Disorder
Clinical signs
Diagnosis
Treatment
Symptomatic dermographism (urticaria factitia)
Triggered by firm stroking, scratching of the skin. In these patients the white line secondary to reflex vasoconstriction is followed by pruritus, erythema, and linear swelling as in a classic wheal-and-flare reaction which may persist up to 30 minutes. Present in 2–5% of the population and mean duration is 6.5 years. Can be passively transferred, and some patients have elevated baseline histamine.
  • Case report of antihistamine-resistant dermatographism due to B-cell lymphoma
  • Moderate stroking of the skin with a blunt, smooth object (eg, closed ball point pen tip, wooden tongue depressor) or dermographometer, Skin responses are assessed 10 min after provocation.
  • Non-sedating antihistamines (e.g. cetirizine) are effective when symptoms are mild and can be combined or used in 2-3X usual doses
  • Fpr severe cases the drugs of choice are diphenhydramine or hydroxyzine 25-50 mg QID
  • Addition of H2 antihistamines may be of benefit
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Delayed pressure urticaria/angioedema
Triggered by application of pressure ½ - 12 hours (usually 4-8 h) before onset of symptoms. Urticaria may persist from 8-72 h. Typical areas of involvement are pressure bearing areas (palms, buttocks, thighs, feet). The lesions can develop after hammering, jogging, walking, prolonged sitting, or pushing a heavy load.
Clinically heterogeneous because some patients have swelling secondary to pressure with normal-appearing skin but in other patients, the urticaria predominate and may be associated with significant swelling. Frequently associated with severe burning and pain, and systemic problems such as flu-like symptoms, fever, malaise, arthralgia, leukocytosis. Usually associated with non-pressure induced chronic urticaria.
  • Sandbag test - sling with weights (7 kg weight on 3 cm wide strap) placed over the volar surface of the forearm, shoulder, upper back, or thigh for 15 min
  • Alternatively to sandbag, weighted rods (5 kg with 6.5 cm diameter or 2.5 kg with 1.5 cm diameter) are applied for 15 min
  • Dermatographometers are used in research (100 grams/mm2 for 70 seconds).
  • Patient reports symptoms over next 24 hours.
  • Antihistamines/LTRA may have little effect (but superior to placebo)
  • Steroids often required (usual range prednisone 15–25 mg QOD)
  • Treatment with clobetasol propoionate 0.05% foam (Olux) BID x 4 weeks to affected areas (e.g. thighs, feet) has been reported
  • Treatment of associated non-pressure chronic urticaria (which is common)
  • Bernstein: calcium channel blockers plus azatadine
  • One trial showed benefit using nimesulide (COX-2 inhibitor) and ketotifen, equivalent to high-dose prednisone
  • Grundmann: dapsone 25 mg PO QD week 1, 50 mg week 2, 100 mg week 3, 150 mg >4 weeks, plus 1 g vitamin C
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Cholinergic urticaria
Characterized by small, punctate wheals surrounded by a prominent erythematous flare associated with exercise, hot showers, sweating, spicy foods, and anxiety that may raise core body temperature >0.7-1°C. It tends to appear first over the upper thorax and neck but can spread distally to involve the entire body. In some patients, these hives become confluent and resemble angioedema, and some have symptoms of cholinergic stimulation, such as lacrimation, salivation, and diarrhea. May occur with wheezing. May occur without visible skin lesions (cholinergic pruritus). Occurs primarily in teens and young adults. Rare reports of patients with cholinergic urticaria and hypotension (can differentiate from exercise induced anaphylaxis which do not react with passive heating test). Condition may resolve in 5-7 years.
  • Mechanism may be neurogenic and/or degranulation due to factors in sweat (positive autologous sweat skin test)
  • Reported that elevation of core body temperature (without sweating) induced by endotoxin failed to trigger cholinergic urticaria
  • Subtypes
    • Non-follicular - most common, positive autologous sweat test (but negative autologous serum skin test), satellite wheals form to acetylcholine skin test
    • Follicular - follicular wheals, weak or no response to autologous sweat (but positive autologous serum skin test), no satellite wheals to acetylcholine skin test

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  • Exercise using a machine (stationary bicycle or treadmill) to the point of sweating, then continue for 15 minutes. If this test is positive, then passive heating of one/both arms in 44°C warm water bath to cause increase in core body temp of ≥1°C (alternatively, increase in core body temp >0.7°C with warming blankets or warm water bath)
  • Some patients may react to skin testing with own sweat (autologous sweat testing) in the non-follicular subtype
  • Methacholine skin testing (0.01 mg/0.1ml saline) has poor sensitivity and specificity
  • Kaplan: start with cetirizine 10 mg QID, decrease if that stops it to the lowest dose that works, or increase up to to 60 mg/day if a partial response is obtained. If that fails, switch to hydroxyzine 50 mg QID before giving up on antihistamines. It is not known to respond to steroids or cyclosporine.
  • For patients with poor response to antihistamines, mast cell stabilizing agents such as ketotifen may be effective
  • Danazol may be effective, but evidence is limited
  • Autologous sweat desensitization reported
  • Case reports of effectivess with omalizumab
  • Anticholinergic agents have not been shown to be effective for cholinergic urticaria
  • Patients with severe cholinergic urticaria may manifest systemic symptoms consistent with anaphylaxis and should be provided with an epinephrine injector
Idiopathic cold contact urticaria
(acquired cold urticaria, ACU)
Triggered by exposure of skin to cold air, cold liquids, or cold objects. The location of the urticaria is confined to the portions of the body that have contacted the cold, although the symptoms are often maximal after the exposed area is warmed. Patients with history of oropharyngeal edema after cold drinks are at high risk of shock from swimming in cold water.
Since many patients show critical temperature thresholds of 20°C (68°F) and higher. Several cases of death due to anaphylaxis while swimming in cold water have been reported. Peaks in young adults and mean duration is 4.8-7.9 years.
  • May be antibody mediated (IgE, IgG, IgM) and passively transferred
  • Histamine peaks 4-8 minutes after exposure
  • Ice cube test (also known as cold stimulation time test, CSST): place an ice cube in a thin plastic bag on the patient's forearm for 4-5 minutes and observe the area for 10 minutes. If the patient has cold urticaria, the area will become pruritic about 2 minutes after removing the ice cube, and by 10 minutes a large hive the shape of the ice cube will form.
  • TempTest® where available to determine patient's threshold. This device allows simultaneous skin exposure to 12 different temperatures from 4°C to 42°C.
  • A site tested is refractory to further testing for 24 h
  • A response in <3 min indicates a greater sensitivity
  • Ice cube test has a sensitivity of 83-90% and specificity of 100%
  • There is no clear-cut established threshold temperature, but it is often recommended that patients avoid temperatures lower than 25°C (77°F)
  • In situations where there may be generalized cold exposure, patients should be prescribed an automatic epinephrine injector
  • Cyproheptadine (Periactin) 8–16 mg daily in divided doses renders the ice cube test negative in most patients and affords considerable objective relief of symptoms when they are exposed to cold
  • Kaplan general approach to cold urticaria: antihistamine taken QID; then gradually decreased to lowest effective dose. E.g. cetirizine 10 mg QID, If that fails, use cyproheptadine, again starting at 4/day. But if that does not work within 2 weeks, increase to 6/day and then 8/day before quitting as long as sedation is not limiting. If nothing works, try omalizumab
  • Ketotifen, combinations of H1 with H2 antagonists or LTRAs have been reported to be effective
  • Steroids have not been effective in preventing outbreaks
  • Attempts to desensitize patients using ice baths have been reported, but caution must be exercised because highly sensitive patients could have anaphylactoid symptoms. After desensitization,tolerance is maintained by daily cold showers.
  • For patients undergoing surgery, the OR temperature should be increased and all fluids/blood products should be prewarmed to prevent cold-induced symptoms. Pretreatment with H1 and H2 antagonists and corticosteroids has been reported to prevent reactions during surgery.
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Familial atypical cold urticaria (FACU)

Proposed diagnostic criteria
1. Rash: Localized pruritic erythema after cold exposure with urticaria, angioedema, or both
2. Autosomal dominant pattern of disease inheritance
3. Rash resolution usually <1 h after rewarming
4. Absence of fever, chills, or joint complaints
5. Age of onset in childhood with lifelong duration of symptoms
6. Negative ice cube test result (no wheal formation)

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FCAS - familial cold auto-inflammatory syndrome
  • Ice cube test: negative for urticaria, but erythema may develop
  • Erythema/urticaria may appear in areas where water on skin has been evaporated by air (e.g. erythema along tracks of dried tears after crying)
  • 1st-generation antihistimines, higher doses of 2nd-generation antihistamines, or combination therapy with a LTRA might be required to control symptoms
  • Daily 2nd generation antihistamines may be considered for prophylaxis
  • Risk of life-threatening anaphylaxis, especially when exposed to aquatic activities. Advise avoidance of aquatic activities and carry epinephrine
Phospholipase Cγ2–Associated Antibody Deficiency and Immune Dysregulation (PLAID)

Deletions in PLCG2 gene cause gain of PLCγ2 function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function.

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Cold contact urticaria associated with abnormal serum proteins
Cold contact urticaria that is associated with a diseases characterized by abnormal immunoglobulins that have some cold-dependent property:
  • Cryoglobulinemia
  • Cold agglutinin disease
  • Cryofibrinogenemia
  • Paroxysmal cold hemoglobinuria (Donath-Landsteiner antibody associated with secondary syphilis)
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  • Ice cube test
  • Therapy is directed toward the underlying disease plus antihistamines
Systemic cold urticaria
Severe generalized hive formation on systemic cold challenge occurring over covered or uncovered parts of the body. Symptoms are unrelated to exercise or other activities.
  • Ice cube test negative
  • Hydroxyzine plus cyproheptadine in high dosage has been successfully used
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Cold-induced cholinergic urticaria
Exercise in a cold environment inducing hives similar to those seen with cholinergic urticaria; however, hive formation does not occur if exercise performed in a heated environment. In this disorder the cold exposure is systemic rather than local, and it should be suspected if any patient's symptoms suggest either cold urticaria or cholinergic urticaria and if standard tests for each disorder are negative.

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  • Ice cube test negative
  • Exercise in a cold room or running on a winter's day leads to generalized urticaria
  • Hydroxyzine plus cyproheptadine in high dosage has been successfully used
Cold-dependent dermographism
Hive formation is seen if skin is scratched and then chilled.
  • Ice cube test and systemic cold challenge negative
  • Scratching the skin yields a weakly positive dermatographic response, but dramatic accentuation is seen when the scratched area is chilled
High-dose antihistamines:
  • Double-triple the dose of non-sedating antihistamines, or...
  • Diphenhydramine 200 mg/day or...
  • Combination of hydroxyzine 100–200 mg/day and cyproheptadine 8–16 mg/day
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Delayed cold urticaria
Urticaria develop 9-48 hours after cold exposure
  • Ice cube test
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Localized cold urticaria
Only certain areas of the body are affected after cold contact. May have predisposing conditions, such as cold injury, or occur at sites of allergen injections, ragweed immunotherapy, or insect bites.

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  • Ice cube test at affected site

Cold reflex urticaria
Ice cube test is positive but hives form in the vicinity of the contact site, not where the ice cube is applied. The appearance of the hives resembles the punctate lesions of cholinergic urticaria, and there is no confluent hive where the ice cube is applied.
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  • Ice cube test is positive but hives form in the vicinity of the contact site, not where the ice cube is applied

Heat contact urticaria (local heat urticaria)
Triggered by warm object in direct contact with affected skin. Whealing typically develops within a few minutes after heat exposure, and it resolves after 1-3 h. Rare, <100 cases reported.
Application of test tube containing 45°C water or metal cylinder or TempTest device heated to 45°C, applied to skin for 5 min
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  • Antihistamines are the first choice
  • In difficult-to-treat patients, omalizumab can be effective
Exercise-induced urticaria/anaphylaxis
Combinations of urticaria, angioedema, wheezing, and hypotension occurring as a result of exercise. Symptoms may not occur with each exercise experience. The disorder is distinguished from cholinergic urticaria by the following criteria:
  • Hot showers, sweating in the absence of exercise, and anxiety do not trigger attacks of exercise-induced anaphylaxis (as they do in cholinergic urticaria)
  • The urticaria are large (10–15mm) rather than the small, punctate lesions seen in cholinergic urticaria.
  • Consider diagnosis of a mast cell activation syndrome
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Treadmill testing

Aquagenic urticaria
Very rare (30 total cases reported), lesions identical to cholinergic urticaria triggered by skin contact with water of any temperature. Salinity of water important in some cases. Systemic symptoms including anaphylaxis have been reported.
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Application of 35°C tap or distilled water in compress (e.g. small wet towel) to upper body for 30 min
  • Antihistamines reported to be variably helpful
  • Pretreatment with anticholinergic agents, such as scopolamine, has been shown to suppress hives after water exposure.
  • Treatments with petrolatum barrier cream, SSRIs, and UVA or UVB phototherapy have been reported to be effective in refractory cases
  • A case refractory to antihistamines (in a HIV patient) improved with stanozolol
Idopathic Aquagenic Pruritus
Occurs after skin contact with water, involving intense itching without visible skin changes and without an under- lying pathology (polycythemia vera, Hodgkin disease, and blood disorders) or drugs that could induce this symptom.
  • Pathophysiology is unknown, but inappropriate activation of the autonomic nervous system could be involved. Neurotransmitters, such as acetylcholine and vasoactive intestinal peptide, are indeed released in the skin on contact with water in patients with IAP, whereas the role of histamine appears to be minimal.

  • Propranolol at 10-40 mg/d may be most effective treatment in the absence of contraindications
  • Conventional treatments include adding sodium bicarbonate to bath water, antihistamines, or phototherapy, which relieve symptoms in 24%, 47%, and 50% of patients, respectively
Solar urticaria

Brief exposure to certain wavelengths of light causes urticaria within 3-10 minutes. Typically, pruritus occurs first, at about 30 seconds, followed by erythema/edema confined to the light-exposed area and surrounded by a prominent erythematous zone caused by an axon reflex. Usually disappears within 1-3 hours. When large areas of the body are exposed, systemic symptoms including anaphylaxis may occur. Bruised skin seems more sensitive to develop symptoms.

  • Types I (activated by wavelengths 2800–3200Å) and IV (4000-5000Å) can be passively transferred and may therefore be antibody (IgE?) mediated.
  • Type VI (4000Å), is a metabolic disorder in which protoporphyrin IX acts as a photosensitizer.
  • The mechanism in types II (3200-4000Å), III (4000-5000Å), and V (2800-5000Å) is unknown; they cannot be passively transferred with serum.

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Exposure of normally-covered skin (e.g. buttocks) to UVA (6 J/cm2), UVB (60 mJ/cm2) and visible light (projector)
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  • Therapy requires antihistamines, avoidance of sunlight, protective garments to cover the skin, and use of topical preparations to absorb or reflect light. No single modality of treatment is uniformly effective.
  • Ordinary window glass 3mm thick will absorb most ultraviolet radiation below 3200Å and protect patients with type I
  • Type VI responds to oral β-carotene, which absorbs light at the same wavelengths as protoporphyrin IX
  • 5% PABA (sunscreen) can be helpful in the 2800–3200Å range; however, it is more difficult to screen out the visible spectrum. The most effective agents for this purpose contain titanium oxide, zinc oxide, or both.
  • H1 antihistamines may have variable effectiveness
  • The efficacy of antimalarial, corticosteroid agents or psoralen and UVA photochemotherapy in these disorders is not clear and must be evaluated for each type
  • Reported improvement with afamelanotide (α-melanocyte stimulating hormone analogue) that increases melanisation of the skin and protects it from penetration of UV–visible wavelengths
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Vibratory urticaria/angioedema
A physically induced angioedema in which patients develop pruritus and swelling minutes after vibratory stimuli. They do not have dermographism or pressure urticaria. Autosomal dominant, however non-familial sporadic cases have been described. Resolves by 24 hours.
Stimulate patient's forearm with a laboratory vortex for 4-10 minutes. Rapid swelling of the entire forearm and a portion of the upper arm ensues.
  • Avoid vibratory stimuli (lawn mowing, riding a motorcycle, horseback riding, mountain biking, exposure to vibrating machinery, etc.)
  • Warming up before exercise may be helpful
  • H1 antihistamines and ketotifen may be helpful
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  • Passive transfer by serum
    • Cold urticaria
    • Solar (type I and IV)
    • Dermographism


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References