a frigore - Alergología e Inmunología Clínica

Alergol Inmunol Clin 2001; 16: 218-224
C. Carrasquer Moya,
J.L. López-Baeza,
E. Fernández Alonso,
M. Durá, A. Peláez
Hernández
Allergology Service.
University Clinical Hospital.
Valencia (Spain)
Correspondence address:
Dra. C. Carrasquer Moya
Servicio de Alergología
Hospital Clínico Universitario
Blasco Ibáñez 17
E-46010 Valencia, Spain
218
Review article
Urticaria a frigore: clinical and diagnostic
features
Urticaria a frigore, or cold urticaria, characterised by the rapid onset of pruritus, erythema,
whealing and angioedema after exposure to a cold stimulus, is one of the physical
urticarias and represents about 2-3% of all urticarias. In the present paper we shall review
the most salient clinical and diagnostic features of this entity and describe the clinical
characteristics of eight patients with this form of urticaria. The basic sequence of
erythema, oedema and pruritus may be triggered in response to a number of cold stimuli
such as low environmental temperatures, cold wind or the manipulation of cold
objects. The ingestion of cold meals and/or drinks may induce tumefaction of the labial
mucosa and, less frequently, lingual, pharyngeal or laryngeal oedema. Massive exposure,
such as that occurring during swimming or other aquatic sports, may induce marked
hypotension and loss of consciousness due to the massive release of mediators.
The anamnesis in these patients should therefore aim at detecting signs of severity such
as involvement of the oropharyngeal mucosa, or the presence of general signs such as
headache, arthralgia, abdominal pain or haemodynamic repercussions during cold-water
bathing, and these aspects should be clearly explained to the patient. In the present
review we propose a classification of this condition and describe the clinical and diagnostic
features of cold urticaria, together with the most salient clinical data of eight patients
with this complaint. Only two patients evidenced a mild and transient increase of
the circulating IgE and immune complex levels, which were later within the normal
ranges in subsequent assessments. No abnormal findings were detected in the chest Xrays
or in the parasitologic studies of the faeces.
Key words: Cold urticaria. Urticaria a frigore. Cold. Urticaria. Antihistamines.
Urticaria a frigore: características clínicas y
diagnósticas
La urticaria por frío, o "urticaria a frigore", caracterizada por la rápida aparición de
prurito, eritema, lesiones habonosas y angioedema tras la exposición a un estímulo
frío, forma parte de las urticarias físicas y representa el 2-3% del conjunto de las urticarias.
Se abordará la revisión de los aspectos clínicos y diagnósticos más destacados
de esta entidad, junto con la descripción de las características clínicas de ocho
pacientes con este tipo de urticaria. La secuencia básica de eritema, edema y prurito
puede desencadenarse en respuesta a diferentes estímulos fríos, como bajas temperaturas
ambientales, viento frío, o manipulación de objetos fríos. La ingesta de comidas
o bebidas frías puede provocar tumefacción de la mucosa labial y, con menos
frecuencia, edema en lengua, faringe o laringe. Asimismo, la exposición masiva, co-

mo la que acontece durante la natación, es capaz de causar hipotensión
marcada y pérdida de conciencia debido a la liberación
masiva de mediadores. La anamnesis en estos pacientes
debe ir encaminada, por tanto, a la detección de signos de gravedad
de la urticaria a frigore como la afectación de la mucosa
bucofaríngea, o de la presencia de signos generales como
cefalea, artralgias, dolor abdominal o repercusión hemodinámica
durante el baño en aguas frías, aspecto que debe ser explicado
a los pacientes. En esta revisión se propone una clasificación
y se describen las características clínicas y
diagnósticas de la urticaria por frío, junto con los datos clínicos
más destacados de ocho pacientes afectos de este tipo de
urticaria. Únicamente en dos pacientes se objetivó un incremento
ligero y transitorio de las cifras de IgE e inmunocomplejos
circulantes, que se hallaron en el intervalo normal en
determinaciones posteriores. Tampoco se encontraron hallazgos
patológicos en la radiología de tórax ni en el examen parasitológico
de las heces.
Palabras clave: Urticaria a frigore. Urticaria. Frío. Antihistamínicos.
CLINICAL OBSERVATIONS
We have studied eight consecutive patients with clinical
manifestations suggestive of cold urticaria. After recording
a detailed anamnesis, skin tests with airborne
allergens were carried out followed by a cold challenge
test (with ice) and various complementary explorations.
Table I summarises the clinical features and the results
of the cold (ice) challenge test in these patients, together
with the presence or absence of clinical manifesta-
Table I. Clinical features and results of the cold contact challenge test in eight patients
Urticaria a frigore
tions in association to low environmental temperatures
(cold), to the ingestion of cold food or beverages and to
physical exercise-stress (a useful criterion in the differential
diagnosis to other forms of physical urticaria, such as
cholinergic urticaria). Table I also states the latency time
in the cold challenge test, that is the time elapsed between
the application of the stimulus and the development of
wheals.
The clinical manifestations were in most cases those
of urticaria, with associated angioedema in some patients.
One of the patients also evidenced systemic manifestations
and, in this particular case, a shorter latency time was recorded
between the exposure to a cold stimulus and the
onset of symptoms. Most of the patients reported clinical
symptoms upon exposure to cold environmental temperatures,
and six of them also described clinical symptoms
with the intake of cold food or beverages. In all eight patients,
the symptomatology occurred exclusively in association
to cold stimuli and not with any other types of
triggering factors, such as physical exertion or psychologic
stress.
There was no family history of cold urticaria in any
of the eight cases, nor of association to any other form of
urticaria. Only in one case was there a personal past history
of any atopic condition (allergic rhinitis due to grass
pollen hypersensitivity).
The cold challenge test yielded positive results in seven
of the eight patients, with an early positive response
in the one patient who reported both skin and systemic
manifestations.
A number of complementary explorations and assessments
were carried out in all cases, with results within
the normality ranges for most patients (Table II). Only in
two cases were initially high levels of total IgE and circu-
Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8
Age (years) 52 29 22 18 52 22 29 22
Gender Male Male Female Female Female Female Female Male
Clinical manifestations Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria
Dyspnoea Angioedema Angioedema
Cold water immersion Yes No Yes Yes No Yes No No
Cold No Yes Yes Yes Yes Yes Yes Yes
Foods Yes No Yes No No No No No
Physical exertion/stress No No No No No No No No
Family history No No No No No No No No
Ice-cube test Positive Positive Positive Negative Positive Positive Positive Positive
Latency time (min) 10 12 2 – 5 5 6 5
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C. Carrasquer Moya, et al
Table II. Results of the complementary explorations and analyses in eight patients
lating immune complexes detected, and these parameters
returned to normality in later assessments.
All patients received detailed explanations about
their disorder and lifestyle recommendations, in particular
regarding the avoidance of cold stimuli that might trigger
symptoms and of potentially life-threatening situations or
activities (most particularly in the one patient who also reported
systemic manifestations).
Five of the eight patients studied are at present under
therapy with cetirizine and the remaining three are receiving
mizolastine. Symptom control has been good up to
the present time, with absence of clinical manifestations or
attenuated symptoms upon eventual exposure to a cold stimulus.
In the particular case of the one patient with systemic
manifestations, long-term therapy with mizolastine
appeared to be more effective than cetirizine in controlling
the patient’s symptoms. In this type of patients, therefore,
long-term control of the symptom evolution and of the effectiveness
of therapy by an allergy specialist is required.
CLINICAL ASPECTS AND CLASSIFICATION
220
Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8
Complete blood count
ESR
Blood biochemistry
ASAT, ALAT
T4, TSH
Serologies
Syphilis
Echinococcosis
Hepatitis
Epstein-Barr virus
Chlamydia
Mycoplasma
ANA
N N N N N N N N
Ig quantitation ↑ Ig E ↑ Ig E
Circulating immune complexes
C3 C4 CH50 Protein electrophoresis
↑↑ ↑↑
Cryoglobulins
Faecal parasites and ova
Plain chest film
N N
The basic sequence of erythema, oedema and pruri-
tus may be triggered in response to a number of cold stimuli,
such as low environmental temperatures, cold wind,
or the manipulation of cold objects. The ingestion of cold
foods or beverages may induce tumefaction of the labial
mucosa and, although less frequently, lingual, pharyngeal
and/or laryngeal oedema. Massive exposure to cold, such
as that occurring during swimming or other water sports,
can induce severe hypotension and loss of consciousness
because of the sudden and massive release of vasoactive
mediators 2 . In consequence, the anamnesis in these patients
must procure the detection of signs of severity of
the cold urticaria, such as involvement of the oropharyngeal
mucosa or the presence of systemic signs such as headache,
arthralgia, abdominal pain or haemodynamic repercussions
during bathing in cold waters, and these
aspects must not only be actively sought but also carefully
explained to the patients 3 .
Cold urticarias may be classified according to two
different criteria: (1) the presence or absence of a family
history of the condition (familial or acquired cold urticaria),
and (2) the results of the cold contact challenge test
(typical or atypical cold urticarias) (Table III) 4 .
The response to the cold contact challenge test is
considered to be "typical" when a wheal is induced in less

Table III. Classification of cold urticaria based on the results of
the cold contact challenge test
Typical Atypical
Idiopathic Systemic
Secondary Localised
Cold-induced cholinergic
Reflex local
Cold-induced dermographism
than 20 minutes in the cold-stimulated area; the result is
termed "atypical" when there is no response, when the response
occurs in an area distant from the stimulated one, or
when no immediate response occurs. Acquired cold urticarias
with a positive cold contact challenge test ("typical"
cold urticaria) constitute about 80-90% of all these urticaria
types; they can be further subclassified into primary
(or idiopathic) cold urticarias and cold urticarias secondary
to a systemic disease.
The familial form of cold urticaria is a rare condition
with an autosomal dominant inheritance pattern, recently
related by Hoffman et al. to a locus in chromosome
1 (1q44) 4 . This form usually has its onset during childhood
and persists throughout life. It is clinically characterised
by the development of erythematous and painful maculopapular
lesions (the patients usually describe a
burning sensation rather than pruritus) that begin to appear
a few minutes after the exposure to cold and may persist
for 48 hours. There is generally no mucosal involvement,
and the ice-cube test is usually negative 5 . The immediate
form is characterised by the onset of the lesions shortly after
the exposure to cold and the frequent association of fever,
chills, leukocytosis, arthro-myalgia and headache,
which last for 4 to 6 hours. Histologically, the lesions
show a polymorphonuclear cell infiltrate. In the delayed
form the lesions appear 9 to 18 hours after the exposure to
cold, and the biopsy samples evidence a mononuclear cell
infiltrate.
The primary (or idiopathic) acquired form of cold
urticaria is the most frequent form of urticaria a frigore.
Although it may debut at any age, it is more frequent in
young adults and, in some cases, a past history may be
found of upper airway viral infection, infectious mononucleosis,
syphilis, viral hepatitis, erythema nodosum, insect
stings, thyroid disease or drug administration (penicillin,
oral contraceptives, griseofulvin) 6 .
The lesions may appear a few minutes to one hour
after the exposure to the cold stimulus, and both cold
Urticaria a frigore
winds and cold, rainy days are important triggering factors.
After the ingestion of cold foods, the patients may
develop angioedema in the oral cavity or the pharynx,
which may be occasionally associated to systemic symptoms
such as stifling, palpitations, headache, wheezing or
even loss of consciousness upon bathing in cold water.
Cold urticaria has been associated to pressure urticaria,
cholinergic urticaria and dermographism. Although its
course is unpredictable, the mean duration of the complaint
is usually about six years 2,7 . Wanderer et al. 5 have
described a number of clinical patterns of primary acquired
cold urticaria: type I (30% of the cases) is characterised
by the onset of urticaria and/or localised angioedema;
type II (32%) includes the presence of one or more episodes
of urticaria and/or generalised angioedema without
symptoms of hypotension (mild systemic reaction), and
type III (38%) involves severe systemic reactions with one
or more episodes of urticaria and/or generalised angioedema,
hypotension or shock. Furthermore, a correlation has
been observed between the time required for the cold challenge
test to induce a positive response and the degree or
type of clinical manifestations the patient may evidence
upon "natural" exposure to cold: the earlier the response
is, the greater the risk will be of developing systemic manifestations
and thus hypotension or anaphylactic shock.
Thus, cold-induced hypotension and systemic reactions
occur more frequently in patients with a cold contact challenge
test that produces a positive response in 3 minutes
or less 5 .
The secondary acquired form of cold urticaria is a
very rare form of urticaria a frigore (0.5% of all cases) 7 .
The clinical manifestations include whealing, Raynaud’s
phenomenon, purpura, or skin necrosis. This condition has
been associated to a number of disorders characterised by
the existence of abnormal immunoglobulins that evidence
some form of cold-dependent properties. The presence of
cryoglobulins may be idiopathic or occur in the context of
connective tissue disease, chronic lymphoid leukaemia,
multiple myeloma, Waldenström’s disease, secondary syphilis
(which may feature paroxysmal cold haemoglobinuria
due to Donath-Landsteiner antibodies) or hepatitis C 2,8,9 .
Atypical cold urticaria encompasses a number of
forms of generalised or localised urticaria (Table III) appearing
upon exposure to a cold stimulus, even though the
cold challenge test is negative. The systemic form is a rare
disorder characterised by generalised urticarial lesions that
are not restricted to the areas exposed to cold; it may be
associated to severe and life-threatening anaphylactoid re-
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C. Carrasquer Moya, et al
actions. The localised form involves the onset of urticaria
and/or angioedema in localised areas of the body surface;
there have been some reports of cases in association to insect
stings, to skin tests with allergens, to the administration
of immunotherapy or to tetanus vaccination 5,10 . In
cold-induced cholinergic urticaria the typical lesions,
small pruritic papules 1-7 mm in diameter, appear after total
body exposure to cold or after physical exertion in a
cold environment; thus, physical exercise performed at
low environmental temperatures triggers the apparition of
the lesion, while they do not occur if the physical exercise
is performed in a warm environment. The ice-cube and
acetylcholine tests are negative, a useful detail for the differential
diagnosis to cholinergic urticaria in which the
acetylcholine test is positive.
In local reflex cold urticaria, the ice-cube test triggers
the apparition of urticarial lesions distant from the
area of cold application. In the case of cold-dependent
dermographism, wheals describing the pressure-stimulated
area occur only upon cold exposure; this condition may
occur with exclusively cutaneous manifestations or in association
to systemic symptoms such as abdominal pain,
vomiting or diarrhoea. Cold-dependent dermographism
should be differentiated from typical cold urticaria, which
is sometimes associated to dermographism.
AETIOLOGY
A review of the various reported series of patients
with cold urticaria shows that most cases are idiopathic.
This type of urticaria has been related to a number of clinical
contexts (Table IV), among them the presence of
cryoproteins, infections (such as infectious mononucleosis,
Table IV. Aetiologic implications
222
rubella or syphilis) and the administration of various drugs
(penicillin, oral contraceptives and griseofulvin) 5 .
PATHOGENESIS
The pathogenesis of cold urticaria is not well known although,
as in other types of urticaria, the mast cell is the fundamental
cell type involved. Increased levels of different mediators
released in the course of mast cell degranulation, such as
histamine, prostaglandin D 2, platelet activation factor and tumour
necrosis factor alpha (TNF-α) have been detected in the
skin and in the blood of these patients. Increased expression of
TNF-α and of interleukin 3 (IL-3) in the endothelial cells of
healthy and affected skin have been reported in patients with
different types of urticaria, including urticaria a frigore 6 .
The involvement of immunologic mechanisms in
which immunoglobulins (in some cases, the sera of these patients
can induce a response to cold in the form of urticarial
phenomena when transfused to healthy individuals; this phenomenon
is mediated by IgE-type immunoglobulins, although
there have also been descriptions of IgM and IgA
mediation), neuropeptides such as substance, chemotactic
factors and cytokines participate has also been postulated 7,8 .
DIAGNOSIS
The diagnostic procedure for a patient with cold urticaria
should encompass in the first place a detailed anamnesis
for orientation of the suspicion diagnosis. In patients
with a suggestive history, the cold challenge test should be
performed and a number of complementary explorations
and analyses should be requested.
Author(s) Year No. of cases Idiopathic Cryoproteins Infectious disease
Neittaanmäki13 1985 220 168 2 cryoglobulinaemias 11 viral airway disease
(1 of them with lymphoma) 4 pneumonia, 3 rubella
Wanderer5 1986 50 46 2 cryoglobulins
(1 with CLL)
1 infectious mononucleosis
Henquet14 1992 30 26 1 cryofibrinogen No
Huszl et al15 1994 42 37 No 5 odontologic infections
Koeppel et al8 1996 104 99 4 cryoglobulins
1 cryofibrinogen
1 HIV
Mathelier-Fusade et al3 1998 35 32 No No
CLL = chronic lymphoid leukaemia; HIV = human immune deficiency virus.

Table V. Complementary explorations and analyses
recommended in the study of a cold urticaria patient
Complete blood count, ESR Antinuclear antibodies
Blood biochemistry with liver C3, C4, CH50
function tests Serologies (Epstein-Barr virus, syphilis,
T4, TSH hepatitis B and C, echinococcosis,
Protein electrophoresis Chlamydia, Mycoplasma
Immunoglobulin quantitation Parasites and ova in faeces
Cryoglobulins Plain chest film
The most commonly used cold challenge test is the
ice-cube one, in which an ice cube is placed for four minutes
upon the volar aspect of the patient’s forearm and
the stimulated area is inspected ten minutes later. Patients
with cold urticaria usually manifest pruritus in the stimulated
area two minutes after removal of the ice cube and develop
a wheal reproducing the size and shape of the ice
cube after ten minutes 2 . A longer contact time (20 minutes)
has been suggested to increase the sensitivity of the
test. Furthermore, a correlation appears to exist between
the time required for a positive result to appear and the intensity
of the urticaria, so that earlier positivities imply a
greater risk of systemic manifestations and thus of hypotension
or anaphylactic shock 6 .
If the ice-cube test is negative, the next test to perform
is the immersion of the arm in cold (5-10ºC) water
for five to ten minutes. If these two tests are negative, but
the clinical suspicion persists, total body exposure to cold
may be carried out by placing the lightly-clothed patient
for a certain period (5 to 30 minutes) in a room with an
environmental temperature of 4ºC. Strict and close medical
control is imperative in this case because of the risk of
triggering systemic symptoms.
In order to rule out the presence of underlying disease
in these patients, the complementary assessments summarised
in Table V are recommended 5,6,11 .
MANAGEMENT
The most important aspect in the therapeutic management
of cold urticaria is that of the preventive measures.
Therefore, the patient should be warned of the risk implicit
in a number of situations of activities that may represent a
threat to life, such as the ingestion of cold meals or beverages
or practising aquatic or sports activities at low environmental
temperatures. An ice-cube test with a positive res-
Urticaria a frigore
ponse after less than 3 minutes is considered to be a risk factor
contraindicating the practise of water sports 5 . If the patient
is to undergo surgery a number of precautionary measures
should be observed, such as the administration of
intravenous infusion at a temperature of 37ºC and raising the
temperature in the operating theatre. Patients with a high degree
of cold sensitivity should be given epinephrine and corticosteroids
for self-administration should the need arise 15 .
Regarding drug therapy, antihistamines may be effective
in reducing or suppressing the symptoms. Even
though ciproheptadine was long considered to be the drug
of first choice, it has been relegated by the newer non-sedative
antihistamines with a lesser rate of side effects. The
association of H 1 and H 2 antihistamines does not appear to
have evidenced greater efficacy than the use of H 1 antihistamines
alone 2,15 . Doxepine, a tricyclic antidepressant with
marked H 1 antihistamine effects, has been used with success
at a dose of 50-75 mg/day in cases with insufficient
or scarce response to antihistamine therapy 16 . Stanazolol (a
synthetic testosterone-derived anabolic steroid with minimal
androgenic effects) has been demonstrated to be effective
in the management of familial cold urticaria 17 . In
cooperative patients with a high level of motivation, some
authors propose induction of cold tolerance or cold desensitisation,
in which the patient undergoes progressive contact
with cold water with gradual increase of the exposure
time and of the exposed body surface until he/she tolerates
total body immersion. This procedure should be carried
out with the patient admitted into hospital because of the
risk of triggering an anaphylactic reaction during the tolerance
induction procedure 15 .
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