Evaluation of Urticaria and Angioedema

Peter C. Schalock

Arthur J. Sober

Urticaria (hives) is a pruritic, often immune-mediated skin eruption of well-circumscribed wheals on an erythematous base. It is estimated that up to one fifth of the population will experience an urticarial episode, with women more likely to be affected than men (especially with regard to chronic urticaria). Angioedema is a related condition involving the deeper layers of the skin. Approximately half of patients have urticaria with angioedema, 40% have pure urticaria, and 10% have pure angioedema. If the process occurs for less than 6 weeks, it is termed acute, but if it persists beyond 6 to 8 weeks, it is termed chronic. Most chronic urticaria resolves within 1 year, although persistence well beyond that occurs in approximately 10% of cases. The diagnostic responsibilities of the primary physician include searching for precipitants and underlying causes and distinguishing urticaria from urticarial vasculitis, a manifestation of connective tissue disease. Eliciting the cause can be difficult and is not always possible. In the absence of an identifiable and remediable precipitant, one needs to provide symptomatic relief.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11)

Urticaria

Mechanisms

Urticaria is the consequence of a mast cell release of mediators that increase vascular permeability, which leads to extravasation into the skin of protein-rich fluid from small blood vessels, usually postcapillary venules. Many mechanisms have been implicated, and much remains incompletely understood, but mast cell activation is usually the final common pathway. Precipitants range from physical stimuli to autoimmune mechanisms. In foodinduced and some forms of drug-induced disease, ingested or infused antigens trigger mast cell activation by an immunoglobulin E (IgE)-mediated pathway. In other drug-induced cases (e.g., opiates, amphetamines), direct activation by the drug does not occur. Hyperreactivity to acetylcholine (perhaps related to inadequate production of cholinesterases) is the suspected mechanism in persons with physical urticaria. Physical urticarias may also have some degree of IgE-mediated pathophysiology. In some cases, if not a substantial proportion of them, idiopathic chronic urticaria may represent a form of autoimmune activation of mast cells.

Regardless of the initial trigger, mast cell activation remains the final common pathway, with a release of mediators from mast cells or circulating basophils increasing vascular permeability. Histamine serves as a principal mediator, producing a classic wheal and flare on intracutaneous injection. Transient histamine elevations even occur in the extremities of patients with physical urticarias. Other possible mast cell-derived mediators include bradykinin, eosinophilic and high molecular weight neutrophilic chemotactic factors, prostaglandin D2, leukotrienes, and plateletactivating factors. Substance P may contribute to the flare that surrounds urticarial wheals. Heat, fever, emotional stress, alcohol, and the premenstrual state can exacerbate urticaria independent of the specific pathophysiology. Additional precipitants and mediators of the urticarial reaction are constantly being identified.

Clinical Presentations

The localized accumulation of fluid produces the characteristic edematous, erythematous, well-circumscribed itchy wheals, which blanch on pressure, range in size from a few millimeters to several centimeters, and manifest serpiginous borders. Individual lesions may persist for 12 to 24 hours, but most resolve spontaneously much sooner. Central clearing can lead to an annular pattern. The common final pathway for urticaria of most causes produces a rather stereotypical presentation, but each of the common types has a few distinguishing characteristics.

Food- and Drug-Induced Urticarias.

The attacks tend to be brief and usually do not cause chronic urticaria, but attacks may be accompanied by angioedema. The most commonly implicated foods include eggs, shellfish, true nuts, peanuts, fish, and milk, and the most common drugs are penicillins and sulfa-containing agents. Intravenous iodinated contrast agents, opiates, and amphetamines appear to cause the direct release of mediators from the mast cells. Aspirin and nonsteroidal anti-inflammatory agents (NSAIDs) produce urticaria in a doserelated nonimmunologic manner in susceptible persons, perhaps because they have an underlying abnormality in prostaglandin synthesis, which these agents block. Patients with urticarial reactions to aspirin can tolerate sodium salicylate or choline salicylate, which do not inhibit cyclooxygenase. Latex is an important example of a contact antigen common to medical settings that may trigger acute urticaria, angioedema, and even anaphylaxis by an IgE-mediated pathway. The powder that coats latex examination gloves is especially sensitizing, though the powder itself is not latex. Rather, the latex protein is taken up by the powder and subsequently becomes aerosolized. This issue is decreasing with nonpowdered gloves and extensive use of nonlatex exam gloves.

Chronic urticaria is often erroneously ascribed to exposure to food additives. Although benzoic acid derivatives (e.g., sodium benzoate) and several azo food dyes (e.g., tartrazine and sunset yellow) have been implicated, placebo-controlled trials revealed that food additives accounted for no more than 10% of cases. For those who are allergic to the metal nickel, a minority may experience urticaria with ingestion. Chocolate and peanuts are the most common sources.

Physical Urticarias.

These include dermatographism, pressure urticaria, cold urticaria, and cholinergic urticaria. In dermatographism, gentle stroking of the skin produces an immediate wheal and flare response. In pressure urticaria, the application of pressure at a right angle to the skin results in a red swelling after a latent period of up to 4 hours. In cold urticaria, the application of cold produces pruritic, erythematous eruptions within minutes. Cholinergic urticaria is characterized by tiny, 1- to 3-mm punctate lesions surrounded by erythema; they are intensely pruritic and triggered by exercise or a hot shower. Some exercise-induced disease may require prior ingestion of a food to which the patient is allergic. Aquagenic urticaria is characterized by tiny perifollicular hives that appear after contact with water. Solar urticaria develops in susceptible persons on exposure to ultraviolet light.

Autoimmune Disease.

An autoimmune form of mast cell disease has been postulated and might account for many of the otherwise idiopathic cases of chronic urticaria encountered. A whealproducing, noncytokine IgG mediator directed against the mast cell IgE receptor and causing the mast cell release of histamine has been identified in up to half of patients with chronic urticaria. Many of these patients also have autoantibodies to thyroid antigens, which perhaps accounts for the increased frequency of urticaria in persons with active Hashimoto thyroiditis. More than 25% of persons with chronic urticaria have antithyroid antibodies or antibodies to thyroglobulin. In studies of such patients (whether euthyroid or with clinical thyroid disease), treatment with exogenous thyroid hormone to lower the level of thyroidstimulating hormone often resulted in resolution of the urticaria. More work remains to test these hypotheses.

Infectious Diseases.

The formation of antigen-antibody complexes that trigger mast cell release has been the purported mechanism of the urticaria seen in some infectious diseases. For example, in the prodromal phase of hepatitis B, symmetric arthritis of the small joints of the hands may accompany an urticarial reaction, which is believed to be complement mediated. Some patients with chronic “idiopathic” urticaria reported that their urticaria resolved with treatment for Helicobacter pylori infection. These observations raise the possibility that H. pylori antigens may be responsible for some of the “idiopathic” disease encountered.

Angioedema

The mechanisms for angioedema are basically the same as for urticaria, which accounts for the simultaneous appearance of both types of lesions in some patients. The autoimmune mechanism described previously for urticaria and associated with Hashimoto thyroiditis is likely to account for a large fraction of idiopathic cases. Compared to urticaria, the extravasation of fluid in angioedema occurs in deeper layers of the skin and subcutaneous tissue, especially in the periorbital, perioral, pharyngeal, palmar, and plantar surfaces of the body. The edema is more diffuse, and the overlying skin appears normal and less itchy than in urticaria. Submucosal involvement in the upper airway and gastrointestinal tract can lead to hoarseness, life-threatening airway obstruction, nausea, vomiting, and abdominal discomfort. Sometimes, the abdominal pain is severe enough to mimic an acute abdomen. Most precipitants of urticaria can also trigger angioedema. Chronic angioedema and a few causes of acute angioedema have unique mechanisms and no associated urticaria.

Hereditary Angioedema

Hereditary angioedema is an autosomal dominant hereditary disease characterized by reduced or defective production of the inhibitor of the first component of complement (C1 INH). In type I, the most common form, C1 INH levels are markedly reduced and levels of C4 are low, whereas in type II, the patient has normal to elevated amounts of a dysfunctional C1 INH. Half of patients have no family history of the condition. There is no urticaria.

A characteristic presentation has been described of generalized skin swelling (involving the extremities, face, genitals, and trunk) in conjunction with abdominal discomfort occurring in greater than 97% of episodes; oropharyngeal involvement is uncommon (0.3% to 0.9%). Onset early in life portends a worse prognosis with more severe episodes.

Acquired Angioedemas

In patients with certain malignancies (adenocarcinoma, lymphoma, chronic lymphocytic leukemia), autoantibodies to C1 INH may develop and lead to attacks of angioedema. C1 levels fall, as do levels of C4 and C1 INH. Such patients do not report urticaria.

The angioedema that is occasionally seen with the use of angiotensin-converting enzyme inhibitors (ACEIs) appears to be mediated by bradykinins, purportedly occurring in persons who slowly metabolize kinins and experience a tissue-kinin buildup with ACEI therapy. It typically occurs shortly after the initiation of treatment with an ACEI, but it may develop at any time. Risk factors include African American race, age greater than 65 years, a history of drug rash with other agents, and seasonal allergies. Nonetheless, the absolute incidence rate over 10 years of observation is modest (1.74 episodes per 1,000 persons). Examination of the relative risks of angioedema with use of other drugs that target the renin-angiotensin-aldosterone system compared to ACEIs finds it similar for the direct renin inhibitor aliskiren, but reduced by two thirds for angiotensin II receptor antagonists, which do not affect bradykinins.

Unlike the angioedemas related to C1 INH, the autoimmune form associated with antibodies against the mast cell IgE receptor often presents with chronic urticaria, as well as angioedema (see earlier discussion).

Urticarial Vasculitis

Urticarial vasculitis superficially resembles urticaria but represents a vasculitic process heralding systemic autoimmune disease (e.g., systemic lupus, Sjögren syndrome). The skin lesions differ from those of urticaria, in that the wheals last for longer than 24 hours and manifest a more indolent appearance, which includes some central clearing, purpura, and residual pigmentation; the lesions hurt more than they itch. Patients also have systemic symptoms (e.g., fever, arthralgias, and abdominal pain) and may not obtain much relief from antihistamines. Laboratory studies may reveal an elevated sedimentation rate, the presence of antinuclear antibodies, and evidence of glomerulonephritis (microscopic hematuria, albuminuria). Biopsy demonstrates leukocytoclastic changes and extravasation of red cells, findings not seen with urticaria.

DIFFERENTIAL DIAGNOSIS (3, 4 and 5)

The causes of acute urticaria/angioedema are usually more straightforward, whereas the causes of chronic disease tend to be more elusive because the relation to precipitants is often less clear (Table 181-1). Urticaria needs to be differentiated from urticarial vasculitis, a presentation of connective tissue disease.