Behrman: nelson textbook of pediatrics, 16th ed

Behrman: Nelson Textbook of Pediatrics, 16th ed., Copyright 2000 W. B. Saunders
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Chapter 147 - Urticaria-Angioedema
(Hives)
CLINICAL MANIFESTATIONS.
Urticaria, or hives, is a common skin disorder characterized by usually well-
circumscribed but sometimes coalescent, localized or generalized, erythematous,
raised skin lesions (wheals or welts) of various sizes. The lesions may be
intensely pruritic or itch little, if at all. The individual hive usually resolves within
48 hr, but new ones may continue to appear singly or in crops. When urticaria
persists for longer than 6 wk, the condition is arbitrarily deemed chronic. Urticaria
has been attributed to edema of the upper corium as a result of dilatation and
increased permeability of the capillaries.
In angioedema (angioneurotic edema), the deeper layers of skin or submucosa
and subcutaneous or other tissues are involved; the upper respiratory tract and
the gastrointestinal tract are common target organs. The distinction between
urticaria and angioedema is frequently not clear; the lesions appear to differ only
in the depth of tissue involvement.
INCIDENCE.
As many as 20% of individuals experience hives at some time during life.
Urticaria is somewhat more frequent in females than in males.
PATHOGENESIS.
The principal noncytotoxic mechanism for urticaria and angioedema is interaction
of antigen with mast cell- or basophil-bound IgE antibodies. The release of
histamine from these cells causes vasodilation and increased vascular
permeability and stimulates an axon reflex, which produces a typical wheal and
flare reaction. Leukotrienes may contribute to the edema of the IgE-mediated
reaction. A second mediator pathway for urticaria involves the complement
system. Two complement component split products, C3a and C5a, act as
anaphylatoxins and trigger histamine release from mast cells and basophils by
direct action on the cell surfaces, independent of antibodies. C3a and C5a can
be generated through both the classic and alternative complement pathways. A
third mediator pathway involves the plasma kinin-forming system of the
coagulation scheme. Bradykinin is at least as potent as histamine in increasing
vascular permeability. Both non-IgE immunologic reactions and nonimmunologic
events can cause urticaria and angioedema when they activate the complement
and kinin-forming systems. Autoimmune chronic urticaria, a subgroup of chronic
urticaria, is due to IgG autoantibodies directed against the alpha subunit of the
IgE receptor of mast cells and basophils.
ETIOLOGY.
A clinical classification of urticaria is given in Table 147.1
TABLE 147-1 -- Types of Urticaria (Angioedema)
Caused by ingestants (IgE mechanism in some cases) Foods, particularly fish, shellfish, nuts, eggs, and peanuts; food additives (tartrazine, azo dyes, benzoates) Anisakis simplex, a parasite of seafoods Drugs (penicillin, aspirin, sulfonamides, codeine, angiotensin-converting enzyme inhibitors) Caused by contactants (IgE mechanism in some cases) Plant substances (e.g., stinging nettle) Animal, insect (tarantula hairs, Portuguese man-of-war, cat scratch, moth scales) Drugs applied to the skin Animal saliva Caused by injectants (IgE mechanism in some cases) Drugs (particularly penicillin), transfused blood, therapeutic antisera, insect stings and bites (papular urticaria), allergenic extracts Caused by inhalants (IgE mechanism) Pollens, danders, and ? molds Caused by infectious agents (mechanism unknown) Parasites Viruses (e.g., hepatitis, infectious mononucleosis) Bacteria ( Streptococcus, mycoplasma) ? Fungi Caused by physical factors (mechanism mostly unknown) Dermographism Cold urticaria Delayed pressure urticaria Solar urticaria Aquagenic urticaria Local heat urticaria Exercise induced Vibratory angioedema Episodic angioedema with eosinophilia (? a distinct entity) Cholinergic urticaria (a distinct entity) Associated with systemic diseases (mechanism mostly unknown) Collagen-vascular (systemic lupus erythematosus, cryoglobulinuria, Sjogren's syndrome) Cutaneous vasculitis Serum sickness-like disease Malignancy (leukemia-lymphoma) Hyperthyroidism Urticaria pigmentosa (systemic mastocytosis) Associated with genetic disorders (various mechanisms) Familial cold urticaria Hereditary angioedema Amyloidosis with deafness and urticaria C3b inactivator deficiency Chronic urticaria and angioedema (mechanism unknown) Psychogenic urticaria (existence as an entity uncertain) DIFFERENTIAL DIAGNOSIS. With a few exceptions, no laboratory tests establish or exclude the diagnosis of urticaria and angioedema. Allergy skin testing is generally not helpful except when specific drug (penicillin) or food allergies are identified. Dermographism is frequent in patients with urticaria, is associated with increased cutaneous responsiveness to histamine, and can complicate allergy skin testing. In the absence of any clue suggesting an ingestant cause, elimination diets generally are not useful. The diagnosis is clinical and requires that the physician be aware of the various forms of urticaria. A careful history usually identifies the type. Except when there are obvious associations with IgE-mediated reactions, naming the "cause" of urticaria may be difficult. Drugs and foods are the most common causes of urticaria. The cause of chronic urticaria is identified in only 10% of cases; some patients demonstrate autoantibodies to the IgE receptor. Some forms of urticaria need special mention. Papular urticaria usually occurs in small children, generally on the extremities and other exposed parts at the sites of insect bites. Cholinergic urticaria appears as wheals 1-2 mm in diameter surrounded by large areas of erythema (flares) and frequently involves the skin of the neck. It is caused by exercise, hot showers, and occasionally by anxiety. Affected individuals have increased sensitivity to cholinergic mediators, which can be demonstrated when an intradermal injection of 0.01 mg of methacholine (Mecholyl) in 0.1 ml of saline causes a localized hive surrounded by smaller, satellite lesions. Urticaria is probably more often due to viral infection than is commonly recognized. It is particularly associated with hepatitis, especially during the prodromal stages, and with infectious mononucleosis. Viral infections can also produce erythema multiforme, often confused with urticaria, in which typical iris or target lesions occur and mucosal involvement is common. In some patients, typical hives change spontaneously into lesions of erythema multiforme, which can be a sign of drug allergy . Urticaria pigmentosa typically occurs during the first few years of childhood and has a distinctive presentation. Systemic mastocytosis is a serious form of urticaria pigmentosa in which mast cells infiltrate skeleton, liver, spleen, and lymph nodes. In adults, and rarely in children, urticaria may be associated with malignancy or collagen-vascular disorders. Cold urticaria is the most common form caused by physical factors. Urticarial lesions, which may be pruritic or painful or burning, appear on exposure to cold and are confined to the exposed parts of the body. The lesions develop not only on exposure to cold weather but also with local application of cold. The cooling of skin associated with evaporation on emerging from water can produce urticaria. Swimming in cold water is hazardous; death may occur in patients so exposed. There are two forms: a primary acquired form and a familial form. Cold urticaria can occur in adults with systemic diseases such as cryofibrinogenemia, cryoglobulinemia, cold-agglutinin disease, and secondary syphilis. In some cases of primary acquired urticaria, the phenomenon has been passively transferred using purified IgE and IgM fractions of serum from affected patients. After appropriate cold challenge, there are also increased concentrations of histamine, eosinophil and neutrophil chemotactic factors, and platelet-activating factor in venous blood draining the challenge site. Primary acquired cold urticaria appears and disappears spontaneously; in some cases, its onset occurs with a viral illness. Hereditary angioedema, a potentially life-threatening form of angioedema is the most important familial form of angioedema. 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. Exercise-induced anaphylaxis presents with varying combinations of pruritus, urticaria, angioedema, wheezing, laryngeal obstruction, or hypotension after exercise. Cholinergic urticaria is differentiated by positive results on heat challenge tests and the rare occurrence of anaphylactic shock. The combination of ingestion of various food allergens (shrimp, celery, wheat) and postprandial exercise results in cutaneous mast cell degranulation; food or exercise alone may not produce this reaction. Skin biopsy for diagnosis of possible urticarial vasculitis is recommended for urticarial lesions that persist at the same location for more than 24 hr or those with pigmented or purpuric components. Additional features suggestive of urticarial vasculitis include painful lesions, poor response to antihistamines, a high erythrocyte sedimentation rate, and features of systemic inflammation (fever). TREATMENT. In most instances, urticaria is a self-limited illness requiring little treatment other than antihistamines. Hydroxyzine (Atarax), 0.5 mg/kg, is one of the most effective antihistamines for control of urticaria, but diphenhydramine (Benadryl), 1.25 mg/kg, and other antihistamines are also effective at the expense of sedation. Loratadine or cetirizine also can be effective and are preferable because of reduced frequency of impairment of function and learning. Epinephrine 1:1,000, 0.01 mL/kg, maximum of 0.3 mL, usually affords rapid relief of acute, severe urticaria. Hydroxyzine (0.5 mg/kg every 4-6 hr) has been the drug of choice for cholinergic and chronic urticaria, but a nonsedating antihistamine such as loratadine is preferable. The combined use of H1 - and H2 - type antihistamines is sometimes helpful to control chronic urticaria; doxepin, an antagonist of both H1 and H2 receptors, can be helpful. H2 antihistamines alone may exacerbate urticaria. Cyproheptadine (Periactin) (2-4 mg every 8-12 hr) is especially useful as a prophylactic agent for cold urticaria, but a nonsedating antihistamine is preferable. Cyproheptadine can cause appetite stimulation and weight gain in some patients. Sunscreens are the only effective treatment for solar urticaria. Corticosteroids have varying effects on chronic urticaria; the doses required to control the urticaria are often so large that they cause serious side effects. Treatment with small doses of cyclosporine has been effective in a few adults with chronic urticaria, but use of large doses has been limited by nephrotoxicity. Chronic urticaria does not often respond favorably to dietary manipulation. Treatment of autoimmune chronic urticaria includes intravenous immunoglobulin or plasmapheresis, or both. Unfortunately, chronic urticaria may persist for years.

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