Key Points
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The distinction between acute and chronic urticaria/angioedema has important diagnostic and therapeutic implications. Recurrent angioedema without urticaria suggests the possibility of hereditary angioedema.
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The most common type of swelling in children is acute urticaria/angioedema. The cause of acute urticaria can often be determined and is most likely to involve IgE-mediated reactions, viral infections or bites and stings.
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Chronic urticaria/angioedema is typically idiopathic; however, physical stimuli often contribute to the symptoms. Extensive diagnostic evaluation of chronic urticaria is usually not warranted.
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First-line treatment of urticaria/angioedema is nonsedating antihistamines with dosing up to four times the usual dose if necessary.
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Omalizumab or cyclosporine may be considered for patients with chronic urticaria who do not respond to high-dose antihistamines and do not have an underlying urticarial vasculitis.
Urticaria (hives or wheals) typically presents as a pruritic generalized eruption with erythematous circumscribed borders and pale, slightly elevated centers ( Figure 52-1A ). Angioedema is characterized by an asymmetric nondependent swelling that is generally not pruritic ( Figure 52-1B ). The pathophysiology of urticaria and angioedema is similar and is due to increased vascular permeability. However, the underlying mechanisms can be very distinct: mast cells are usually implicated in urticaria but bradykinin may be the cause in angioedema. Affected patients may manifest symptoms that range from transient and mildly annoying hives to severe and potentially fatal angioedema. Quality of life has been reported to be moderately to severely impaired in patients with chronic urticaria, and children with chronic urticaria exhibit significantly greater psychiatric morbidity than controls. An efficient and cost-effective approach to the management of urticaria and angioedema depends on a careful assessment of the characteristics and likely cause of the swelling. This chapter provides a framework to differentiate the various types of urticaria and angioedema, then outlines a directed evaluation and treatment plan based on the etiology ( Box 52-1 ).
- •
The distinction between acute and chronic urticaria/angioedema has important diagnostic and therapeutic implications.
- •
The most common type of swelling in children is acute urticaria/angioedema.
- •
The cause of acute urticaria can usually be determined and is most likely to involve IgE-mediated reactions, viral infections or bites and stings.
- •
The cause of chronic urticaria/angioedema is typically idiopathic; however, physical stimuli often contribute to the symptoms.
- •
Chronic urticaria/angioedema must be distinguished from urticarial vasculitis.
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Recurrent angioedema without urticaria suggests the possibility of hereditary angioedema.
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Most cases of chronic urticaria/angioedema resolve within 3 to 4 years.
Epidemiology/Etiology
Epidemiology
Urticaria/angioedema is conventionally classified as either acute or chronic, the latter being defined as the continuous or frequent occurrence of lesions for longer than 6 weeks. While arbitrary, this distinction has significant implications regarding the cause, course and treatment of the swelling. Most urticaria/angioedema is acute, particularly in children. Acute urticaria/angioedema can occur during anaphylaxis, and this possibility needs to be considered when urticaria or angioedema is associated with respiratory, gastrointestinal, cardiovascular or nervous system involvement. Approximately 50% of affected patients experience both urticaria and angioedema, 40% only urticaria, and 10% only angioedema. Surveys have indicated that 15% to 23% of the population experience urticaria at least once during their lifetime, while the prevalence of chronic urticaria is estimated to be 0.5% to 5%, with females over-represented. Atopic individuals are at increased risk for acute urticaria/angioedema and some forms of physical urticaria; however, most patients with chronic urticaria/angioedema are not atopic.
The prevalence of hereditary angioedema (HAE) due to C1 inhibitor (C1INH) deficiency (HAE-C1INH) is approximately 1 : 50,000. The prevalence of HAE with normal C1INH (HAE-nlC1INH) is unknown but likely less than HAE-C1INH. Acquired C1INH deficiency is only seen in adults and has an estimated prevalence of 1 : 500,000. Bradykinin-mediated angioedema can also be associated with use of angiotensin-converting enzyme inhibitors and possibly with recurrent idiopathic angioedema.
Etiology
Most urticaria/angioedema is caused by mast cell degranulation with released mediators causing activation of sensory nerves, vasodilation, plasma extravasation, up-regulation of endothelial cell adhesion molecules and recruitment of inflammatory cells. Basophils may also play an important role. The causes of mast cell degranulation in urticaria/angioedema are variable. IgE-mediated mast cell degranulation is responsible for many cases of acute urticaria/angioedema in children, most commonly from drugs and foods. Many acute and most chronic urticaria/angioedema cases involve mast cell activation due to nonimmunologic or immune processes not involving IgE, such as direct mast cell degranulators, viral infections, anaphylatoxins, various peptides/proteins and several types of physical stimuli. Viral infections are the most common cause of acute urticaria in children.
The underlying cause of mast cell degranulation in chronic urticaria/angioedema usually cannot be determined. Lesions demonstrate a nonnecrotizing mononuclear cell infiltrate around small venules, with increased numbers of basophils, eosinophils and T helper cells. Filaggrin is overexpressed in urticarial lesions, the level correlating with urticaria severity. Activation of thrombin with subsequent generation of C5a has also been suggested as a potential underlying mechanism in chronic urticaria. Some children with celiac disease and severe chronic urticaria showed improvement of the urticaria following institution of a gluten-free diet. At least 40% of patients with chronic urticaria have circulating autoantibodies with specificity for IgE or the high-affinity FcεR. Skin testing with autologous serum or plasma may detect these antibodies. Approximately 30% of children with chronic urticaria have positive autologous serum skin tests. The functional and prognostic significance of these autoantibodies remains unclear.
An increased prevalence of thyroid antimicrosomal and antithyroglobulin antibodies has been described in urticaria/angioedema, with about half of these patients having goiters or abnormal thyroid function; however, no causal relationship has been demonstrated. Conversely, an increased cumulative prevalence of urticaria/angioedema has been found in thyroid disease patients with antimicrosomal and antithyroglobulin antibodies (primarily Hashimoto’s thyroiditis) but not in patients with other types of thyroid disease. Activation of complement by the complement controller domain of thyroperoxidase has been suggested to be an important contributor to development of urticaria/angioedema in patients with thyroid autoimmunity. An association between urticaria and a variety of autoimmune diseases has also been described, although the nature of the relationship remains uncertain.
Severe urticaria/angioedema associated with marked weight gain, pronounced leukocytosis and striking eosinophilia (Gleich syndrome) has been shown to involve increased serum levels of cytokines (including IL-5) during attacks. Other cases of urticaria/angioedema have been reported in association with parathyroid disease, polycythemia vera, hemolytic uremic syndrome, Schnitzler syndrome (chronic urticaria, monoclonal IgM, arthralgia, fever and adenopathy) and pregnancy. Cyclical urticaria occurring prior to menses may be an autoimmune progesterone-induced dermatitis. Genetic causes of swelling include HAE, Muckle-Wells syndrome, vibratory angioedema, familial cold autoinflammatory syndrome, familial localized heat urticaria of delayed type, erythropoietic protoporphyria with solar urticaria, C3 inactivator deficiency with urticaria, and serum carboxypeptidase N deficiency with angioedema.
HAE-C1INH is an autosomal dominant disease caused by a functional deficiency of the plasma protein C1INH. Two major types of HAE-C1INH have been described: type I HAE comprises 85% of cases and is characterized by low C1INH antigenic and functional levels; type II HAE comprises the other 15% of cases and is characterized by normal C1INH antigenic levels with low C1INH functional activity due to secretion of a dysfunctional protein. Type I and type II HAE are caused by mutations in the C1INH gene ( SERPING1 ), resulting in increased plasma kallikrein activity and generation of the vasoactive mediator bradykinin. Familial recurrent angioedema with normal C1INH gene and protein was originally called type III HAE, but has now been named HAE-nlC1INH. Initially thought to affect primarily women exposed to increased estrogen levels, it has become clear that both men and women are affected, with a variable effect of estrogens. Several coagulation factor XII gene mutations have been found in a minority of HAE-nlC1INH kindreds; however, the underlying cause of the disease remains unclear. C1INH deficiency may also be acquired; however, this occurs primarily in older adults and has not been reported in children.
Familial cold autoinflammatory syndrome and Muckle-Wells syndrome have been shown to be associated with mutations in a gene that encodes cryopyrin. The family of autoinflammatory urticarial syndromes is referred to as cryopyrinopathies. Neonatal-onset multisystem inflammatory disease (NOMID) is a particularly severe cryopyrinopathy. The IL-1 receptor antagonist anakinra has been used successfully to prevent attacks. A hereditary cold urticaria syndrome due to genomic deletions of PLCG2 has been shown to lead to a gain of phospholipase Cγ2 function associated with antibody deficiency, susceptibility to infection, and autoimmunity.
Differential Diagnosis
Recognition of urticaria and angioedema on examination is generally straightforward. The single most important step in the differential diagnosis is to visualize the lesions during swelling. Individual urticarial lesions seldom last for more than a few hours (up to 24 hours), which distinguishes urticaria from almost all other skin diseases. In addition, urticarial lesions blanch with pressure and new hives frequently develop as the older ones fade. If the lesions do not itch, the diagnosis should be reconsidered. Angioedema is not dependent and is typically not symmetrical. Figure 52-2 presents an algorithm for the approach to the differential diagnosis.
Acute Urticaria/Angioedema
Acute urticaria/angioedema by definition lasts less than 6 weeks and is most commonly caused by exposure to allergens, toxins or sensitizers, or infections. A cause for acute urticaria/angioedema can frequently be determined. Most cases in children will be secondary to IgE-mediated reactions or viral infections. Penicillin and other antibiotics frequently cause urticaria/angioedema. The most common foods associated with IgE-mediated urticaria/angioedema vary with the age of the patient. In younger children, egg, milk, soy, peanut and wheat are the most common allergens, whereas fish, seafood, nuts and peanuts are common offenders in older children. Acute urticaria can also be triggered by ingestion of fish containing high levels of bioactive amines in the absence of specific IgE (scombroid poisoning). Urticaria and angioedema are the most common manifestations of anaphylactic reactions to insect stings and bites. Immunologic reactions to the saliva of bedbugs, fleas or mites can cause papular urticaria, especially on the legs of children. Recently, acute urticaria/angioedema occurring 3 to 6 hours following the ingestion of beef, pork, lamb or venison has been described in patients with IgE against galactose-α-1,3-galactose. Urticaria multiforme (or acute annular urticarial hypersensitivity) is distinguished by transient annular urticarial lesions, often accompanied by angioedema, that respond to antihistamines.
Urticaria/angioedema can also result from exposure to direct mast cell degranulators (such as strawberries, narcotic drugs, polymyxin antibiotics, d -tubocurarine or dextran volume expanders), penetrating substances (such as nettles, Portuguese man-of-war, other forms of sea life, moth and butterfly scales, tarantula hairs or caterpillar foot processes), or substances that can produce urticaria on contact with intact skin (such as latex, industrial chemicals, benzoic acid, sorbic acid and numerous other agents). Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) can provoke acute urticaria/angioedema in children and adults.
Chronic Urticaria/Angioedema
This is a diagnosis of exclusion, based on history, examination and carefully selected testing. No clear relationship has been found between chronic urticaria and food allergy, ingestion of food additives or focal infections. Parasitic infestations may be suggested by finding substantial eosinophilia, elevated IgE level, abdominal symptoms or a history of recent foreign travel. Helicobacter pylori infection has also been suggested as having a link to chronic urticaria.
Chronic urticaria is further subdivided into chronic spontaneous urticaria (CSU, previously referred to as chronic idiopathic urticaria) or inducible urticaria (previously known as physical urticaria) based on whether there is a precipitating stimulus. CSU has no identifiable cause and is the most common form of chronic urticaria/angioedema. Patients with CSU may have autoimmune features (see above). Inducible urticaria involves mast cell degranulation precipitated by discrete physical stimuli ( Table 52-1 ). Inducible urticaria is often but not always encountered in the setting of co-existing CSU. The percentage of children in whom chronic urticaria also has a physical component ranges from 1% to > 10%. Patients may swell in response to one or several physical stimuli, including mechanical pressure or stroking, heat or cold, sunlight or water. Specific physical challenges can be performed to confirm inducible urticaria/angioedema. Dermographism may occur in up to 2% to 5% of the general population ( Figure 52-3A ), and can account for the majority of hives in some patients. Delayed pressure urticaria is more angioedematous than urticarial and causes significant morbidity. Primary and secondary acquired forms of cold urticaria have been described. Primary acquired cold urticaria is often seen in children and is frequently associated with asthma, allergic rhinitis and progression to frank anaphylaxis. Patients with acquired cold urticaria have drowned when exposed to cold water, and must be warned to avoid cold water and never to swim alone. Cold urticaria should be distinguished from familial cold autoinflammatory syndrome, which is marked by cold-induced erythematous rash, fever, arthralgias, leukocytosis and conjunctivitis. Cholinergic urticaria ( Figure 52-3B ) is relatively common in children, may be confused with exercise-induced anaphylaxis, and can be associated with angioedema, wheezing or even syncope. Persistent cholinergic erythema, a variant of cholinergic urticaria, can be mistaken for a drug eruption or cutaneous mastocytosis. Many patients have combinations of different physical urticarias, such as cold and cholinergic urticaria, cold and localized heat urticaria, or dermographism with cold urticaria.
| Type | Provoking Stimuli | Diagnostic Test | Comment |
|---|---|---|---|
| Mechanically Provoked | |||
| Dermographism (urticaria factitia) | Rubbing or scratching of skin causes linear wheals | Stroking the skin (especially the back) elicits a linear wheal | Primary (idiopathic or allergic) or secondary (urticaria pigmentosa or transient following virus or drug reaction) |
| Delayed dermographism | Same | Same | Rare |
| Delayed-pressure urticaria | At least 2 hr after pressure is applied to the skin, deep, painful swelling develops, especially involving the palms, soles and buttocks | Attach two sandbags or jugs of fluid (5–15 lb) to either end of a strap and apply over the shoulder or thigh for 10 to 15 min. A positive test exhibits linear wheals or swelling after several hours | Can be disabling and may be associated with constitutional symptoms such as malaise, fever, arthralgia, headache and leukocytosis |
| Immediate-pressure urticaria | Hives develop within 1 to 2 min of pressure | Several minutes of pressure elicit hives | Rare; seen in conjunction with hypereosinophilic syndrome |
| Thermally Provoked | |||
| Acquired cold urticaria | Change in skin temperature rapidly provokes urticaria | Place ice cube on extremity for 3 to 5 min, then observe for pruritic welt and surrounding erythema as the skin rewarms over subsequent 5 to 15 min | Relatively common, may occur transiently with exposure to drugs or with infections; other rare cases may be associated with cryoproteins or may be transferable by serum |
| Familial cold autoinflammatory syndrome | Intermittent episodes of rash, arthralgia, fever and conjunctivitis occur after generalized exposure to cold | Symptoms occur 2 to 4 hr after exposure to cold blowing air | Autosomal dominant inflammatory disorder previously called familial cold ‘urticaria’; results from mutation of CIAS1 gene, coding for cryopyrin |
| Cholinergic urticaria | Heat, exertion or emotional upsets cause small punctate wheals with prominent erythematous flare. May be related more to sweating than to heat per se | Methacholine cutaneous challenge is sometimes helpful; better to reproduce the lesions by exercising in a warm environment or while wearing a wetsuit or plastic occlusive suit | Differs from exercise-induced anaphylaxis in that it features smaller wheals and is induced by heat as well as by exercise but does not generally cause patients to collapse. Relatively common in patients with chronic urticaria; can be passively transferred by plasma in some patients |
| Localized heat urticaria | Urtication occurs at sites of contact with a warm stimulus | Hold a test tube containing warm water against the skin for 5 min | Rare |
| Miscellaneous Provoked | |||
| Solar urticaria | Urticaria develops in areas of skin exposed to sunlight | Controlled exposure to light; can be divided depending on the wavelength of light eliciting the lesions | Types include genetic abnormality in protoporphyrin IX metabolism as well as types that can be passively transferred by IgE in serum |
| Aquagenic urticaria | Tiny perifollicular urticarial lesions develop after contact with water of any temperature | Apply towel soaked in 37°C water to the skin for 30 min | Rare; systemic symptoms can occur; females affected more than males; familial form has been described |
Idiopathic anaphylaxis often includes a prominent component of urticaria or angioedema and can be difficult to distinguish from severe urticaria/angioedema. The angioedema of idiopathic anaphylaxis can also resemble HAE; however, a positive family history as well as complement abnormalities will clearly identify HAE-C1INH.
Urticarial vasculitis must be distinguished from chronic idiopathic urticaria/angioedema. When flagrant, urticarial vasculitis is characterized by palpable purpura and bruising or discoloration that persists after the hive disappears. Persistence of individual urticarial lesions for more than 24 hours or a poor response to antihistamine therapy may suggest the possibility of urticarial vasculitis, which ranges from relatively benign cutaneous hypersensitivity vasculitis to the hypocomplementemic urticarial vasculitis syndrome. In children, most cases of cutaneous vasculitis represent Henoch-Schönlein purpura or hypersensitivity vasculitis. The hypocomplementemic urticarial vasculitis syndrome is rarely seen in children.
Angioedema
Angioedema is usually associated with urticaria that is nondependent, asymmetric and nonpruritic. When it occurs with urticaria, the diagnosis and treatment of angioedema mirrors the parameters described for urticaria. Recurrent angioedema without urticaria (including recurrent unexplained abdominal pain) should suggest a possible diagnosis of HAE. Accurate diagnosis of HAE is essential to avoid morbidity and mortality; however, delays in HAE diagnosis are the rule rather than the exception. Repeated surveys have shown a 10- to 20-year interval between onset of symptoms and establishment of the correct diagnosis. Half of all HAE patients begin swelling during the first decade of life, with almost all patients manifesting symptoms by age 18.
Angioedema may also occur during the treatment of hypertension with angiotensin-converting enzyme (ACE) inhibitors or, less commonly, with angiotensin II receptor blockers. ACE is a peptidase that degrades bradykinin (among other peptides), and the mechanism of ACE inhibitor-associated angioedema is suspected to be due to diminished catabolism of bradykinin. There are also several forms of facial edema that can be confused with angioedema, including the granulomatous cheilitis accompanying Crohn’s disease and the Melkersson-Rosenthal syndrome (a rare syndrome of recurrent orofacial swelling, relapsing facial paralysis and fissured tongue).
Evaluation and Management
History
A discerning history is the most important diagnostic procedure in the evaluation of urticaria/angioedema. One should determine whether the urticaria/angioedema is acute or chronic, the duration of the individual lesions, the presence of pruritus (a defining symptom for urticaria), when lesions occur, where the patient is when lesions occur, what has the patient suspected, and the response to prior treatment. Specific inquiry should be made about drugs (including over-the-counter products), foreign sera, foods, food additives, herbal or homeopathic treatments, psychologic factors, inhalants, bites and stings, direct contact of skin with various agents, connective tissue diseases and exposure to physical agents. Associated respiratory, gastrointestinal or musculoskeletal symptoms should be inquired about.
In many patients, the disease is aggravated by vasodilating stimuli such as heat, exercise, emotional stress, alcoholic drinks, fever and hyperthyroidism. Premenstrual exacerbations also are common. Aspirin and other cyclooxygenase (COX)-1 inhibiting NSAIDs can cause acute urticaria or lead to exacerbations in up to 30% of patients. A retrospective review of 1,007 charts of atopic children revealed that 41 (4.07%) had experienced NSAID-induced facial angioedema. Intermittent use of NSAIDs was associated with a higher rate of angioedema than chronic regular use. COX-2 inhibitors and acetaminophen do not typically trigger urticaria or angioedema.
Angioedema attacks in HAE-C1INH have distinct manifestations, including: prolonged duration (typically 72 or more hours); frequently triggered by minor trauma or stress; often preceded by a prodromal syndrome; displaying periodicity with attacks of angioedema interspersed by periods of remission (daily episodes suggest an alternate diagnosis); swelling most commonly affecting the extremities, face, gastrointestinal tract or upper airway; and a history of lack of response to prior treatment with antihistamines, corticosteroids or epinephrine. Virtually all HAE-C1INH patients experience extremity and gastrointestinal attacks during their lifetime. Abdominal attacks can be severe, and may resemble a surgical abdomen. Recurrent school absences because of abdominal pain may be a presenting symptom. It is not unusual to obtain a history of a normal exploratory laparotomy for presumed appendicitis. Laryngeal attacks are considerably less common, although over 50% of HAE-C1INH patients will experience a laryngeal attack at some point in their life. Angioedema of the larynx in HAE-C1INH can result in closure of the airway and asphyxiation. In the past, over 30% of HAE-C1INH patients died from airway attacks. A positive family history of angioedema can usually be elicited although up to 25% of HAE-C1INH patients have de novo SERPING1 mutations.
HAE-nlC1INH is also characterized by recurrent prolonged attacks of angioedema that can cause asphyxiation. Attack frequency varies considerably between affected individuals, from carriers who are asymptomatic to patients with multiple attacks per year. There is a striking female preponderance of patients, and affected women tend to have more severe symptoms than affected men. Like HAE-C1INH, the inheritance pattern of HAE-nlC1INH is autosomal dominant; however, the penetrance is often much lower with evidence of obligate asymptomatic carriers, particularly men. HAE-nlC1INH patients appear to manifest symptoms at a somewhat older age than HAE-C1INH patients. They are also less likely to suffer abdominal attacks.
Physical Examination
Urticarial lesions typically are generalized and may involve any part of the body. Individual lesions often coalesce into large lesions. Angioedema is usually asymmetric and typically involves loose connective tissue such as the face or mucous membranes such as the lips or tongue. Occasionally, the appearance of the lesions gives a clue as to the type of urticaria being encountered: linear wheals suggest dermographism; small wheals surrounded by large areas of erythema suggest cholinergic urticaria; wheals limited to exposed areas suggest solar or cold urticaria; and wheals mainly on the lower extremities suggest papular urticaria or urticarial vasculitis.
Diagnostic Procedures
The laboratory evaluation of patients with urticaria or angioedema must be tailored to the clinical situation. In most cases no specific etiology can be established, and the diagnostic approach should therefore be carefully selected and cost effective. If the history or examination provides clues to the cause of the urticaria/angioedema, the evaluation should be pursued using the appropriate tests (e.g. skin testing to confirm IgE-mediated food or drug allergy). In the absence of a specific likely cause, the laboratory evaluation should be minimal. Box 52-2 summarizes a limited laboratory evaluation that could be performed in patients with chronic urticaria/angioedema. Because the cause of chronic urticaria or angioedema is not related to extrinsic allergen exposure in the vast majority of cases, routine skin testing is not cost effective. Patients with a history suggestive of physical urticaria may be challenged to confirm the diagnosis (see Table 52-1 ).
Basic Tests
Routine screening:
Complete blood count (CBC) with differential
Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
Optional tests based on history and physical:
Liver function tests
Antimicrosomal antibodies, antithyroglobulin antibodies
Anti-FcεR or anti-IgE antibodies or autologous skin testing
Stool for ova and parasites
Physical challenges
C4, C1INH antigen, C1INH function
Discretionary Tests Based on Evaluation
If vasculitis is suspected:
Antinuclear antibody
Skin biopsy
CH 50
Rheumatoid factor
Cryoglobulins
If liver function tests abnormal:
Serology for viral hepatitis
If HAE-nlC1INH is suspected
F12 mutation
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