Acquired cold urticaria: clinical picture and update on diagnosis and treatment

Acquired cold urticaria: clinical picture and update on diagnosis and treatment

Clinical dermatology • Review article
doi: 10.1111/j.1365-2230.2007.02376.x
Acquired cold urticaria: clinical picture and update on diagnosis and
treatment
F. Siebenhaar, K. Weller, A. Mlynek, M. Magerl, S. Altrichter, R. Vieira dos Santos, M. Maurer and
T. Zuberbier
Department of Dermatology and Allergy, Charite´-Universita¨tsmedizin Berlin, Berlin, Germany
Summary
Acquired cold urticaria (ACU) is a frequent subtype of physical urticaria that is caused
by the release of proinflammatory mast cell mediators after cold exposure. Although
the underlying causes of ACU still remain to be clarified in detail, a wide range of
diseases has been reported to be associated with ACU. This review gives an overview of
the clinical picture, the differential diagnoses, diagnostic tests and the aetiology of ACU,
and summarizes current and novel therapeutic options based on the current literature.
Clinical picture and epidemiology
Acquired cold urticaria (ACU) is a frequently encountered subtype of physical urticaria characterized by the
development of weal-and-flare type skin reactions
and ⁄ or angiooedema caused by release of histamine,
leukotrienes and other proinflammatory mast-cell mediators after exposure of the skin to cold. ACU is the fourth
commonest type of longlasting urticaria after chronic
spontaneous urticaria, dermographic urticaria ⁄ urticaria factitia and cholinergic urticaria. ACU symptoms
typically occur minutes after the skin is exposed to cold
air, liquids or objects. Symptoms of ACU are usually
limited to cold-exposed skin areas, but extensive cold
contact may result in generalized urticarial symptoms
and ⁄ or in systemic reactions including headache, dyspnoea, hypotension and loss of consciousness, which
most frequently results from extensive cold contact
during water exposure.1 Thus, patients with ACU are
endangered by drowning when swimming in cold
water as well as by suffocation due to pharyngeal
angiooedema after consuming cold foods and beverages.
Patients with a history of oropharyngeal oedema seem
Correspondence: Professor Dr Marcus Maurer, Department of Dermatology
and Allergy, Charite´-Universita¨tsmedizin Berlin, Charite´platz 1, 10117 Berlin, Germany.
Email: [email protected]
Conflict of interest: none declared
Accepted for publication 30 November 2006
to be at particularly high risk for developing shock-like
reactions after aquatic activity.2
ACU most frequently affects young adults. The mean
duration of the disease is 4–5 years, with remission or at
least improvement of symptoms in 50% of patients
within 5 years. Women are affected twice as often as
men. The incidence of ACU has been estimated to be
0.05%3. Within the physical urticaria subgroups of
urticarias, the frequency of ACU varies between 5.2%
and 33.8%, depending on the study and the geographical region, i.e. higher incidences are found in regions
with a cold climate.3,4
Differential diagnosis
ACU may be easily distinguished from other types of
urticaria by careful history-taking and disease-specific
diagnostic tests. Classically, ACU is subdivided into
primary and secondary ACU, which are merely different
designations in accordance with an unknown (primary)
or suspected (secondary) underlying cause or disease for
ACU. There are very rare subforms of ACU that cannot
be diagnosed by cold-contact stimulation tests (CST), as
symptoms occur from exposure to unique environmental conditions. It has been suggested that these entities
should be classified as atypical ACU (Table 1).5 In
addition, there are other, very rare atypical subtypes of
cold urticaria, including two hereditary familial cold
syndromes: delayed cold urticaria and familial cold
auto-inflammatory syndrome (FCAS). The latter is
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Acquired cold urticaria: clinical picture and update on diagnosis and treatment • F. Siebenhaar et al.
Table 1 Examples of differential diagnoses of classic acquired cold urticaria (ACU)5.
Atypical cold urticaria
Diagnostic distinction
Atypical acquired cold urticaria
Delayed cold urticaria
Cold-dependent dermographism
Cold-induced cholinergic urticaria
Systemic atypical cold urticaria
Immediate CST-negative (subtypes have additional diagnostic distinctions, listed below)
Delayed development of urticarial lesions up to 24 h after testing
Induction of urticarial lesions after stroking precooled skin
Induction of urticarial symptoms by exercise in cold environments
Induction of severe urticarial symptoms by exposure to unique environmental conditions;
tendency to systemic symptoms
Hereditary subtypes of cold urticaria
Delayed cold urticaria (AD)
Familial cold auto-inflammatory
syndrome (AD)
History of delayed urticarial lesions; negative immediate CST; delayed development of
urticarial-like lesions after 9–18 h that typically resolve into hyperpigmentation
Episodic cold-induced urticarial-like lesions associated with conjunctival injection, fever, and
other systemic inflammatory symptoms; often delayed development of lesions (1–2 h)
AD, autosomal dominant.
caused by a mutation of CIAS1, leading to the activation
of IL-1b (cold-induced auto-inflammatory syndrome)
(Table 1).5,6
Aetiology
The underlying causes and mechanisms involved in
the aetiology and pathogenesis of ACU still remain
largely unclear. ACU has been reported to be associated with viral or bacterial infections including
borreliosis, hepatitis, infectious mononucleosis, and
human immunodeficiency virus infection.7–9 In addition, cases associated with Helicobacter pylori colonization, acute toxoplasmosis and other parasitic infections
have been described.10,11 Infections of the upper
respiratory tract, teeth or urogenital tract may also
be associated with ACU. This possibly explains why
patients with ACU occasionally benefit from antibiotic
therapy.3 However, the complex interactions between
the infectious agent, the immunological host response,
and the development of ACU symptoms have not been
clarified in detail.
More infrequent immunological findings in patients
with ACU include cryoglobulinaemia, composed of
monoclonal IgG and mixed types of IgG ⁄ IgM and
IgG ⁄ IgA ⁄ cryoglobulins. Anti-lamin B antibodies,
reduced levels of C1-esterase inhibitor and C4, and
increased levels of platelet-activating factor and platelet
factor 4 have also been described in single cases.12–16
Hymenoptera stings and food and drug intolerance have
also been reported as a cause of ACU in a few cases.17,18
In up to 70% of patients with ACU, increased levels of
IgE antibodies can be found, and some studies report a
higher incidence of atopy in patients with ACU.4
Additionally, the prevalence of functional anti-IgE
antibodies (IgG and IgM) has been described in
242
patients with ACU.19 However, the exact role of IgE
and ⁄ or anti-IgE antibodies as pathogenetically relevant
factors in ACU has not yet been clarified in detail.
Finally, an association with haematological, lymphatic
or neoplastic diseases has been reported in a few cases
of ACU.
Diagnostic procedures in acquired cold
urticaria
The first aim of diagnostic measures is to confirm ACU
by performing simple cold-provocation testing.6 A
positive immediate cold-stimulation test (CST), i.e.
the development of urticarial skin lesions at sites of
cold challenge, verifies the presence of ACU.5,20
Various CSTs have been described, the most common
of which involves the application of an ice cube to the
skin.2
Secondly, in order to evaluate patients with ACU
objectively, i.e. to determine their disease activity and to
monitor their response to therapeutic interventions,
threshold testing for critical cold-stimulation times
and ⁄ or temperatures should be performed.6 Ice-cube
challenge tests are not suitable or standardized for
threshold testing; evidence obtained from controlled
studies supporting the value of these tests in characterizing the activity and course of ACU is very limited for
time thresholds1,21 and is absent for temperature
thresholds. This is not surprising, as both tests are
difficult to perform and standardize, especially in the
case of temperature-threshold testing. Recently, an
improved method has been reported to perform standardized cold provocation testing.20 This Peltier effectbased electronic device (TempTest; Emo Systems
GmbH, Berlin, Germany) allows exposure of the skin
to thermal elements with defined temperatures and
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Acquired cold urticaria: clinical picture and update on diagnosis and treatment • F. Siebenhaar et al.
therefore is ideally suited to assess thresholds of both
stimulation temperatures and times in patients with
ACU (Fig. 1).
As very little is known about the aetiology of ACU,
the underlying causes can only be identified in a
minority of patients with ACU, even if comprehensive
testing is performed. Therefore, additional diagnostic
measures should be limited to exclude major underlying
diseases and to identify associated diseases where
suggested by the patient’s history.
Treatment of acquired cold urticaria
(a)
(b)
Avoidance of cold
Avoidance of cold exposure is desirable (but not always
achievable) as this will prevent ACU symptoms,
including serious life-threatening events. Detailed
information on the properties of relevant cold stimuli
is required to equip the patient with skills to avoid
dangerous cold exposure, e.g. humidification and
chilling of the skin, or swimming in water that is
below the patient’s individual critical temperature
threshold. Threshold testing (e.g. using TempTest)
can help patients to recognize and control cold
exposure in their daily life.20
(c)
Symptomatic therapy
The treatment of ACU with antihistamines is the most
common and, as of yet, the most effective symptomatic therapeutic option to prevent and reduce
patients’ weal-and-flare skin reactions and pruritus
after cold exposure.22,23 However, sufficient reduction
of urticarial symptoms in many patients with ACU
requires high dosing with antihistamines, up to four
times the daily recommended dose.23 Therefore, it is
assumed that most patients with ACU receive insufficient treatment because antihistamines are used in
inadequately low doses. Because of this, many
patients with ACU suffer from severe and avoidable
impairment of their quality of life. In addition,
insufficiently treated patients with severe ACU are at
risk of developing life-threatening complications.
These include suffocation resulting from pharyngeal
angiooedema induced by cold foods or beverages, and
(d)
Figure 1 Peltier effect-based electronic device (TempTest) for
diagnosing and monitoring ACU symptoms. (a,d) Control unit
with ⁄ without applicator; (b) applicator with 12 stimulators;
(c) example of use.
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drowning after experiencing shock-like symptoms
during aquatic activity. Consequently, studies are
needed to identify the optimum antihistaminic treatment regimens for patients with ACU. In addition,
further treatment options for the therapy of severe
ACU with high risk of life-threatening reactions
and ⁄ or an insufficient response to antihistamines,
including the concomitant use of leucotriene antagonists,24 ciclosporin,25 corticosteroids26 or anti-IgE27
should be considered.
Emergency medication
Patients with severe ACU, i.e. risk of oropharyngeal
oedema or shock-like reactions, should be equipped
with an emergency medication kit containing corticosteroids, antihistamines and an epinephrine (adrenaline) injector. Patients must be educated to use their
emergency kits appropriately.
Curative therapy
In some patients, antibiotic therapy should be considered. Occasionally, patients with ACU have been shown
to benefit from such treatment even if no underlying
infection can be detected.3 The reported treatment
strategies include high doses of penicillin [e.g. oral
phenoxymethylpenicillin 1 MU ⁄ day for 2–4 weeks (our
experience) or intramuscular benzylpenicillin 1 MU ⁄
day for 20 days and tetracyclines over 2–4 weeks (e.g.
doxycycline 200 mg ⁄ day for 3 weeks)].28 However, it is
not yet clear whether an antibiotic treatment in ACU
cures an unidentified infection focus or if it interacts
either directly or indirectly with unknown diseasetriggering factors.
Further treatment options
The induction of cold tolerance (hardening) is an
effective method of treating patients with ACU. However, the initial induction of cold tolerance needs to be
done very cautiously under supervision because of the
risk of systemic reactions. Furthermore, high patient
compliance is required (daily cold showers) as discontinuation results in a complete recurrence of symptoms.29 Treatment with topical capsaicin, the pungent
principle ingredient of chilli peppers, has also been
reported to prevent ACU symptoms.30 Capsaicin treatment results in the depletion of neuropeptides from
sensory nerve fibres, which have been proposed to make
an important contribution to the induction of ACU skin
reactions,30 even though the pathogenetic role of
244
sensory nerve fibres and neuropeptides in ACU remains
to be clarified in detail.
Learning points
• When ACU is suspected, cold-stimulation tests
should be performed to confirm the diagnosis.
• In addition, threshold testing should be performed to determine the severity and course of
ACU.
• A basic laboratory programme should include
differential blood count and erythrocyte sedimentation rate. When suspected, the patient should be
checked for underlying disease, such as infections.
• Patients with ACU should be aware that avoidance of cold exposure is the best prophylaxis.
• Patients should be informed about the possible
occurrence of severe anaphylactic reactions and
danger of suffocation due to oropharyngeal oedema and supplied with an emergency kit.
• High doses of antihistamines may be required to
relieve ACU symptoms.
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