral placebo alone
Subjects were rechallenged after two weeks of therapy. Patients in both active treatment groups
showed a significant reduction in the mean diameter of the induced wheals compared to placebo, and
patients in the group receiving montelukast were significantly better than those receivingdesloratadine alone, with fewer episodes and reduced symptoms. The use of other antihistamines in
combination with montelukast has not been studied, although different agents are probably also
effective.
A few case reports describe successful treatment with omalizumab [29,30], although this application is
not approved by the US Food and Drug Administration.
CHOLINERGIC URTICARIA Cholinergic urticaria (sometimes called generalized heat urticaria) describes
hives that are precipitated by an increase in core body temperature. Common triggers include exercise,
strong emotions, and bathing in hot water [31].
Epidemiology Cholinergic urticaria is believed to account for approximately 30 percent of all cases of
physical urticaria and approximately 5 percent of all cases of chronic urticaria [32]. Cholinergic urticaria
typically has its onset during the second or third decade of life [33-35]. Whereas one study noted a
predominance in male patients [33], others have found that both sexes are affected equally [34,35].
Familial cases are rare but have been reported (in which all affected individuals were male) [36].
Clinical features The classic initial appearance of cholinergic urticaria is that of numerous small (1 to 3
mm), punctate wheals surrounded by large flares (picture 5). Many patients note a tingling, itching, or
burning sensation of the skin before the appearance of the hives [33]. As the response progresses, the
flares may coalesce to form large areas of erythema. The wheals typically begin on the trunk and neck
and spread distally to involve the face and extremities, although lesions may begin anywhere on the
body. In rare cases, cholinergic urticaria has been reported to progress to include systemic symptoms
such as hypotension, angioedema, and bronchospasm [33,37,38].
As mentioned earlier, any trigger that results in an elevation of core body temperature may provoke the
onset of cholinergic urticaria. Exercise is one of the most common triggers, and cholinergic urticaria may
be confused with exercise-induced urticaria if other triggers are not considered. However, the two
conditions can usually be distinguished, because a variety of triggers precipitate cholinergic urticaria,
7/30/2019 Physical and Cold Urticarias
6/26
while exercise or exertion is usually the sole trigger for exercise-induced urticaria. (See 'Exercise-induced
urticaria' below.)
Other typical inciting factors for cholinergic urticaria include hot baths or showers, strong emotional
feelings, and ingestion of spicy or hot foods [33,34]. In one study, a patient with preexisting cholinergic
urticaria experienced a flare of his condition while undergoing dialysis treatments [39]. A decrease in the
patient's dialysate temperature by 1.5C led to resolution of his symptoms, and rechallenge with fluid at
a higher temperature reproduced his urticaria.
Pathogenesis As with many of the other physical urticarias, a variety of pathogenetic mechanisms
have been postulated in cholinergic urticaria, and there may be different mechanisms at work in
different patients. Elevated levels of histamine have been detected in the serum during an attack [38].
One theory of pathogenesis proposed that urticaria in this condition was caused by the cholinergic
nervous system [37]. In some patients, the injection of methacholine intradermally induces urticaria,
which can be reversed by administration of atropine [33,40,41]. Patients with cholinergic urticaria have
been shown to have an increased number of muscarinic receptors on cutaneous mast cells in areas that
demonstrate hives [42].The presence of a more typical antigen-antibody reaction or a transferableserum factor has been investigated in a series of passive transfer experiments using sera from patients
with cholinergic urticaria that were injected into the skin of a primate [43]. When the monkey
subsequently was injected with acetylcholine, a cutaneous reaction was observed with 7 of 16 patient
sera. (See 'Diagnosis and testing' below.)Many of the triggers for cholinergic urticaria also lead to
increased sweating, and a subgroup of patients with symptoms suggestive of cholinergic urticaria have
urticaria only in response to sweating.
Several studies have suggested that cholinergic urticaria might be caused by an IgE-mediated allergy to
some component of human sweat [44-47]. Some patients demonstrate immediate reactions to skin
testing with their own diluted sweat [44,47,48]. An IgE-mediated mechanism was also implicated in a
case report of a patient successfully treated with anti-IgE therapy [46]. Another found that a group of 18patients with cholinergic urticaria appeared to have two separate mechanisms for their condition [45].
One subset reacted when skin tested to their own sweat, and had a positive acetylcholine skin test. The
rest of the patients had a negative acetylcholine test and were skin test negative to sweat.
There have been several reports of patients with cholinergic urticaria that was associated with
hypohidrosis [49,50]. An explanation was proposed that occlusion of the pores of the stratum corneum
could cause hypohidrosis and subsequent abnormal leakage of inflammatory sweat materials into the
upper dermis, resulting in a whealing reaction [50].
Diagnostic testing The presentation of the lesions of classic cholinergic urticaria in the context of
typical inciting triggers is often sufficient to make the diagnosis, and a clinical diagnosis is usually all that
is required in routine practice. However, several methods of provocation testing have been proposed,
which are largely used in research settings (table 1):
An intradermal injection of 0.01 mg of methacholine in 0.1 mL saline that produces a local area of hives
is diagnostic. However, only about one-third of patients with cholinergic urticaria demonstrate a positive
test, so this procedure cannot be used to exclude the diagnosis [33,40]. In addition, there are currently
no injectable forms of methacholine commercially available in the United States.Another diagnostic
strategy used in research protocols involves non-exertional elevation of the patient's core body
7/30/2019 Physical and Cold Urticarias
7/26
temperature. Patients may have one or both arms submerged in a 40C hot water bath until the core
body temperature has increased at least 0.7C [51]. The appearance of generalized urticaria confirms
the diagnosis of cholinergic urticaria.
Treatment Identification and avoidance of known triggers are the first steps in controlling cholinergic
urticaria. Bathing in hot water and performing strenuous exercise during hot weather are to be avoided.
Medical therapy consists predominantly of oral H1 antihistamines. Typically these are taken daily,
although as needed administration is possible if triggers are easy to identify in advance.We usually
initiate therapy with a second generation antihistamine, as described previously. (See 'Overview of
treatment approach' above.) Cetirizine, a less sedating metabolite of hydroxyzine, has shown efficacy at
doses twice normal (10 mg twice daily) [52].If cetirizine at twice normal dose is not effective, we
typically change to the first generation antihistamine hydroxyzine, which has been used successfully for
decades [5,34]. This agent is highly sedating for some patients. Therapy should be initiated with a low
dose which is increased gradually until the urticaria is controlled, which typically occurs at doses of 100
to 200 mg divided over 24 hours. Studies comparing the hydroxyzine to cetirizine have not been
performed, but clinical experience suggests that some patients who do not respond to cetirizine do
respond to hydroxyzine.Ketotifen (not available in the United States) has also shown efficacy in treatingcholinergic urticaria at doses of 3 to 8 mg daily [53,54]. This agent is highly sedating for some
patients.The anabolic steroid danazol can be effective [55,56]. This agent is postulated to correct the
low blood levels of protease inhibitors that occur in some patients with cholinergic urticaria [57]. Given
its potential for adverse effects, however, this medication should be reserved only for severe cases
refractory to antihistamines.Omalizumab has been used successfully in the treatment of cholinergic
urticaria [46,48], although failures are also reported [58].Desensitization may be possible as patients will
sometimes experience a period of latency after an episode of cholinergic urticaria. In most cases, these
relatively symptom-free periods lasted only a few hours but could last more than 24 hours if the initial
episode was severe. One study described two patients who treated themselves on a nightly basis using a
dose of antihistamine that was followed three hours later by a hot bath [34].Oral anticholinergic agents
have NOT been shown to be effective [34].
Prognosis The prognosis for cholinergic urticaria is generally favorable. One study reported only 31
percent of patients with a persistence of symptoms greater than 10 years [33]. Another estimated that
the average duration of symptoms is 7.5 years (range, 3 to 16 years) [59].
LOCAL HEAT URTICARIA Local heat urticaria describes a rare disorder in which a warm stimulus must
come into direct contact with the skin and results in the formation of a wheal at the heated site within
minutes [25]. The pathogenesis involves histamine release, implicating the mast cell in the cause of this
condition [60]. Passive transfer experiments, however, have been negative. There is one case report of a
familial, delayed-type variant of local heat urticaria [61].
Diagnostic testing is conducted by the application of a test tube containing water at 44C to the arm for
four to five minutes [25]. Other authors recommend using a cylinder heated to 50C to 55C [51] (table
1). A localized hive should develop within a few minutes after removal of the heated object. The patient
should refrain from taking antihistamines for several days before the test. Occasionally, positive test can
only be obtained on specific areas of skin that have displayed symptoms in the past [62].
7/30/2019 Physical and Cold Urticarias
8/26
Therapy using antihistamines and oral cromolyn has not been effective for local heat urticaria [25].
Desensitization using daily hot baths was successful in one patient but carries some risk for a systemic
reaction [63].
EXERCISE-INDUCED URTICARIA Urticaria with exercise has been shown to occur in two distinct
situations.
Cholinergic urticaria Patients with cholinergic urticaria develop hives after exercising or after
experiencing any other trigger that elevates core body temperature. Systemic symptoms are
uncommon, but can occur. (See 'Cholinergic urticaria' above.)Exercise-induced anaphylaxis Urticaria
with exercise may also be an early manifestation of exercise-induced anaphylaxis. Unlike in cholinergic
urticaria, exercise is the only trigger in exercise-induced anaphylaxis, and passively raising the core body
temperature is not sufficient to induce symptoms. This disorder is reviewed in detail elsewhere. (See
"Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, and diagnosis".)
The hives of exercise-induced anaphylaxis are typically larger in size than those of cholinergic urticaria,
although cases of exercise-induced anaphylaxis presenting with punctate lesions have been reported.
AQUAGENIC URTICARIA Aquagenic urticaria is a rare condition in which urticaria develop as a result
of direct skin contact with water.
Epidemiology There are fewer than 50 cases of aquagenic urticaria reported in the medical literature
[2,64-68]. Women seem to have a slightly higher incidence than men, and in most cases, the age of
onset is during or slightly after puberty. Familial occurrences have been reported on several occasions
[65-67]; in one report the condition existed across three generations of a single family [65].
Clinical features The lesions of aquagenic urticaria are characteristically small, punctuate (1 to 3 mm),
perifollicular wheals that may occur on all parts of the body, although generally not on the palms and
soles. In appearance, they are indistinguishable from the wheals of cholinergic urticaria. However, inaquagenic urticaria, hives appear rapidly after direct contact with various sources of water (ie, distilled,
tap, or saline).
In some patients, salinity appears to be important. One patient experienced urticaria after exposure to
tap water, snow, and sweat but did not develop symptoms after exposure to sea water [69]. Another
developed hives on exposure to sea water, but not fresh water, although over time she also because
sensitive to tap water as well [70]. Hive formation is not influenced by the temperature or pH of the
water [68]. Alcohol and other liquid organic solvents applied to the skin do not lead to wheal formation
[67,68]; however, they can potentiate the reaction to water, likely by enhancing the permeability of the
skin [71].
Wheals appear rapidly within 20 to 30 minutes following exposure to water; once the water source is
removed from the skin, the wheals generally fade within 30 to 60 minutes [2]. Systemic symptoms are
rare, but have been reported [66,72]. A refractory period lasting several hours has been demonstrated
after an attack [73]. Repeated, short, purposeful exposures to water can lead to exhaustion of the wheal
response [71].
7/30/2019 Physical and Cold Urticarias
9/26
Aquagenic urticaria is occasionally associated with other forms of physical urticaria. Case reports
describe patients with aquagenic urticaria and coexisting dermographism [66,74], cholinergic urticaria
[67,73,74], or cold urticaria [75].
Pathogenesis The pathogenesis of this condition is poorly understood and may not be the same in all
patients. Several theories have been proposed based upon studies in small numbers of subjects. Serum
histamine levels are variable from patient to patient, as is the response to pretreatment with oral
antihistamines.
The following mechanisms have been postulated:
Several researchers have proposed that water is primarily acting as a solvent in aquagenic urticaria,
solubilizing an antigen that then permeates the skin and activates dermal mast cells. Water may interact
with sebum (the oily substance produced by sebaceous glands in the skin) to form a substance capable
of acting as a direct mast cell degranulator, resulting in histamine release [64]. One study demonstrated
that patch testing with a patient's sweat produced only erythema, whereas testing with sweat and
sebum produced marked urticaria [68]. Others have proposed that the causative antigen(s) normally
reside at the epidermal layer of the skin and solubilization in water allowing these antigens to diffusemore deeply into the skin [67]. It is possible that different antigens in different skin layers are involved.
In another study, removal of the stratum corneum layer of the skin enhanced reactivity upon contact
with water [71]. Similarly, pretreatment of the skin with organic solvents enhanced wheal formation to
water. These investigators concluded that enhancing the ability of water to penetrate the stratum
corneum layer of the skin increases the wheal-provoking effects of water in these patients.Another
theory suggested that activation of the cholinergic pathway was essential for the formation of aquagenic
urticaria, based upon the ability of the acetylcholine antagonist scopolamine to suppress wheal
formation when applied to the skin before water exposure in two patients [71]. However, other studies
did not find evidence for a cholinergic mechanism, as pretreatment with atropine did not suppress
subsequent wheal formation [67]. In addition, methacholine injection testing, often positive incholinergic urticaria, was negative in a series of patients with aquagenic urticaria [68].
The studies reviewed above were performed before the publication of those implicating hypersensitivity
to sweat allergens in cholinergic urticaria, and comparative mechanistic studies of the two conditions
have not been undertaken. (See 'Cholinergic urticaria' above.)
Diagnostic testing The standard test for aquagenic urticaria is the application of a compress of 35C
water to the upper body for 30 minutes (table 1). Although water of any temperature can provoke
aquagenic urticaria, using ambient-temperature water avoids confusion with cold-induced or local heat
urticaria. The upper body is chosen as the preferred site, because other areas, such as the extremities,
are affected less commonly in aquagenic urticaria [76]. The patient should refrain from taking
antihistamines for several days before the test.
In some case reports, rinsing specific areas of the body with water or performing direct bath and shower
challenges has been attempted. Use of these approaches may be required when localized testing using a
small water compress is negative, although it should be avoided in patients with a history of significant
systemic symptoms.
7/30/2019 Physical and Cold Urticarias
10/26
Differential diagnosis Aquagenic pruritus, cholinergic urticaria, cold-induced urticaria, and local heat
urticaria may have inciting factors that can be confused with those of aquagenic urticaria.
Aquagenic pruritus is itching of the skin upon contact with water, without the development of actual
hives or other objective findings.Cholinergic urticaria can be elicited by sweating, exercise, heat, and
strong emotions, whereas aquagenic urticaria requires the skin to be in direct contact with water.Cold-
induced urticaria can be differentiated from aquagenic urticaria by the history of reactions upon
exposure to cold air and tolerance of warm or hot water.Local heat urticaria can be distinguished from
aquagenic pruritus by reactions to warm but dry triggers (heating pad or test tube filled with warm
water).
Treatment A trial of H1 antihistamines is warranted in all patients as an initial intervention, although
the success of these agents is variable [71,77].
Barrier creams were reported to be effective in a small number of patients, although this may only be
practical in very specific circumstances [71,76].
In cases in which antihistamines failed to provide symptomatic benefit, other measures have beenattempted. UVB light treatments twice a week in a child with coexisting aquagenic urticaria, cholinergic
urticaria, and dermographism resulted in improvement by 20 weeks [74]. Two reports have documented
the benefits of PUVA therapy [78,79].
Stanozolol was effective in a patient with HIV infection, hepatitis C virus infection, and aquagenic
urticaria, who had failed therapy with oral antihistamines [72]. Symptoms recurred when stanozolol was
stopped.
SOLAR URTICARIA Solar urticaria involves the induction of urticaria, most commonly following direct
exposure of the skin to sunlight [80]. The number of patients affected by this condition is small, and
most data are case reports and small series [81-84]. The largest series included 87 cases confirmed byphototesting [85].
Epidemiology Retrospective reviews of patients with urticaria found that only approximately 0.5
percent were classified as solar urticaria [81,82]. There is a higher incidence in women [83,85]. Patient
age at onset, atopic history, and the wavelength of light responsible for the reaction varies significantly
among patients. Geographic and racial differences have not been described.
Clinical features Solar urticaria generally presents with classic-appearing urticarial lesions developing
within minutes after exposure to direct sunlight, and occurring on skin that was uncovered (picture 6).
However, in the series of 87 cases, 76 and 83 percent developed symptoms through thin clothing and
glass, respectively [85]. Limited exposures provoke only itching or burning erythema, while more
prolonged exposures lead to typical wheals. A more delayed onset of symptoms (several hours after
light exposure) has been reported in a few patients [86,87].
The severity of the symptoms generally increases with the intensity of the sun exposure. Areas of skin
that frequently are exposed to sunlight are less sensitive than areas that are usually covered [88]. The
exact mechanism of this "hardening" phenomenon remains unknown [89]. A more severe reaction may
be provoked by purposeful sunbathing rather than by normal daily sunlight exposure. Systemic,
anaphylactic reactions are possible if the exposed body surface area is large enough [5].
7/30/2019 Physical and Cold Urticarias
11/26
When the patient is removed from the sun exposure, symptoms usually fade rapidly. Most patients note
disappearance of the urticaria within 24 hours.
Pathogenesis It has been hypothesized that solar urticaria is dependent on the presence in the skin of
a precursor molecule that is activated by exposure to a particular wavelength of light and becomes a
photoallergen. This antigen can be activated in vivo or in vitro by irradiating a sample of the patient's
serum [83]. The origin of the precursor molecule has not been determined yet. The fact that passive
transfer is not always successful could indicate that there are different photoallergens at work in
different patients. One group has suggested that the disorder be divided into two subtypes: type I solar
urticaria, due to IgE antibodies directed against an abnormal photoallergen present only in affected
patients, and type II solar urticaria, due to circulating IgE antibodies against a normal photoallergen
present in most people [90].
Diagnosis and testing Clinical history may be sufficient to differentiate solar urticaria from other
conditions. If there is clinical uncertainty, the diagnosis can be established using phototesting (table 1).
The patient should refrain from taking antihistamines for several days before the test.
A simple form of testing may be performed by exposing a small area of the patient's skin to natural
sunlight, which induces erythema or urticaria. The reaction generally fades quickly after the test is
halted. However, patients with cholinergic or local heat urticaria might react to this type of testing as
well.
More formal evaluation is performed with a visible light source, or using instruments that generate UVA
or UVB. The patient's skin is exposed to varying wavelengths using a monochromatic light source. Most
patients demonstrate a threshold wavelength at which symptoms develop, which is referred to as the
action spectrum. In some patients, testing with monochromatic light failed to provoke urticaria,
although exposure to other light sources, such as natural sunlight, high-intensity ultraviolet light, or
slide-projector light, did cause symptoms [84].
Some patients exhibit an inhibition spectrum, which when applied to the skin during or immediately
after the action spectrum, inhibits the development of the wheal reaction [91]. However, application of
the inhibition spectrum before the action spectrum does not prevent symptoms [83], so this
phenomenon has no immediate clinical utility.
Differential diagnosis A variety of photosensitive disorders have been described. Two that can
present with symptoms similar to solar urticaria are polymorphous light eruption and erythropoietic
protoporphyria. (See "Approach to the patient with macular skin lesions", section on 'Photodistributed
macular eruptions'.) The symptoms of solar urticaria could initially be mistaken for common sunburn,
however, the lesions of solar urticaria develop within minutes of sun exposure.
Polymorphous light eruption In this idiopathic condition, which is far more common than solar
urticaria, papular and papular-vesicular lesions appear on sun-exposed areas, although there is less of a
predilection for the face (picture 7 and picture 8). The lesions of polymorphous light eruption tend to
last two to six days, which usually allows differentiation from solar urticaria, in which lesions resolve
within 24 hours. (See "Polymorphous light eruption".)Erythropoietic protoporphyria This condition
can demonstrate urticaria on sun-exposed areas, although the lesions are typically painful rather than
pruritic. Erythropoietic protoporphyria usually presents in early childhood, and there is a family history
7/30/2019 Physical and Cold Urticarias
12/26
of the disorder. The cutaneous lesions of erythropoietic protoporphyria can develop within minutes of
sun exposure, and diffuse edema of the skin in sun-exposed areas may resemble angioedema. Petechiae
and purpuric lesions may be seen. With time, the skin may become lichenified and leathery, with labial
grooving and nail changes (picture 9). This disorder is reviewed separately. (See "Erythropoietic
protoporphyria".)
Treatment and prognosis H1 antihistamines provide symptomatic treatment and can be used orally
or topically. These medications are effective in reducing pruritus and wheal formation but may not
eliminate the erythema. In most of the initial studies, terfenadine was used, and higher-than-standard
doses often were required to achieve symptom relief [92]. Whether this finding is true for all
antihistamines, including some of the newer agents, remains to be determined. Topical and systemic
steroids can be used if antihistamines are insufficient. (See 'Overview of treatment approach' above.)
Desensitization may be useful in some cases. It has been demonstrated that skin that is regularly
exposed to sunlight becomes less reactive than that which is usually covered [88]. Patients may be
repeatedly exposed to ultraviolet light sources, although the desensitized state typically lasts only a few
days. The use of psoralen plus ultraviolet A radiation (PUVA) has been shown to induce a longer-lasting
effect, although the potential long-term adverse effects are greater [92].
At least one instance of the successful use of cyclosporine (4.5 mg per kg per day) for refractory solar
urticaria has been reported [93].
A small number of case reports describe resolution or improvement with omalizumab treatment
[30,94,95].
Plasmapheresis has been used alone and in conjunction with PUVA therapy [96-98]. This modality has
been reported to improve symptoms in the few patients included in these studies. One study failed to
demonstrate a lasting benefit with plasmapheresis [99]. The effectiveness of this therapy may depend
on the characteristics of the specific photoallergen at work (ie, circulating antigen versus cutaneousantigen).
The long-term outlook for patients with solar urticaria has been uncertain because of the small number
of cases. A review of 87 patients found that 25 percent of 60 subjects who were available for follow-up
reported complete resolution of their conditions [85]. An additional 32 percent reported improvement,
whereas 35 percent were unchanged, and 8 percent believed that their conditions had worsened. Most
of the original case reports indicated that the condition was persistent, and although many experienced
overall improvement in symptoms, few patients experienced complete resolution.
VIBRATORY ANGIOEDEMA Vibratory angioedema refers to the development of pruritus and swelling
after the application of a vibratory stimulus to the skin. Hives are usually not observed in this syndrome.
Epidemiology Reports of vibratory angioedema are rare. The condition was initially described in four
members of one family, in which there was an autosomal dominant inheritance pattern [100]. This was
followed by another familial report [101], and the condition was given the name hereditary vibratory
angioedema. Other case reports of patients with vibratory angioedema have been sporadic and
generally related to the subject's occupation.
7/30/2019 Physical and Cold Urticarias
13/26
Clinical features Common triggers for vibratory angioedema include mowing the lawn, riding a
motorcycle, horseback riding, or mountain biking. At risk occupations include jackhammer operator,
machinist [102], carpenter [102], and metal grinder [103].
Patients generally complain of local pruritus, erythema, and swelling arising within a few minutes after
exposure to vibration and affecting the area that was most exposed to the stimulus (often the hands).
There are rare cases of delayed onset symptoms beginning one to two hours after exposure [104].
Symptoms peak in severity at four to six hours and typically resolve by 24 hours. In some episodes, the
symptoms may persist for several days. The severity and duration of the symptoms may vary and seem
to be proportional to the intensity and duration of the applied vibratory stimulus and to the area of
exposed body surface. Patterson's initial report described systemic symptoms of headache and
generalized erythema [100]. One patient developed carpal tunnel syndrome, and slowed median nerve
conduction was documented only during episodes of edema [103].
Pathogenesis The pathogenesis of vibratory angioedema has not been satisfactorily elucidated yet.
Elevated levels of serum histamine and mast cell degranulation have been documented during
symptomatic episodes [102,104,105]. Most investigators favor a nonimmunologic reaction (eg, direct
mast cell stimulation from the vibration causes degranulation and local release of histamine) andpassive transfer experiments have been negative [100,105]. In a study of vibration exercise in 37 healthy
subjects, approximately one-half developed a pruritic erythematous eruption [106].
Diagnostic testing Several methods for reproducing the vibratory stimulus and classifying the reaction
have been used in the literature [2]. The patient should refrain from taking antihistamines for several
days before the test. The subject's arm is held on a level plane, and a vortex mixer is placed in contact
with the skin (table 1). The vibratory stimulus is applied for five minutes, and the site is observed for five
to six hours. The test is considered positive if the area becomes erythematous, pruritic, and edematous
around the full circumference of the arm, although one study found that this test also induced a positive
response in 7 of 20 normal volunteers [107], suggesting that this response may not be entirely
abnormal, as mentioned previously. Dermographism and pressure urticaria should be excluded usingthe appropriate tests.
Treatment Patient avoidance of specific vibratory stimuli is the first line of therapy, although this may
not be possible in occupational cases.
H1 antihistamines have been used successfully [108]. (See 'Overview of treatment approach' above.)
A state of tolerance was achieved in one patient by using twice-daily vibration challenges until
symptoms were delayed in onset and reduced in duration [105]. The patient eventually attained
complete control of her symptoms by using a five-minute desensitization protocol every five to seven
days. However, a state of tolerance could not be induced in another case report [108].
INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. (See
"Patient information: Hives (urticaria)".) We encourage you to print or e-mail this topic review, or to
refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.
SUMMARY AND RECOMMENDATIONS
7/30/2019 Physical and Cold Urticarias
14/26
Clinical manifestations Physical urticarias are forms of chronic urticaria in which hives (sometimes
with angioedema) are induced by environmental stimuli. Physical urticarias vary in severity from mild to
disabling. Some forms can escalate to systemic reactions and anaphylaxis. (See 'Introduction' above and
'Prevalence' above.)
The more common physical urticaria syndromes include dermographism, cholinergic urticaria, and
delayed pressure urticaria/angioedema.Rare disorders include urticaria/angioedema following exposure
to heat, exercise, water, vibration, or sunlight. (See sections on specific disorders above).
Diagnosis and treatment Physical urticarias can often be diagnosed based upon history and physical
examination. In some cases, physical challenge procedures are needed to clarify or confirm the
responsible trigger (table 1). These challenges are usually performed by allergy or dermatology
specialists with experience with these techniques, as overly aggressive challenges can induce systemic
reactions. Patients with past systemic reactions should only be challenged by an allergist in a medical
setting equipped to manage anaphylaxis. (See 'When to refer' above.)
The management of physical urticaria begins with accurate identification and avoidance of the triggering
stimulus.For initial pharmacotherapy, we suggest a less-sedating, second generation antihistamine(Grade 2C). Options include cetirizine (10 mg daily), loratadine (10 mg daily) or fexofenadine (180 mg
daily). Many patients will require a doubling of the standard dose to impact symptoms significantly (eg,
cetirizine, 10 mg twice daily). (See 'Overview of treatment approach' above.)Subsequent management
proceeds in a stepwise manner and includes H2 antihistamines, first generation H1 antihistamines, and
in some cases, limited courses of systemic glucocorticoids. (See 'Overview of treatment
approach' above.)Specific physical urticarias are more or less responsive to pharmacotherapy, and
others agents have shown utility in certain disorders (eg, antileukotriene agents in delayed pressure
angioedema). (See sections on specific disorders above).Steroid-sparing therapies should be considered
for patients requiring systemic glucocorticoids beyond two to three months. Depending on the disorder,
options include phototherapy, physical desensitization protocols, and immunomodulatory agents. (See
sections on specific disorders above).
Use of UpToDate is subject to the Subscription and License Agreement
REFERENCES
1. Khakoo G, Sofianou-Katsoulis A, Perkin MR, Lack G. Clinical features and natural history of physical
urticaria in children. Pediatr Allergy Immunol 2008; 19:363.
2. Kontou-Fili K, Borici-Mazi R, Kapp A, et al. Physical urticaria: classification and diagnostic guidelines.
An EAACI position paper. Allergy 1997; 52:504.
3. Magerl M, Borzova E, Gimnez-Arnau A, et al. The definition and diagnostic testing of physical and
cholinergic urticarias--EAACI/GA2LEN/EDF/UNEV consensus panel recommendations. Allergy 2009;
64:1715.
4. Kirby JD, Matthews CN, James J, et al. The incidence and other aspects of factitious wealing
(dermographism). Br J Dermatol 1971; 85:331.
5. Orfan NA, Kolski GB. Physical urticarias. Ann Allergy 1993; 71:205.
6. Jedele KB, Michels VV. Familial dermographism. Am J Med Genet 1991; 39:201.
7. Shelley WB, Shelley ED. Follicular dermographism. Cutis 1983; 32:244.
8. Warin RP. Factitious urticaria: red dermographism. Br J Dermatol 1981; 104:285.
9. Matthews CN, Kirby JD, James J, Warin RP. Dermographism: reduction in weal size by
chlorpheniramine and hydroxyzine. Br J Dermatol 1973; 88:279.
10. Greaves M. Chronic urticaria. J Allergy Clin Immunol 2000; 105:664.
7/30/2019 Physical and Cold Urticarias
15/26
11. Schafer CM. Physical urticarias. Immunol Allergy Clin North Am 1995; 15:679.
12. Smith JA, Mansfield LE, Fokakis A, Nelson HS. Dermographia caused by IgE mediated penicillin
allergy. Ann Allergy 1983; 51:30.
13. Warner DM, Ramos-Caro FA, Flowers FP. Famotidine (pepcid)-induced symptomatic
dermatographism. J Am Acad Dermatol 1994; 31:677.
14. Garafalo J, Kaplan AP. Histamine release and therapy of severe dermatographism. J Allergy Clin
Immunol 1981; 68:103.
15. Murphy GM, Zollman PE, Greaves MW, Winkelmann RK. Symptomatic dermographism (factitious
urticaria)--passive transfer experiments from human to monkey. Br J Dermatol 1987; 116:801.
16. Breathnach SM, Allen R, Ward AM, Greaves MW. Symptomatic dermographism: natural history,
clinical features laboratory investigations and response to therapy. Clin Exp Dermatol 1983; 8:463.
17. Deutsch PH. Dermatographism treated with hydroxyzine and cimetidine and ranitidine. Ann Intern
Med 1984; 101:569.
18. Juhlin L, de Vos C, Rihoux JP. Inhibiting effect of cetirizine on histamine-induced and 48/80-induced
wheals and flares, experimental dermographism, and cold-induced urticaria. J Allergy Clin Immunol
1987; 80:599.
19. Kaur S, Greaves M, Eftekhari N. Factitious urticaria (dermographism): treatment by cimetidine and
chlorpheniramine in a randomized double-blind study. Br J Dermatol 1981; 104:185.20. Cook J, Shuster S. The effect of H1 and H2 receptor antagonists on the dermographic response.
Acta Derm Venereol 1983; 63:260.
21. Johnsson M, Falk ES, Volden G. UVB treatment of factitious urticaria. Photodermatol 1987; 4:302.
22. Krause K, Ardelean E, Kessler B, et al. Antihistamine-resistant urticaria factitia successfully treated
with anti-immunoglobulin E therapy. Allergy 2010; 65:1494.
23. Barlow RJ, Warburton F, Watson K, et al. Diagnosis and incidence of delayed pressure urticaria in
patients with chronic urticaria. J Am Acad Dermatol 1993; 29:954.
24. Dice JP. Physical urticaria. Immunol Allergy Clin North Am 2004; 24:225.
25. Kaplan, AP. Urticara and angioedema. In: Middleton's allergy: Principles and practice, 7th ed,
Adkinson, NF, Bochner, BS, Busse, WW, et al (Eds), Mosby, Philadelphia 2009. p.1063.
26. Berkun Y, Shalit M. Successful treatment of delayed pressure urticaria with montelukast. Allergy2000; 55:203.
27. Nettis E, Pannofino A, Cavallo E, et al. Efficacy of montelukast, in combination with loratadine, in
the treatment of delayed pressure urticaria. J Allergy Clin Immunol 2003; 112:212.
28. Nettis E, Colanardi MC, Soccio AL, et al. Desloratadine in combination with montelukast suppresses
the dermographometer challenge test papule, and is effective in the treatment of delayed pressure
urticaria: a randomized, double-blind, placebo-controlled study. Br J Dermatol 2006; 155:1279.
29. Bindslev-Jensen C, Skov PS. Efficacy of omalizumab in delayed pressure urticaria: a case report.
Allergy 2010; 65:138.
30. Metz M, Altrichter S, Ardelean E, et al. Anti-immunoglobulin E treatment of patients with
recalcitrant physical urticaria. Int Arch Allergy Immunol 2011; 154:177.
31. Duke, WW. Urticaria caused specifically by the action of physical agents. JAMA 1924; 83:3.
32. Poon E, Seed PT, Greaves MW, Kobza-Black A. The extent and nature of disability in different
urticarial conditions. Br J Dermatol 1999; 140:667.
33. Hirschmann JV, Lawlor F, English JS, et al. Cholinergic urticaria. A clinical and histologic study. Arch
Dermatol 1987; 123:462.
34. Moore-Robinson M, Warin RP. Some clinical aspects of cholinergic urticaria. Br J Dermatol 1968;
80:794.
35. Zuberbier T, Althaus C, Chantraine-Hess S, Czarnetzki BM. Prevalence of cholinergic urticaria in
young adults. J Am Acad Dermatol 1994; 31:978.
7/30/2019 Physical and Cold Urticarias
16/26
36. Onn A, Levo Y, Kivity S. Familial cholinergic urticaria. J Allergy Clin Immunol 1996; 98:847.
37. Grant, RT, Pearson, RSB, Comeau, WJ. Observations on urticaria provoked by emotion, by exercise,
and by warming the body. Clin Sci 1936; 2:253.
38. Soter NA, Wasserman SI, Austen KF, McFadden ER Jr. Release of mast-cell mediators and
alterations in lung function in patients with cholinergic urticaria. N Engl J Med 1980; 302:604.
39. Confino-Cohen R, Goldberg A, Magen E, Mekori YA. Hemodialysis-induced rash: a unique case of
cholinergic urticaria. J Allergy Clin Immunol 1995; 96:1002.
40. Commens CA, Greaves MW. Tests to establish the diagnosis in cholinergic urticaria. Br J Dermatol
1978; 98:47.
41. Sigler RW, Levinson AI, Evans R 3rd, et al. Evaluation of a patient with cold and cholinergic urticaria.
J Allergy Clin Immunol 1979; 63:35.
42. Shelley WB, Shelley ED, Ho AK. Cholinergic urticaria: acetylcholine-receptor-dependent immediate-
type hypersensitivity reaction to copper. Lancet 1983; 1:843.
43. Murphy GM, Greaves MW, Zollman PE, Winkelmann RK. Cholinergic urticaria, passive transfer
experiments from human to monkey. Dermatologica 1988; 177:338.
44. Adachi J, Aoki T, Yamatodani A. Demonstration of sweat allergy in cholinergic urticaria. J Dermatol
Sci 1994; 7:142.
45. Fukunaga A, Bito T, Tsuru K, et al. Responsiveness to autologous sweat and serum in cholinergicurticaria classifies its clinical subtypes. J Allergy Clin Immunol 2005; 116:397.
46. Metz M, Bergmann P, Zuberbier T, Maurer M. Successful treatment of cholinergic urticaria with
anti-immunoglobulin E therapy. Allergy 2008; 63:247.
47. Takahagi S, Tanaka T, Ishii K, et al. Sweat antigen induces histamine release from basophils of
patients with cholinergic urticaria associated with atopic diathesis. Br J Dermatol 2009; 160:426.
48. Otto HF, Calabria CW. A case of severe refractory chronic urticaria: a novel method for evaluation
and treatment. Allergy Asthma Proc 2009; 30:333.
49. Itakura E, Urabe K, Yasumoto S, et al. Cholinergic urticaria associated with acquired generalized
hypohidrosis: report of a case and review of the literature. Br J Dermatol 2000; 143:1064.
50. Kobayashi H, Aiba S, Yamagishi T, et al. Cholinergic urticaria, a new pathogenic concept:
hypohidrosis due to interference with the delivery of sweat to the skin surface. Dermatology 2002;204:173.
51. Casale TB, Sampson HA, Hanifin J, et al. Guide to physical urticarias. J Allergy Clin Immunol 1988;
82:758.
52. Zuberbier T, Mnzberger C, Haustein U, et al. Double-blind crossover study of high-dose cetirizine
in cholinergic urticaria. Dermatology 1996; 193:324.
53. McClean SP, Arreaza EE, Lett-Brown MA, Grant JA. Refractory cholinergic urticaria successfully
treated with ketotifen. J Allergy Clin Immunol 1989; 83:738.
54. Czarnetzki BM. Ketotifen in cholinergic urticaria. J Allergy Clin Immunol 1990; 86:138.
55. Wong E, Eftekhari N, Greaves MW, Ward AM. Beneficial effects of danazol on symptoms and
laboratory changes in cholinergic urticaria. Br J Dermatol 1987; 116:553.
56. La Shell MS, England RW. Severe refractory cholinergic urticaria treated with danazol. J Drugs
Dermatol 2006; 5:664.
57. Eftekhari N, Ward AM, Allen R, Greaves MW. Protease inhibitor profiles in urticaria and angio-
oedema. Br J Dermatol 1980; 103:33.
58. Sabroe RA. Failure of omalizumab in cholinergic urticaria. Clin Exp Dermatol 2010; 35:e127.
59. Sibbald RG. Physical urticaria. Dermatol Clin 1985; 3:57.
60. Grant JA, Findlay SR, Thueson DO, et al. Local heat urticaria/angioedema: evidence for histamine
release without complement activation. J Allergy Clin Immunol 1981; 67:75.
7/30/2019 Physical and Cold Urticarias
17/26
61. Michalsson G, Ros AM. Familial localized heat urticaria of delayed type. Acta Derm Venereol 1971;
51:279.
62. Darling M, Lambiase MC, Hodson DS. Localized heat induced urticaria: report of a case. J Drugs
Dermatol 2004; 3:75.
63. Daman L, Lieberman P, Ganier M, Hashimoto K. Localized heat urticaria. J Allergy Clin Immunol
1978; 61:273.
64. SHELLEY WB, RAWNSLEY HM. AQUAGENIC URTICARIA. CONTACT SENSITIVITY REACTION TO
WATER. JAMA 1964; 189:895.
65. Treudler R, Tebbe B, Steinhoff M, Orfanos CE. Familial aquagenic urticaria associated with familial
lactose intolerance. J Am Acad Dermatol 2002; 47:611.
66. Luong KV, Nguyen LT. Aquagenic urticaria: report of a case and review of the literature. Ann Allergy
Asthma Immunol 1998; 80:483.
67. Czarnetzki BM, Breetholt KH, Traupe H. Evidence that water acts as a carrier for an epidermal
antigen in aquagenic urticaria. J Am Acad Dermatol 1986; 15:623.
68. Chalamidas SL, Charles CR. Aquagenic urticaria. Arch Dermatol 1971; 104:541.
69. Tkach JR. Aquagenic urticaria. Cutis 1981; 28:454, 463.
70. Gallo R, Cacciapuoti M, Cozzani E, Guarrera M. Localized aquagenic urticaria dependent on saline
concentration. Contact Dermatitis 2001; 44:110.71. Sibbald RG, Black AK, Eady RA, et al. Aquagenic urticaria: evidence of cholinergic and histaminergic
basis. Br J Dermatol 1981; 105:297.
72. Fearfield LA, Gazzard B, Bunker CB. Aquagenic urticaria and human immunodeficiency virus
infection: treatment with stanozolol. Br J Dermatol 1997; 137:620.
73. Davis RS, Remigio LK, Schocket AL, Bock SA. Evaluation of a patient with both aquagenic and
cholinergic urticaria. J Allergy Clin Immunol 1981; 68:479.
74. Parker RK, Crowe MJ, Guin JD. Aquagenic urticaria. Cutis 1992; 50:283.
75. Mathelier-Fusade P, Aissaoui M, Chabane MH, et al. Association of cold urticaria and aquagenic
urticaria. Allergy 1997; 52:678.
76. Bayle P, Gadroy A, Messer L, Bazex J. Localized aquagenic urticaria: efficacy of a barrier cream.
Contact Dermatitis 2003; 49:160.77. Wasserman D, Preminger A, Zlotogorski A. Aquagenic urticaria in a child. Pediatr Dermatol 1994;
11:29.
78. Martnez-Escribano JA, Quecedo E, De la Cuadra J, et al. Treatment of aquagenic urticaria with
PUVA and astemizole. J Am Acad Dermatol 1997; 36:118.
79. Juhlin L, Malmros-Enander I. Familial polymorphous light eruption with aquagenic urticaria:
successful treatment with PUVA. Photodermatol 1986; 3:346.
80. Merklen, P. Urticaria. In: La pratique dermatologique: trait de dermatologie applique'e, Besnier, E,
Brocq, L, Jacquet, L (Eds), Masson et Cie, Paris 1904. p.728.
81. Champion RH. Urticaria: then and now. Br J Dermatol 1988; 119:427.
82. Humphreys F, Hunter JA. The characteristics of urticaria in 390 patients. Br J Dermatol 1998;
138:635.
83. Uetsu N, Miyauchi-Hashimoto H, Okamoto H, Horio T. The clinical and photobiological
characteristics of solar urticaria in 40 patients. Br J Dermatol 2000; 142:32.
84. Ryckaert S, Roelandts R. Solar urticaria. A report of 25 cases and difficulties in phototesting. Arch
Dermatol 1998; 134:71.
85. Beattie PE, Dawe RS, Ibbotson SH, Ferguson J. Characteristics and prognosis of idiopathic solar
urticaria: a cohort of 87 cases. Arch Dermatol 2003; 139:1149.
86. Monfrecola G, Nappa P, Pini D. Solar urticaria with delayed onset: a case report. Photodermatol
1988; 5:103.
7/30/2019 Physical and Cold Urticarias
18/26
87. Ghigliotti G, Brusati C, Guarrera M, Nigro A. Persistent solar urticaria. A case report. Photodermatol
Photoimmunol Photomed 1999; 15:140.
88. Blum HF, West RJ. STUDIES OF AN URTICARIAL RESPONSE TO BLUE AND VIOLET LIGHT IN MAN. J
Clin Invest 1937; 16:261.
89. Leenutaphong V, Hlzle E, Plewig G. Solar urticaria: studies on mechanisms of tolerance. Br J
Dermatol 1990; 122:601.
90. Botto NC, Warshaw EM. Solar urticaria. J Am Acad Dermatol 2008; 59:909.
91. Hasei K, Ichihashi M. Solar urticaria. Determinations of action and inhibition spectra. Arch Dermatol
1982; 118:346.
92. Rajatanavin N, Bernhard JD. Solar urticaria: treatment with terfenadine. J Am Acad Dermatol 1988;
18:574.
93. Edstrm DW, Ros AM. Cyclosporin A therapy for severe solar urticaria. Photodermatol
Photoimmunol Photomed 1997; 13:61.
94. Gzelbey O, Ardelean E, Magerl M, et al. Successful treatment of solar urticaria with anti-
immunoglobulin E therapy. Allergy 2008; 63:1563.
95. Waibel KH, Reese DA, Hamilton RG, Devillez RL. Partial improvement of solar urticaria after
omalizumab. J Allergy Clin Immunol 2010; 125:490.
96. Duschet P, Leyen P, Schwarz T, et al. Solar urticaria--effective treatment by plasmapheresis. ClinExp Dermatol 1987; 12:185.
97. Leenutaphong V, Hlzle E, Plewig G, et al. Plasmapheresis in solar urticaria. Dermatologica 1991;
182:35.
98. Hudson-Peacock MJ, Farr PM, Diffey BL, Goodship TH. Combined treatment of solar urticaria with
plasmapheresis and PUVA. Br J Dermatol 1993; 128:440.
99. Collins P, Ahamat R, Green C, Ferguson J. Plasma exchange therapy for solar urticaria. Br J
Dermatol 1996; 134:1093.
100. Patterson R, Mellies CJ, Blankenship ML, Pruzansky JJ. Vibratory angioedema: a hereditary type of
physical hypersensitivity. J Allergy Clin Immunol 1972; 50:174.
101. Epstein PA, Kidd KK. Dermo-distortive urticaria: an autosomal dominant dermatologic disorder.
Am J Med Genet 1981; 9:307.102. Keahey TM, Indrisano J, Lavker RM, Kaliner MA. Delayed vibratory angioedema: insights into
pathophysiologic mechanisms. J Allergy Clin Immunol 1987; 80:831.
103. Wener MH, Metzger WJ, Simon RA. Occupationally acquired vibratory angioedema with
secondary carpal tunnel syndrome. Ann Intern Med 1983; 98:44.
104. Metzger WJ, Kaplan AP, Beaven MA, et al. Hereditary vibratory angioedema: confirmation of
histamine release in a type of physical hypersensitivity. J Allergy Clin Immunol 1976; 57:605.
105. Ting S, Reimann BE, Rauls DO, Mansfield LE. Nonfamilial, vibration-induced angioedema. J Allergy
Clin Immunol 1983; 71:546.
106. Rittweger J, Beller G, Felsenberg D. Acute physiological effects of exhaustive whole-body vibration
exercise in man. Clin Physiol 2000; 20:134.
107. Mathelier-Fusade P, Vermeulen C, Leynadier F. [Vibratory angioedema]. Ann Dermatol Venereol
2001; 128:750.
108. Lawlor F, Black AK, Breathnach AS, Greaves MW. Vibratory angioedema: lesion induction, clinical
features, laboratory and ultrastructural findings and response to therapy. Br J Dermatol 1989; 120:93.
2011 UpToDate, Inc. All rights reserved. | Subscription and License Agreement
Licensed to: k g
7/30/2019 Physical and Cold Urticarias
19/26
COLD URTICARIA
INTRODUCTION Cold urticaria, or cold contact urticaria, is a subtype of physical urticaria (table 1). It is
characterized by itchy wheals (hives) and/or angioedema due to cutaneous mast cell activation and
release of proinflammatory mediators after cold exposure. The underlying causes are largely unknown.
Cold urticaria is reviewed here. Other urticaria disorders, including acute and chronic spontaneous
urticaria are discussed separately. (See "Physical urticarias" and "New onset urticaria: Epidemiology,
clinical manifestations, and etiologies" and "Chronic urticaria: Standard management and patient
education" and "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history".)
EPIDEMIOLOGY The incidence of cold urticaria was estimated to be 0.05 percent in Central Europe
[1]. The frequency of cold urticaria among physical urticaria subtypes varies between 5 and 34 percent,
partly depending upon the geographic region (ie, higher incidences are found in regions with colder
climates and lower rates are seen in regions with a warmer climate) [1-4].
Cold urticaria most frequently affects young adults [3,5]. Both sexes are affected with similar frequency
in most studies [1,3,6], although one study reported that females were affected twice as often as males[5]. Up to half of patients with cold urticaria are atopic and one-fourth have other types of inducible
urticaria, most commonly symptomatic dermographism and cholinergic urticaria [1,7].
PATHOGENESIS Cold urticaria symptoms are brought about by the activation of mast cells and
subsequent release of histamine and other proinflammatory mediators. Following a cold stimulation
test, cutaneous mast cells in patients with cold urticaria show signs of degranulation, and serum levels
of mast cell mediators are increased [8]. This results in pruritus, burning and erythema from activation
of skin nerves, and vasodilation of skin vessels with extravasation causing wheals and angioedema.
The underlying etiology of cold urticaria remains unclear, since the mechanisms and signals for mast cell
activation have not been identified. Consequently, about 95 percent of cold urticaria cases areidiopathic (essential) [5,9]. Most of the remaining cases are secondary to cryoglobulinemia. (See
'Differential diagnosis' below.) Further systematic studies are needed to identify and characterize the
underlying cause(s) of cold urticaria.
A number of diseases have been associated with essential cold urticaria, largely in case reports.
Associations have been reported with viral, parasitic, and bacterial infections, including Lyme disease,
hepatitis, infectious mononucleosis, acute toxoplasmosis, Helicobacter pylori colonization, and HIV
infection [10-14]. In addition, cold urticaria has been associated with Hymenoptera stings, food and drug
intolerance, and hematologic, lymphatic, or neoplastic conditions [15,16]. It is not clear why these
infectious or immune events are associated with cold urticaria.
A variety of laboratory abnormalities have been found in patients with cold urticaria, including the
following:
In a small series, the majority of patients with cold urticaria exhibited mast cell-activating anti-IgE
antibodies [17].Associations noted in case reports include cryoglobulinemia, anti-lamin-B antibodies,
reduced levels of C1-esterase inhibitor and C4, and increased levels of platelet-activating factor and
platelet factor 4 [18-22].
7/30/2019 Physical and Cold Urticarias
20/26
CLINICAL MANIFESTATIONS Cold urticaria is characterized by the development of wheal-and-flare
skin reactions (picture 1) and/or angioedema after the skin is exposed to cold air, liquids, or objects [23].
Wheals and angioedema typically develop minutes after exposure. Cold urticaria symptoms are usually
limited to cold-exposed skin areas. However, extensive cold contact may result in systemic reactions,
ranging from generalized urticaria to anaphylaxis, with symptoms involving the respiratory,
gastrointestinal, and/or cardiovascular systems [6].
In a series of 30 pediatric patients with cold urticaria seen in a tertiary referral center, one-third had a
history of cold-induced anaphylaxis [7]. In another series of mostly adult patients, also from a tertiary
referral clinic, nearly one-third experienced at least one severe systemic reaction with hypotension
and/or respiratory compromise, and almost half of patients reported milder cutaneous systemic
reactions [3]. Almost all patients in these two studies reported reactions triggered by aquatic activities,
whereas only 30 percent experienced symptoms after touching a cold object.
Patients with cold urticaria who participate in aquatic activities (eg, swimming in cold water) are at risk
of death both directly from anaphylaxis and indirectly from drowning during a reaction [5,6,24]. Patients
with cold urticaria are also at risk of suffocation due to oropharyngeal angioedema after consuming cold
foods or beverages, although it is unclear how commonly this occurs.
There are few identified risk factors or predictors of systemic reactions. Patients with a history of cold-
induced oropharyngeal angioedema are at greater risk of a systemic reaction triggered by swimming,
whereas those with a history of only a few hives after swimming appear to be at lower risk [24]. In the
pediatric study described above, the only risk factor identified was a history of a previous cold-induced
systemic reaction [7]. In another study, severe systemic reactions were more frequent in patients
7/30/2019 Physical and Cold Urticarias
21/26
burning sensation in most cases. The test is considered negative if there is no reaction, or erythema or
pruritus/burning only.
Patients who show a negative test reaction to standard cold stimulation tests should be reevaluated and
subjected to further testing if the history strongly suggests cold urticaria. Further testing is performed
using larger areas for provocation (eg, cold pack or cold water bath) or using triggers that induced
urticarial reactions in the past (eg, cold wind, cold water). Atypical cold urticarias should be considered if
the additional stimulation tests are also negative (see 'Differential diagnosis' below).
The author's approach in patients who show a positive test reaction is to test their critical temperature
threshold (highest temperature sufficient to induce a positive test reaction) and/or their cold
stimulation time threshold (shortest duration of cold exposure required to induce a positive test
reaction) [28]. Threshold testing, especially for temperature, can help patients avoid risky situations, and
it allows physicians to gauge disease severity and to monitor treatment responses [27,29]. However,
there are no data indicating that threshold levels are the same whether the area of exposure is localized,
such as with the ice cube test or TempTest, versus a large area, such as submersion in cold water.
Additional diagnostic measures should be limited to the exclusion of major underlying diseases and
identification of associated diseases where suggested by the patients' history. Screening laboratory
studies may include a complete blood count with differential. Underlying causes can only be identified in
a minority of patients with cold urticaria, even if comprehensive testing is performed. (See
'Pathogenesis' above and 'Differential diagnosis' below.)
VARIANT FORMS Most cold urticaria is readily distinguished from other types of urticaria by the
patient history and a cold stimulation test (CST). The immediate CST is negative in rare subforms of cold
urticaria (atypical cold urticarias) that can be either acquired or hereditary [8,15,28,30]:
In delayed cold urticaria, which has both acquired and hereditary forms, the wheal-and-flare reactionoccurs up to 24 hours after cold exposure. Hyperpigmentation typically develops at the site of lesions as
they resolve in the familial form.In familial atypical cold urticaria, symptoms are lifelong and begin in
early childhood. Localized urticaria typically develops on areas exposed to cold air, water, or objects.
Symptoms triggered by cold food and beverages are also common. Systemic inflammatory symptoms
are absent.In cold-dependent dermographism, urticaria is seen only after stroking precooled skin.In
cold-induced cholinergic urticaria, generalized hives only develop when exercising in cold
environments.In systemic cold urticaria, generalized urticaria is seen after systemic cold exposure. This
form is not associated with exercise.In localized cold urticaria, hives only develop at defined skin sites,
such as the face. Thus, the CST is only positive if performed at these sites.In localized cold reflex
urticaria, hives develop near, but not directly where, the ice cube was applied.
DIFFERENTIAL DIAGNOSIS The differential diagnosis of essential cold urticaria includes familial cold
autoinflammatory syndrome and cold urticaria associated with abnormal serum proteins.
Patients with familial cold autoinflammatory syndrome present within the first few months of life. The
development of a papular rash after cold exposure is often delayed by one to two hours. This form is
associated with systemic inflammatory symptoms, including fever and conjunctival injection. (See
"Cryopyrin-associated periodic syndromes and related disorders", section on 'Familial cold
autoinflammatory syndrome'.)Cold urticaria is associated with several diseases that have abnormal cold-
7/30/2019 Physical and Cold Urticarias
22/26
dependent immunoglobulins, including cryoglobulinemia, cryofibrinogenemia, cold agglutinin disease,
and paroxysmal cold hemoglobinuria. (See "Overview of cryoglobulins and cryoglobulinemia" and
"Clinical manifestations and diagnosis of essential mixed cryoglobulinemia" and
"Cryofibrinogenemia" and "Clinical features and treatment of autoimmune hemolytic anemia: Cold
agglutinins" and "Paroxysmal cold hemoglobinuria".)
MANAGEMENT
Cold avoidance Avoidance of cold is recommended, since it prevents the development of cold
urticaria symptoms, including serious life-threatening events. However, avoidance is not always
possible. Knowledge of their temperature threshold can help patients to recognize and avoid critical
cold exposure in their daily lives (eg, swimming in water of subthreshold temperature) [25]. A study of
45 patients with cold urticaria found a mean + SEM critical temperature threshold of 17 + 6 degrees
Celsius or approximately 63 + 11 degrees Fahrenheit (range 4 to 27 degrees Celsius or approximately 39
to 81 degrees Fahrenheit) [31].
Patients who chose to continue to participate in aquatic activities should avoid subthreshold
temperature exposures. A water temperature above 77 degrees Fahrenheit (25 degrees Celsius) issufficient for most patients [7]. Pretreatment with an antihistamine prior to cold exposure is often
recommended, because clinical experience suggests that antihistamine pretreatment prevents skin
reactions and systemic reactions. In addition, patients of all ages at increased risk of systemic reactions
should have an epinephrine autoinjector readily available and should be accompanied by an adult who is
trained in its use. (See 'Clinical manifestations' above and 'Emergency medication' below and
'Antihistamine therapy' below.)
Antihistamine therapy Nonsedating H1 antihistamines are the treatment of choice for cold urticaria
for symptomatic therapy, as with other forms of urticaria [32-35]. Antihistamines are also used as
prophylactic therapy, both to prevent hives and to prevent systemic reactions, although there are no
data to support the indication for the latter. (See "Chronic urticaria: Standard management and patienteducation", section on 'H1 antihistamines'.)
A higher than usual dose of antihistamine (eg, up to four times the daily recommended dose) is required
for sufficient protection from urticarial symptoms in many patients with cold urticaria [33,36,37].
Patients with cold urticaria who are incompletely treated with usual doses may suffer from severe and
avoidable impairment in their quality of life. In addition, insufficiently treated patients with severe cold
urticaria may be at greater risk of developing life-threatening reactions upon cold exposure.
In a randomized, three-way crossover trial, 30 patients with cold urticaria received 5 or 20 mg of
desloratadine or placebo daily, each for 7 days separated by 14-day washout periods [36]. Response to
therapy was assessed by cold stimulation testing using TempTest. Both antihistamine doses decreased
wheal volume 15 and 90 minutes after cold provocation testing, raised the critical temperature
threshold, and increased the critical stimulation time compared with placebo, but there was a stronger
response to the 20-mg dose compared with the 5-mg dose for all of these outcomes.
Nonsedating second-generation H1 antihistamines are preferred for chronic treatment, although some
of these medications may be sedating at higher doses. Some of these H1 antihistamines have been
tested and shown to be effective in randomized controlled trials in patients with cold urticaria (eg,
loratadine, cetirizine, desloratadine, ebastine, and rupatadine; the last two are not available in the
7/30/2019 Physical and Cold Urticarias
23/26
United States), whereas others have not (eg, levocetirizine and fexofenadine) [34,36-38]. The author
starts with the standard daily dose and increases it up to four times that dose if the patient continues to
experience symptoms. For patients who have been completely protected from cold-induced symptoms
for at least six weeks on a higher than standard dose, the dose is then decreased over several months to
the lowest level that provides complete protection. Patients are continued on a prophylactic
antihistamine until they go into remission. The author typically discontinues the medication after three
to six months to determine if remission has been achieved. Patients who participate in aquatic activities
in the summer usually require year-round treatment, whereas other may need protection only during
the winter months.
Other pharmacotherapy Other therapies that were successful in case reports of patients with severe
cold urticaria with a high risk of life-threatening reactions and/or an insufficient response to
antihistamines include the concomitant use of leukotriene antagonists [39], cyclosporine [40],
glucocorticoids [41], and anti-IgE [42,43].
Emergency medication Patients with cold urticaria are at potential risk of oropharyngeal edema
caused by consumption of cold foods or beverages or anaphylaxis due to extensive cold exposure.
Epinephrine is effective treatment for anaphylaxis caused by other triggers, and it appears to beeffective in this setting as well, based upon clinical experience and case reports [44,45]. We recommend
that patients with cold urticaria who have a history of anaphylaxis, systemic symptoms, frequent and
unavoidable cold exposure, and/or a high temperature threshold be prescribed and carry an
epinephrine autoinjector and be taught how and when to use this device. (See "Prescribing epinephrine
for anaphylaxis self-treatment" and "Anaphylaxis: Rapid recognition and treatment" and "Long-term risk
reduction in anaphylaxis" and "Patient information: Use of an epinephrine autoinjector".)
The author also suggests patients carry oral glucocorticoids, for use in treating systemic symptoms that
do not require therapy with epinephrine (eg, extensive urticaria and/or angioedema not involving the
airway that does not respond to antihistamines).
Additional treatment options Further treatment options include cold desensitization, topical
capsaicin, and antibiotic therapy.
Cold desensitization Several case series suggest that desensitization to cold (cold "tolerance"
induction or hardening) by full-body baths/showers in cold water can protect patients with cold urticaria
from cold-induced symptoms [46,47]. Patients are desensitized to the cold by repeatedly exposing
increasingly larger skin areas to incrementally colder water, starting with above-threshold temperatures.
This therapy decreases the critical temperature threshold.
Cold tolerance induction needs to be initiated with great caution and under a physician's supervision
because of the risk of severe systemic reactions. While the term "tolerance" is used, "desensitization" is
more appropriate, since discontinuation for as little as a few days results in a complete loss of
protection. Patients need to be informed that daily cold showers/baths are required to maintain the
desensitized state. Most patients do not continue this therapy for more than a few weeks to months.
Topical capsaicin Treatment with topical capsaicin, the pungent product of chili peppers, prevented
cold urticaria symptoms for four to seven days in a small case series [48]. Capsaicin treatment results in
the depletion of neuropeptides from sensory nerve fibers that may contribute to the induction of cold
urticaria skin reactions. Its use is limited because it causes local irritation at the site of application.
7/30/2019 Physical and Cold Urticarias
24/26
Antibiotic therapy Antibiotic therapy was reported to be effective for some patients with cold
urticaria in two observational studies [1,49]. In one of these series, 46 percent (13/28) of patients
treated with high dose oral penicillin or tetracycline for two to four weeks went into remission and an
additional 29 percent noted attenuated symptoms [1]. However, the rationale for its effectiveness is
unclear, since this approach appeared to induce remission or decrease symptoms even when no
underlying infection could be detected. Randomized controlled trials are needed to assess the efficacy
of this treatment.
PROGNOSIS Remission, or at least improvement of symptoms, occurs in 50 percent of patients within
five to six years [1,3,5,23]. The mean time to resolution in one study was 5.6 3.5 years [3]. There are
no reports of cold urticaria recurring after remission is achieved.
SUMMARY AND RECOMMENDATIONS
Cold urticaria is a subtype of physical urticaria characterized by itchy wheals and/or angioedema due to
skin mast cell activation and the release of proinflammatory mediators after cold exposure (picture 1).
The underlying causes are largely unknown. (See 'Introduction' above and 'Epidemiology' above and'Pathogenesis' above.)Cold urticaria symptoms are usually limited to cold-exposed skin areas and
develop within minutes of cold exposure. However, extensive cold contact may result in systemic
reactions. Occurrence of severe anaphylactic reactions or suffocation due to oropharyngeal edema is
possible. (See 'Clinical manifestations' above.)A cold stimulation test confirms the diagnosis in most
patients (picture 2). (See 'Diagnosis' above.)Avoidance of cold exposure is the best prophylaxis.
However, complete avoidance is difficult for most patients. (See 'Management' above.)We suggest the
use of non-sedating H1 antihistamines for patients with cold urticaria who are unable to sufficiently
avoid cold exposure and have frequent symptoms (Grade 2B). We typically use a second-generation H1
antihistamine, starting at the standard dose and increasing up to four times the standard dose as
needed to control symptoms. (See 'Management' above and 'Antihistamine therapy' above and "Chronic
urticaria: Standard management and patient education", section on 'H1 antihistamines'.)Werecommend treating cold-induced anaphylaxis with epinephrine (Grade 1A). (See 'Emergency
medication' above.)Patients should be informed about the possibility of a systemic reaction and
supplied with emergency medication, including epinephrine for self-injection. (See
'Management' above.)
Use of UpToDate is subject to the Subscri