Urticaria (Hives) and Angioedema

Mitchell R. Lester
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Identifying Hives
Parents frequently consult the pediatrician because their child has hives but the rash is frequently gone before the patient’s office visit. Without the parent showing a picture of the rash on her smart phone, a description of the rash is often adequate for making the diagnosis. Urticaria are raised and well-circumscribed as the result of edema in the superficial dermis. True hives are transient with each individual lesion resolving within 24 hours without ecchymosis. The highly pruritic lesions with blanching erythema may be few or multiple. It is important to distinguish hives from non-urticarial conditions and from conditions causing pruritus without rash (Table 1).

Urticaria and angioedema may be IgE-mediated or non-IgE mediated. Sometimes the mechanism is unknown but in all cases, urticaria and angioedema occur as the result of mast cell activation with the release of pre-formed mediators of inflammation including histamine and tryptase and the synthesis and release of newly-formed mediators.

Urticaria and angioedema coexist in about 15% of affected children and up to 10% of children have angioedema without urticaria. Because angioedema involves deeper dermal and subcutaneous tissues, it is not as well demarcated or as pruritic as urticaria. IgE-mediated angioedema is also transient and usually asymmetric. The differential diagnoses of urticaria and angioedema are usually the same (see below). Therefore, for most patients, the two conditions reflect the same process occurring at different cutaneous depths. However, there are some conditions in which only urticaria or angioedema, but not both, occur (Table 2).

Acute Versus Chronic Urticaria and Angioedema

Chronic urticaria/angioedema (CU) are those lasting for more than 6 weeks. Although the frequency of urticaria/angioedema in those 6 weeks is not defined, the distinction from acute urticaria is important as the differential diagnoses vary. Hives of any duration can occur in any age or gender, but chronic urticaria are most common in young women. Up to 50% of CU resolve within 1 year of onset and 75% or more with 2-3 years. It is not uncommon for a patient with a history of CU to have recurrent episodes after months or years of quiescence.



Acute Urticaria and Angioedema- Differential Diagnosis

Acute urticaria and angioedema are by definition short lived and resolve spontaneously within six weeks. Acute urticaria frequently result from immediate-type (Gell and Coombs Type 1) hypersensitivity reactions. At least 90% of reactions triggered by food in very young children are from cow’s milk, hen’s egg, soy, or wheat allergy. In older children and adults, peanut, tree nuts, shellfish, and finned fish account for more than 90% of new-onset food reactions. Any food can cause allergy, however, so careful history taking is necessary.

Medications are also common triggers to urticaria and angioedema. Antibiotics, NSAIDS, quarternary ammonium muscle relaxants, and latex are common IgE-mediated triggers. The penicillins are frequently implicated because they are commonly prescribed and are good haptens making them more allergenic than other classes of medication. The quarternary ammonium compounds are large molecules that easily cross link mast-cell bound IgE molecules triggering mast cell activation. Opioids and radiocontrast media are non-specific mast cell activators that can trigger urticaria and angioedema in the absence of specific IgE. Angiotensin converting enzyme inhibitors are also non-IgE mediated triggers of angioedema thorough mechanisms involving activation of the kinin system.

Bug bite and flying insect stings cause urticaria. Systemic reactions from hymenoptera stings are IgE-mediated. Local reactions and papular urticaria from bug bites are not classic hives in that individual lesions last for greater than 24 hours. Pediatricians frequently see patients with post-viral urticaria, the mechanism of which is not known.

Finally and importantly, some acute urticaria and angioedema are idiopathic, without an identifiable preceding exposure.

Trigger identification in acute urticaria

The most specific and sensitive tool for identifying the trigger of acute urticaria/angioedema is a thorough history. Mast cell activation begins rapidly after cross-linking of surface bound specific IgE. For instance, onset of IgE-mediated food allergy reactions usually starts within 20-30 minutes, and almost always within 1-2 hours after ingestion. Therefore, the history should focus on exposures and ingestions within a short time before the onset of symptoms. In addition, the history should identify the presence or absence of cofactors that can increase the risk of hives including concurrent viral infections, NSAID use, and exercise.

Laboratory testing is sometimes indicated after a thorough history. In vitro and in vivo tests for specific IgE are useful to confirm or refute diagnostic suspicion after a detailed history. The true value of the tests comes with understanding their interpretation. A positive test does not indicate allergy. It merely reflects sensitization, the presence of specific antibody. IgE-mediated allergy is sensitization and mast cell activation with exposure; that is, there must be symptoms. Therefore, the physician should only request tests for specific IgE to allergens suggested by the history (rather than a “panel”). By so doing, the statistical value (sensitivity, specificity, positive [PPV] and negative predictive values [NPV]) of the tests improves.

In vitro tests (colloquially called RASTs [radioallergosorbent tests]) are easily accessible to any practitioner. RASTs are rarely used these days. Instead, in vitro tests that use the same immunologic principles but a different solid medium are preferred. The newer tests are more sensitive and specific than RASTs and in some cases the sensitivity approaches that of skin tests. The degree of elevation an in vitro test does not indicate severity of allergy; it indicates greater likelihood of allergy. Only the clinical reaction itself is predictive of severity. In vitro tests are more expensive than skin tests and take longer to get results. Because of the range of levels reported, they can also be harder to interpret. However, they are not influenced by antihistamine use, skin disease, or behavior of patents resistant to testing.

Skin testing is more specific and often easier to interpret than in vitro tests, but some of the same caveats apply. As with in vitro tests, a positive test indicates sensitization, not allergy. Food skin tests have a high NPV for IgE mediated reactions, but without a supportive history positive tests to food have <50% PPV. As with in vitro tests, extensive testing without a supportive history is inappropriate. A larger positive skin test indicates greater likelihood of allergy, but not the severity of the allergy. In contrast to in vitro tests, antihistamines and tricyclic antidepressants must be withheld before testing. Patients with atopic dermatitis and dermographism are more likely to have irrelevant or false positive tests.

Chronic Urticaria (Cu) and Angioedema- Differential Diagnosis

CU are present for six weeks or longer. Up to 90% of CU in children are idiopathic. They are virtually never allergic without a clear supportive history. Chronic idiopathic urticaria (CIU) are also called chronic spontaneous urticaria. About 1/3 of CIU are caused by an IgG autoantibody to the a-subunit of FceR1, the high affinity IgE receptor in the surface of mast cells and basophils. Those cases are grouped under CIU, although in reality they are not idiopathic because there is an identifiable cause. It is estimated that about half of CIU resolve spontaneously within a year and 75% within 2-3 years. Some patients have recurrent episodes of CIU and angioedema.

The next most common form of CU are those with physical triggers (Table 3). These inducible episodes might even be considered recurrent acute episodes as each individual occurrence is short lived. However, many patients with CIU have an overlay of a physical trigger that leads to worsening.

The history is usually adequate for identifying physical urticaria, many of which are very rare. The most common physical hive is dermatographism (skin writing), easily demonstrable by lightly stroking or scratching the skin and observing for the appearance of a linear wheal. Cold-induced urticaria/angioedema frequently appear upon rewarming of the skin. Patients commonly report hives while swimming or after coming out of the water or on exposed areas after being outdoors in the winter. Application of an ice cube to the forearm for 5-10 minutes and observing for wheal/flare with rewarming is a specific, but less sensitive test for diagnosis. Because urticaria, angioedema, and anaphylaxis are sometimes part of a spectrum, patients with cold induced urticaria/angioedema, should be cautious when submersed in cold water. Familial cold-induced urticaria is very rare.

Cholinergic and exercise-induced urticaria are sometimes confused, but are differentiated by history and physical appearances. Cholinergic urticaria occur after exercise or after passive heating such as in saunas, sun bathing, etc. Individual punctate wheals are intensely pruritic with wide surrounding erythema that may coalesce. The onset of exercise-induced urticaria is independent of body temperature. The lesions appear more like classic urticaria. As with cold-induced urticaria, these patients are at risk of anaphylaxis. Therefore, they should not exercise vigorously alone and should have auto-injectable epinephrine available during exercise. Solar urticaria are very rare, but may present as classic urticaria on sun exposed areas. Type VI erythropoietic protoporphria is a risk factor for solar urticaria.

On rare occasions in adults (<2%, of which most are vasculitis and not classic hives) and even more rarely in children, CU reflect the early presentation of an underlying systemic disease. Over the decades, numerous conditions have been associated with CU, but none so frequently that routine laboratory testing is necessary. However, the one test that everyone with urticaria/angioedema should have is a thorough and detailed history. If the review of systems is negative, the likelihood of a systemic disease presenting as urticaria becomes even more remote.

Table 1
Non-urticarial rashes mimicking urticaria/angioedema
Atopic dermatitis Morbilliform drug rashes
CAPS Pemphigoid/pemphigus
Cellulitis Photodermatitis
Contact dermatitis Polymorphous light eruption
Dermatitis herpetiformis PUPPPs
Erysipelas Serum sickness
Erythema chronicum migrans (Lyme disease) Urticaria pigmentosa
Erythema marginatum Vasculitis
Erythema multiforme Viral exanthema
Insect bites (papular urticaria)  
Pruritus without rash
Autonomic dysfunction Multiple sclerosis
Cholestasis Non-Hodgkins Lymphoma
Diabetes Polycythemia vera
Dysesthesias Psychiatric illness
Iron deficiency anemia Thyrotoxicosis
Malignancy Uremia
Medication reaction Xerosis
CAPS: Cryopyrin associated periodic syndromes
PUPPPs: Pruritic urticarial plaques and papules of pregnancy


Table 2
Conditions that cause urticaria WITHOUT angioedema. Conditions that cause angioedema WITHOUT urticaria.
CAPS ACE inhibitor reactions
Cutaneous mastocytosis

Contact urticaria
C1 esterase inhibitor deficiency
(hereditary and acquired, types I, II, and III)
  Physical triggers (some)
Physical triggers (some)  
Vasculitides  
ACE: Angiotensin converting enzyme
CAPS: Cryopyrin associated periodic syndromes


Table 3
Physical (inducible) urticaria and angioedema
(in approximate order of decreasing frequency)
Symptomatic dermatographism
Essential (acquired) cold-induced urticaria/angioedema
Cholinergic urticaria
Exercise induced urticaria and angioedema
Delayed pressure urticaria
Vibratory angioedema
Localized heat-induced urticaria/angioedema
Familial cold-induced urticaria
Solar urticaria
Aquagenic urticaria



References
Urticaria (Hives) and Angioedema Urticaria (Hives) and Angioedema 4/4/2016
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