Etiology and Pathogenesis

Acute urticaria and angioedema are often caused by an allergic immunoglobulin (Ig) E–mediated reaction (Table 142-1). This form of urticaria is a self-limited process that occurs when an allergen activates mast cells in the skin. Systemically absorbed allergens that can induce generalized urticaria include foods, drugs (particularly antibiotics), and stinging insect venoms. If an allergen (latex, animal dander) penetrates the skin locally, hives can develop at the site of exposure. Acute urticaria can also result from non–IgE-mediated stimulation of mast cells, caused by radiocontrast agents, viral agents including hepatitis B and Epstein-Barr virus, opiates, and nonsteroidal anti-inflammatory agents. The diagnosis of chronic urticaria is established when lesions recur at least twice a week for > 6 wk and are not physical urticaria or recurrent acute urticaria with repeated exposures to a specific agent (Table 142-2). Often, chronic urticaria is accompanied by angioedema. Rarely, angioedema occurs without urticaria.

Table 142-1 ETIOLOGY OF ACUTE URTICARIA

From Lasley MV, Kennedy MS, Altman LC: Urticaria and angioedema. In Altman LC, Becker JW, Williams PV, editors: Allergy in primary care, Philadelphia, 2000, WB Saunders, p 232.

Table 142-2 ETIOLOGY OF CHRONIC URTICARIA

From Lasley MV, Kennedy MS, Altman LC: Urticaria and angioedema. In Altman LC, Becker JW, Williams PV, editors: Allergy in primary care, Philadelphia, 2000, WB Saunders, p 234.

Urticaria can also be classified according to the temporal relationship with a stimulus and the duration of a typical hive. Lesions that last 1-2 hr are typical of the physical urticarias, in which an inciting stimulus is only briefly encountered. There is prompt mast cell degranulation, and biopsy of these lesions reveals little or no cellular infiltrate. A second form of urticaria can occur spontaneously and last 6-36 hr. These lesions typically have a prominent cellular infiltrate and can be found with food or drug reactions, chronic idiopathic urticaria, chronic autoimmune urticaria, and delayed pressure urticaria. Serum sickness reactions can be seen as a manifestation of drug reactions, and biopsy reveals a small-vessel cutaneous vasculitis. Urticaria in association with systemic lupus erythematosus or other vasculitides appears similar.

Atypical aspects of the gross appearance of the hives or associated symptoms should heighten concern that the urticaria or angioedema may be the manifestation of a systemic disease process. Lesions that burn more than itch, last >24 hr, do not blanch, or are associated with bleeding into the skin (purpura) suggest urticarial vasculitis.

Physical Urticaria

Physically induced urticaria and angioedema share the common property of being induced by environmental factors, such as a change in temperature or direct stimulation of the skin with pressure, stroking, vibration, or light (Table 142-3).

Table 142-3 DIAGNOSTIC TESTING FOR URTICARIA AND ANGIOEDEMA

Chronic Idiopathic Urticaria and Angioedema

A common disorder of unknown origin, chronic idiopathic urticaria and angioedema is often associated with normal routine laboratory values and no evidence of systemic disease. Chronic urticaria does not appear to result from an allergic reaction. It differs from allergen-induced skin reactions or from physically induced urticaria in that histologic studies reveal a cellular infiltrate predominantly around small venules. Skin examination reveals infiltrative hives with palpably elevated borders, sometimes varying greatly in size and/or shape but generally being rounded.

Biopsy of the typical lesion reveals non-necrotizing, perivascular, mononuclear cellular infiltration. Many types of histopathologic processes can occur in the skin and manifest as urticaria. Patients with hypocomplementemia and cutaneous vasculitis can have urticaria and/or angioedema. Biopsy of these lesions in patients with urticaria, arthralgias, myalgias, and an elevated erythrocyte sedimentation rate (ESR) as manifestations of necrotizing venulitis can reveal fibrinoid necrosis with a predominantly neutrophilic infiltrate. Yet the urticarial lesions may be clinically indistinguishable from those seen in the more typical, nonvasculitis cases.

There is an increased association of chronic urticaria with the presence of antithyroid antibodies. Affected patients generally have antibodies to thyroglobulin or a microsomally derived antigen (peroxidase) even if they are euthyroid. The incidence of elevated thyroid antibodies in patients with chronic urticaria is ≈12%, compared with 3-6% in the general population. Although some patients show clinical reduction of the urticaria with thyroid replacement therapy, others do not. Therefore, many investigators believe that these are associated, parallel, autoimmune events, although some believe that thyroid autoimmunity is driving the urticaria. There is currently no strong evidence to support the latter hypothesis.

Thirty-five percent to 40% of patients with chronic urticaria have a positive autologous skin test (ASST) result: If serum from these patients is intradermally injected into their skin, a significant wheal and flare reaction develops. Such patients frequently have a complement-activating IgG antibody directed against the α subunit of the IgE receptor that can cross link the IgE receptor (α subunit) and degranulate mast cells and basophils. An additional 5-10% of patients with chronic urticaria have anti-IgE antibodies rather than an anti–IgE receptor antibody. These patients, classified as having autoimmune urticaria, tend to have a more severe clinical course than patients without evidence of autoantibodies, but the difference is not dramatic.

Diagnosis

The diagnosis of both acute and chronic urticaria is primarily clinical and requires that the physician be aware of the various forms of urticaria.

Urticaria is transient, pruritic, erythematous, raised wheals, with flat tops and edema that may become tense and painful. The lesions may coalesce and form polycyclic, serpiginous, or annular lesions (Figs. 142-1 and 142-2). Individual lesions usually last 20 min to 3 hr, and rarely more than 24 hr. The lesions often disappear only to reappear at another site. Angioedema involves the deeper subcutaneous tissues in locations such as the eyelids, lips, tongue, genitals, and dorsum of the hands or feet.

Figure 142-1 Polycyclic lesions of urticaria associated with prostaglandin E₂ infusion.

(From Eichenfield LF, Friedan IJ, Esterly NB: Textbook of neonatal dermatology, Philadelphia, 2001, WB Saunders, p 300.)

Figure 142-2 Annular urticaria of unknown etiology.

(From Eichenfield LF, Friedan IJ, Esterly NB: Textbook of neonatal dermatology, Philadelphia, 2001, WB Saunders, p 301.)

Drugs and foods are the most common causes of acute urticaria. Allergy skin testing for foods can be helpful in sorting out causes of acute urticaria, especially when supported by historical evidence. The role of an offending food can then be proven by elimination and careful challenge in a controlled setting. In the absence of information implicating an ingestant cause, skin testing for foods and implementation of elimination diets are generally not useful for either acute or chronic urticaria. Skin testing for aeroallergens is not indicated unless there is a concern about contact urticaria (animal dander or grass pollen). Dermatographism is frequent in patients with urticaria and can complicate allergy skin testing by causing false-positive reactions, but this distinction is usually discernable.

An exogenous cause of chronic urticaria is rarely identified, reflecting an autoimmune or idiopathic etiology. An ASST is useful in establishing the diagnosis of autoimmune urticaria. In vitro testing for serum-derived activity that activates basophils involves detection of the expression of the surface marker CD63 or CD203c by donor basophils after incubation with patient serum. The clinical applicability and significance of these tests remains debated. The differential diagnosis of chronic urticaria includes cutaneous or systemic mastocytosis, complement-mediated disorders, malignancies, mixed connective tissue diseases, and cutaneous blistering disorders (e.g., bullous pemphigoid) (see Table 142-2). In general, laboratory testing should be limited to a complete blood cell count with differential, ESR determination, urinalysis, thyroid autoantibody testing, and liver function tests. Further studies are warranted if the patient has fever, arthralgias, or elevated ESR (see Table 142-3). Hereditary angioedema, a potentially life-threatening form of angioedema associated with deficient C1 inhibitor activity, is the most important familial form of angioedema (Chapter 128.3), but is not associated with typical urticaria. In patients with eosinophilia, stools should be obtained for ova and parasite testing, because infection with helminthic parasites has been associated with urticaria. A syndrome of episodic angioedema/urticaria and fever with associated eosinophilia has been described in both adults and children. In contrast to other hypereosinophilic syndromes, this entity has a benign course.

Skin biopsy for diagnosis of possible urticarial vasculitis is recommended for urticarial lesions that persist at the same location for >24 hr, those with pigmented or purpuric components, and those that burn more than itch. Collagen vascular diseases such as systemic lupus may manifest urticarial vasculitis as a presenting feature. The skin biopsy in urticarial vasculitis typically shows endothelial cell swelling of postcapillary venules with necrosis of the vessel wall, perivenular neutrophil infiltrate, diapedesis of red blood cells, and fibrin deposition associated with deposition of immune complexes.

Mastocytosis is characterized by mast cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, and skin. Clinical effects of mast cell activation are common, including pruritus, flushing, urtication, abdominal pain, nausea, and vomiting. The diagnosis is confirmed by a bone marrow biopsy showing increased numbers of spindle-shaped mast cells that express CD2 and CD25. Urticaria pigmentosa is the most common skin manifestation of mastocytosis and may occur as an isolated skin finding. It appears as small, yellow-tan to reddish brown macules or raised papules that urticate on scratching (Darier sign). This sign can be masked by antihistamines. The diagnosis is confirmed by a skin biopsy that shows increased numbers of dermal mast cells.

Physical urticaria should be considered in any patient with chronic urticaria and a suggestive history (see Table 142-3). Papular urticaria commonly occurs in small children, generally on the extremities. It manifests as grouped or linear, highly pruritic wheals or papules mainly on exposed skin at the sites of insect bites.

Exercise-induced anaphylaxis manifests as varying combinations of pruritus, urticaria, angioedema, wheezing, laryngeal obstruction, or hypotension after exercise (Chapter 143). Cholinergic urticaria is differentiated by positive results of heat challenge tests and the rare occurrence of anaphylactic shock. The combination of ingestion of various food allergens (shrimp, celery, or wheat) and postprandial exercise has been associated with urticaria/angioedema and anaphylaxis. In patients with this combination disorder, food or exercise alone does not produce the reaction.

Muckle-Wells syndrome and familial cold autoinflammatory syndrome (FCAS) are rare, dominantly inherited conditions associated with recurrent urticaria-like lesions. Muckle-Wells syndrome is characterized by arthritis and limb pain that usually appears in adolescence. It is associated with progressive nerve deafness, recurrent fever, elevated ESR, hypergammaglobulinemia, renal amyloidosis, and a poor prognosis. FCAS is characterized by a cold-induced rash that has urticarial features but is rarely pruritic. Cold exposure leads to additional symptoms such as conjunctivitis, sweating, headache, and nausea. Patient longevity is usually normal.

Treatment

Acute urticaria is a self-limited illness requiring little treatment other than antihistamines and avoidance of any identified provocateur. Hydroxyzine and diphenhydramine are sedating but are effective and commonly used for treatment of urticaria. Loratadine, fexofenadine, and cetirizine are also effective and are preferable because of reduced frequency of drowsiness and longer duration of action (Table 142-4). Epinephrine 1 : 1,000, 0.01 mL/kg (maximum: 0.3 mL) usually provides rapid relief of acute, severe urticaria/angioedema but is seldom required. A short course of oral corticosteroids should be given only for very severe episodes of urticaria and angioedema that are unresponsive to antihistamines.

Table 142-4 TREATMENT OF UTICARIA AND ANGIOEDEMA

* Monitor blood pressure and serum creatinine, potassium, and magnesium levels monthly.

^† Monitor complete blood count and liver function tests at baseline, every 2 wk for 3 mo, and then every 1-3 mo.

Most forms of physical urticaria respond to avoidance of triggering stimuli in combination with oral antihistamines. The exception is delayed pressure urticaria, which often requires oral corticosteroids. Cyproheptadine in divided doses is the drug of choice for cold-induced urticaria. Treatment of dermatographism consists of local skin care and antihistamines; for severe symptoms, high doses may be needed. The initial objective of therapy is to decrease pruritus so that the stimulation for scratching is diminished. A combination of antihistamines, sunscreens, and avoidance of sunlight is helpful for most patients.

Chronic urticaria only rarely responds favorably to dietary manipulation. Removal of recognized urticarial aggravators such as salicylates and β-blockers should be considered. The mainstay of therapy is the use of nonsedating or low-sedating H₁ antihistamines. In those patients not showing response to standard doses, pushing the H₁ blockade with higher than the usual recommended doses of these agents is a common next approach. The combined use of H₁– and H₂ antihistamines is sometimes helpful to control chronic urticaria when H₁-type antihistamines alone at higher than standard doses do not work (see Table 142-4). Doxepin is an antagonist of both H₁ and H₂ receptors and can be helpful, but its usefulness is limited by adverse effects. H₂-type antihistamines alone may exacerbate urticaria. Antileukotriene agents in combination with antihistamines are occasionally helpful. If hives persist after maximal H₁– and/or H₂-receptor blockade has been achieved, a brief course of oral corticosteroids may be considered, but long-term steroid use is best avoided. Treatment with cyclosporine 4-6 mg/kg/day has been effective in some adults with chronic urticaria but its use is limited by hypertension and/or nephrotoxicity. Immunomodulatory agents that have been used but remain to be formally proven effective include hydroxychloroquine, sulfasalazine, colchicine, dapsone, mycophenylate and omalizumab (anti-IgE), intravenous immunoglobulin, and plasmapheresis have been used to treat autoimmune chronic urticaria refractory to other therapies.

Hereditary Angioedema

Hereditary angioedema (HAE) is an inherited disease caused by low levels of the plasma protein C1 inhibitor (C1-INH) (Chapter 128). Patients typically report episodic attacks of angioedema or deep localized swelling, most commonly on a hand or foot, that begin during childhood and become much more severe during adolescence. Cutaneous nonpitting and nonpruritic edema not associated with urticaria is the most common symptom. Patients usually have a prodrome, a tightness or tingling in the area that will swell, lasting most frequently for several hours, followed by the development of angioedema. The swelling usually becomes more severe over about 10 days and then resolves over about the same period. In some patients attacks are preceded by the development of a rash that is erythematous, not raised, and not pruritic. The second major symptom complex noted by patients is attacks of severe abdominal pain caused by edema of the mucosa of any portion of the gastrointestinal tract. The intensity of the pain can approximate that of an acute abdomen, often resulting in unnecessary surgery. Either constipation or diarrhea during these attacks can be noted. The gastrointestinal edema generally follows the same time course to resolution as the cutaneous attacks.

Laryngeal edema, the most feared complication of HAE, can cause complete respiratory obstruction. Although life-threatening attacks are infrequent, more than half of patients with HAE experience laryngeal involvement at some time during their lives. Dental work with the injection of procaine HCL (Novocain) into the gums is a common precipitant, but laryngeal edema can be spontaneous. The clinical condition may deteriorate rapidly, progressing through mild discomfort to complete airway obstruction over a period of hours. Soft tissue edema can be readily seen when the disease involves the throat and uvula. If this edema progresses to difficulty swallowing secretions or a change in the tone of the voice, the patient may require emergency intubation or even tracheostomy to ensure an adequate airway. Other presentations are less common.

In most cases the cause of the attack is unknown, but in some patients trauma or emotional stress clearly precipitates attacks. In some females menstruation also regularly induces attacks. The frequency of attacks varies greatly among affected individuals and at different times in the same individual. Some individuals experience weekly episodes, whereas others may go years between attacks. Episodes can start at any age.

C1-INH is a member of the serpin family of proteases, similar to α-antitrypsin, antithrombin III, and angiotensinogen. These proteins stoichiometrically inactivate their target proteases by forming stable, one-to-one complexes with the protein to be inhibited. Synthesized primarily by hepatocytes, C1-INH is also synthesized by monocytes. The regulation of the protein production is not completely understood, but it is believed that androgens may stimulate C1-INH synthesis, because patients with the disorder respond clinically to androgen therapy with raised serum levels of C1-INH. C1-INH deficiency is an autosomal dominant disease, with as many as 25% of patients giving no family history. Because all C1-INH–deficient patients are heterozygous for this gene defect, it is believed that half the normal level of C1-INH is not sufficient to prevent attacks.

Although named for its action on the first component of complement (C1 esterase), C1-INH also inhibits components of the fibrinolytic, clotting, and kinin pathways. Specifically, C1-INH inactivates plasmin-activated Hageman factor (factor XII), activated factor XI, plasma thromboplastin antecedent, and kallikrein. Within the complement system, C1-INH blocks the activation of C1 and the rest of the classic complement pathway by binding to C1r and C1s. Without C1-INH, unchecked activation of C1 causes cleavage of C4 and C2, the following proteins in the complement cascade. Levels of C3 are normal. The major factor responsible for the edema formation is now known to be bradykinin, an important nonapeptide mediator that can induce leakage of post-capillary venules. Bradykinin is derived from cleavage of the circulating protein high molecular weight kininogen by the plasma enzyme kallikrein.

Two genetic types of C1-INH deficiency are described that result in essentially the same phenotypic expression. The C1-INH gene is located on chromosome 11 in the p11-q13 region. The inheritance is autosomal dominant with incomplete penetrance. Persons inheriting the abnormal gene can have a clinical spectrum ranging from asymptomatic to severely affected. Type 1 HAE is the most common form, accounting for approximately 85% of cases. Synthesis of C1-INH is blocked at the site of the faulty allele but occurs at the normal allele. The result is transcription of the normal protein, yielding quantitative serum concentrations of C1-INH that are approximately 10-40% of normal. Type 2 HAE accounts for approximately 15% of cases. Mutations near the active site of the inhibitor lead to synthesis of nonfunctional C1-INH protein. Patients with type 2 HAE have either normal or increased concentrations of the protein.

A clinical syndrome resembling HAE and termed type 3 HAE has been described that affects mostly women. In this condition, no abnormalities of complement or of C1-INH have been described, but one third of affected patients have been found to have a gain-of-function abnormality of clotting factor XII.

In the USA, 3 treatment regimens are used for prophylaxis of attacks, but no treatment is currently approved by the U.S. Food and Drug Administration (FDA) for treatment of acute attacks. Impeded androgens like the gonadotropin inhibitor danazol have been found to reliably prevent attacks in the vast majority of patients. Impeded or weak androgens have many side affects that preclude their use in some patients. Their use in children is problematic because of the possibility of premature closure of the epiphyses, and these agents are not used in pregnant women. The fibrinolysis inhibitor ε-aminocaproic acid is effective in preventing attacks and is often used in children, but its use is attended by the development of severe fatigue and muscle weakness over time.

Purified C1-INH prepared from human plasma has been approved for prophylaxis of this disease, but the half-life of this protein is short, on the order of 40 hr. In clinical trials it was given IV two to three times a week. Plasma C1 inhibitor, recombinant C1 inhibitor, a kallikrein antagonist called ecallantide, and a bradykinin type 2 receptor antagonist called Firazyr have all been reported to be effective in the treatment of acute attacks in preliminary double blind studies and are in various stages of review by the FDA.