Chapter 142 Urticaria (Hives) and Angioedema
Urticaria and angioedema affect 20% of individuals at some point in their lives. Episodes of hives that last for <6 wk are considered acute, whereas those that occur at least twice a week for >6 wk are designated chronic. The distinction is important, because the causes and mechanisms of urticaria formation and the therapeutic approaches are different in each instance.
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
| Foods | Egg, milk, wheat, peanuts, tree nuts, soy, shellfish, fish, strawberries (direct mast cell degranulation) |
| Medications | Suspect all medications, even over-the-counter or homeopathic |
| Insect stings | Hymenoptera (honeybee, yellow jacket, hornets, wasp, fire ants), biting insects (papular urticaria) |
| Infections | Bacterial (streptococcal pharyngitis, Mycoplasma, sinusitis); viral (hepatitis, mononucleosis [Epstein-Barr virus], coxsackievirus A and B); parasitic (Ascaris, Ancylostoma, Echinococcus, Fasciola, Filaria, Schistosoma, Strongyloides, Toxocara, Trichinella); fungal (dermatophytes, Candida) |
| Contact allergy | Latex, pollen, animal saliva, nettle plants, caterpillars |
| Transfusion reactions | Blood, blood products, or IV immunoglobulin administration |
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
| Idiopathic | 75-90% of chronic urticaria cases are idiopathic, and 35-40% have immunoglobulin (Ig) G, anti-IgE, and anti-FcεRI (high-affinity IgE receptor α chain) autoantibodies |
| Physical | Dermatographism |
| Cholinergic urticaria | |
| Cold urticaria | |
| Delayed pressure urticaria | |
| Solar urticaria | |
| Vibratory urticaria | |
| Aquagenic urticaria | |
| Rheumatologic | Systemic lupus erythematosus |
| Juvenile rheumatoid arthritis | |
| Endocrine | Hyperthyroidism |
| Hypothyroidism | |
| Neoplastic | Lymphoma |
| Mastocytosis | |
| Leukemia | |
| Angioedema | Hereditary angioedema (autosomal dominant inherited deficiency of C1-esterase inhibitor) |
| Acquired angioedema | |
| Angiotensin-converting enzyme inhibitors |
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
| DIAGNOSIS | DIAGNOSTIC TESTING |
|---|---|
| Food and drug reactions | Elimination of offending agent, skin testing, and challenge with suspected foods |
| Autoimmune urticaria | Autologous serum skin test; anti-thyroid antibodies |
| Thyroiditis | Thyroid-stimulating hormone; anti-thyroid antibodies |
| Infections | Appropriate cultures or serology |
| Collagen vascular diseases and cutaneous vasculitis | Skin biopsy, CH50, C1q, C4, C3, factor B, immunofluorescence of tissues, antinuclear antibodies, cryoglobulins |
| Malignancy with angioedema | CH50, C1q, C4, C1-INH determinations |
| Cold urticaria | Ice cube test |
| Solar urticaria | Exposure to defined wavelengths of light, red blood cell protoporphyrin, fecal protoporphyrin, and coproporphyrin |
| Dermatographism | Stroking with narrow object (e.g., tongue blade, fingernail) |
| Pressure urticaria | Application of pressure for defined time and intensity |
| Vibratory urticaria | Vibration for 4 min |
| Aquagenic urticaria | Challenge with tap water at various temperatures |
| Urticaria pigmentosa | Skin biopsy, test for dermographism |
| Hereditary angioedema | C4, C2, CH50, C1-INH testing by protein and function |
| Familial cold urticaria | Challenge by cold exposure, measurement of temperature, white blood cell count, erythrocyte sedimentation rate, and skin biopsy |
| C3b inactivator deficiency | C3, factor B, C3b inactivator determinations |
| Chronic idiopathic urticaria | Skin biopsy, immunofluorescence (negative result), autologous skin test |
Cold-Dependent Disorders
Cold urticaria is characterized by the rapid onset of localized pruritus, erythema, and urticaria/angioedema after exposure to a cold stimulus. Total-body exposure as seen with swimming in cold water can cause massive release of vasoactive mediators, resulting in hypotension, loss of consciousness and even death if not promptly treated. The diagnosis is confirmed by challenge testing for an isomorphic cold reaction by holding an ice cube in place on the patient’s skin for 4 min. In patients with cold urticaria, an urticarial lesion develops about 10 minutes after removal of the ice cube and upon rewarming of the chilled skin. Cold urticaria can be associated with the presence of cryoproteins such as cold agglutinins, cryoglobulins, cryofibrinogen, and the Donath-Landsteiner antibody seen in secondary syphilis (paroxysmal cold hemoglobinuria). In patients with cryoglobulins, the isolated proteins appear to transfer cold sensitivity and activate the complement cascade upon in vitro incubation with normal plasma. The term idiopathic cold urticaria generally applies to patients without abnormal circulating plasma proteins such as cryoglobulins. Cold urticaria has also been reported after viral infections. Cold urticaria must be distinguished from the familial cold autoinflammatory syndrome (see later).
Cholinergic Urticaria
Cholinergic urticaria is characterized by the onset of small punctate wheals surrounded by a prominent erythematous flare associated with exercise, hot showers, and sweating. Once the patient cools down, the rash usually subsides in 30-60 min. Occasionally, symptoms of more generalized cholinergic stimulation, such as lacrimation, wheezing, salivation, and syncope, are observed. These symptoms are mediated by cholinergic nerve fibers that innervate the musculature via parasympathetic neurons and innervate the sweat glands by cholinergic fibers that travel with the sympathetic nerves. Elevated plasma histamine values parallel the onset of urticaria triggered by changes in body temperature.
Dermatographism
The ability to write on skin, termed dermatographism (also called dermographism or urticaria factitia), occurs as an isolated disorder or accompanies chronic urticaria or other physical urticaria such as cholinergic and cold urticaria. It can be diagnosed by observing the skin after stroking it with a tongue depressor or fingernail. In patients with dermatographism, a linear response occurs secondary to reflex vasoconstriction, followed by pruritus, erythema, and a linear wheal.
Pressure-Induced Urticaria and Angioedema
Pressure-induced urticaria differs from most types of urticaria or angioedema in that symptoms typically occur 4-6 hr after pressure has been applied. The disorder is clinically heterogeneous. Some patients may complain of swelling secondary to pressure with normal-appearing skin (no urticaria), so the term angioedema is more appropriate. Other lesions are predominantly urticarial and may or may not be associated with significant swelling. When urticaria is present, an infiltrative skin lesion is seen, characterized by a perivascular mononuclear cell infiltrate and dermal edema similar to that seen in chronic idiopathic urticaria. Symptoms occur at sites of tight clothing; foot swelling is common after walking; and buttock swelling may be prominent after sitting for a few hours. This condition can coexist with chronic idiopathic urticaria or can occur separately. The diagnosis is confirmed by challenge testing in which pressure is applied perpendicular to the skin.
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