Definition.

A hive or wheal is a circumscribed, erythematous or white, nonpitting, edematous, usually pruritic plaque that changes in size and shape by peripheral extension or regression during the few hours or days that the individual lesion exists. The edematous central area (wheal) can be pale in comparison to the erythematous surrounding area (flare).

The evolution of urticaria is a dynamic process. New lesions evolve as old ones resolve. Hives result from localized capillary vasodilation, followed by transudation of protein-rich fluid into the surrounding tissue; they resolve when the fluid is slowly reabsorbed. The edema in urticaria is found in the superficial dermis. Lesions of angioedema are less well demarcated. The edema in angioedema is found in the deep dermis or subcutaneous/submucosal locations. The differential diagnosis of hives is found in Box 6.1 and Fig. 6.1 .

Phenotypic classification of urticaria and angioedema. This figure is intended to provide a framework for clinical use based on the author’s and others’ experience that most presentations of urticaria and angioedema can be grouped in distinct categories that can predict prognosis and response to therapy. IgE, immunoglobulin E; NSAID, nonsteroidal antiinflammatory drug.

(From Dreyfus DH. Differential diagnosis of chronic urticaria and angioedema based on molecular biology, pharmacology, and proteomics. Immunol Allergy Clin North Am 2017;37(1):201–15.)

Clinical Presentation.

Lesions vary in size from the 2- to 4-mm edematous papules of cholinergic urticaria to giant hives, a single lesion of which may cover an extremity. They may be round or oval; when confluent, they become polycyclic ( Figs. 6.2 to 6.9 ). A portion of the border either may not form or may be reabsorbed, giving the appearance of incomplete rings (see Fig. 6.4 ). Hives may be uniformly red or white, or the edematous border may be red and the remainder of the surface white. This variation in color is usually present in superficial hives; thicker plaques have a uniform color (see Figs. 6.2 to 6.7 ).

Hives. The most characteristic presentation is uniformly red edematous plaques surrounded by a faint white halo. These superficial lesions occur from transudation of fluid into the dermis.

Hives. Urticarial plaques in different stages of formation.

Hives. The entire palm is affected and is greatly swollen. The lesions resemble those of erythema multiforme.

Hives. Superficial hives vary in color.

Hives. Hives have become more extensive and confluent.

Hives. Angioedema is a deeper, larger hive than those shown in Figs. 6.2 to 6.4 . It is caused by transudation of fluid into the dermis and subcutaneous tissue. The lip is a common site.

Hives. Angioedema. Massive swelling of the entire central area of the back.

Hives. Polycyclic pattern.

Hives may be surrounded by a clear or red halo. Thicker plaques that result from massive transudation of fluid into the dermis and subcutaneous tissue are referred to as angioedema. These thick, firm plaques, like typical hives, may occur on any skin surface, but typically involve the lips, larynx (causing hoarseness or a sore throat), and mucosa of the gastrointestinal (GI) tract (causing abdominal pain) (see Figs. 6.8 and 6.9 ). Bullae or purpura may appear in areas of intense swelling. Purpura and scaling may result as urticaria clear. Hives usually have a haphazard distribution, but those elicited by physical stimuli have characteristic features and distribution.

Symptoms.

Hives itch. The intensity varies, and some patients with a widespread eruption may experience little itching. Pruritus is milder in deep hives (angioedema) because the edema occurs in areas where there are fewer sensory nerve endings than there are near the surface of the skin.

Clinical Classification of Urticaria/Angioedema.

The CU subtypes are found in Box 6.2 .

Urticaria can be provoked by immunologic and nonimmunologic mechanisms, as well as physical stimuli, skin contact, or small vessel vasculitis. Physical and ordinary urticarias may coexist. Angioedema occurs with or without urticaria. Angioedema without urticaria may indicate a C1 esterase inhibitor deficiency. The duration of hives is also an important diagnostic feature ( Table 6.1 ).

H ₁ Receptors.

H ₁ receptors, when stimulated by histamine, cause an axon reflex, vasodilation, and pruritus. Acting through H ₁ receptors, histamine causes smooth muscle contraction in the respiratory and GI tracts and pruritus and sneezing by sensory nerve stimulation. H ₁ receptors are blocked by the vast majority of clinically available antihistamines called H ₁ antagonists (e.g., chlorpheniramine), which occupy the receptor site and prevent attachment of histamine.

H ₂ Receptors.

When H ₂ receptors are stimulated, vasodilation occurs. H ₂ receptors are also present on the mast cell membrane surface and, when stimulated, further inhibit the production of histamine. Activation of H ₂ receptors alone increases gastric acid secretion. Cimetidine, ranitidine, and famotidine are H ₂ -blocking agents (antihistamines). H ₂ receptors are present at other sites. Activation of both H ₁ and H ₂ receptors causes hypotension, tachycardia, flushing, and headache. The H ₂ -blocking agents are used most often to suppress gastric acid secretion. They are used occasionally, usually in combination with an H ₁ -blocking agent, to treat urticaria.

Children With Hives.

Food origin is important in the etiology of infantile urticaria. In one series it accounted for 62% of patients, more than drug etiology (22%), physical urticaria (8%), and contact urticaria (8%).

IgE-Mediated Reactions.

Type I hypersensitivity reactions are probably responsible for most cases of acute urticaria. Circulating antigens such as foods, drugs, or inhalants interact with cell membrane–bound IgE to release histamine. Food allergies are present in 8% of children younger than 3 years of age and in 2% of adults. Food allergies are the most common cause of anaphylaxis. Yellow jackets are the most common cause of insect sting–induced urticaria/anaphylaxis in the United States. Latex-induced urticaria is an IgE-mediated reaction.

Complement-Mediated, or Immune Complex–Mediated, Acute Urticaria.

Complement-mediated acute urticaria can be precipitated by administration of whole blood, plasma, immunoglobulins, and drugs or by insect stings. Type III hypersensitivity reactions (Arthus reactions) occur with deposition of insoluble immune complexes in vessel walls. The complexes are composed of IgG or IgM with an antigen such as a drug. Urticaria occurs when the trapped complexes activate complement to cleave the anaphylatoxins C5a and C3a from C5 and C3. C5a and C3a are potent releasers of histamine from mast cells. Serum sickness (fevers, urticaria, lymphadenopathy, arthralgias, and myalgias), urticarial vasculitis, and systemic lupus erythematosus are diseases in which hives may occur as a result of immune complex deposition.

Nonimmunologic Release of Histamine.

Pharmacologic mediators, such as acetylcholine, opiates, polymyxin B, and strawberries, react directly with cell membrane–bound mediators to release histamine. Aspirin/nonsteroidal antiinflammatory drugs (NSAIDs) cause a nonimmunologic release of histamine. Patients with aspirin/NSAID sensitivity may have a history of allergic rhinitis or asthma. Urticaria may be caused by histamine-containing foods. Fish of the Scombridae family accumulate histamine during spoilage. The mechanism of radiocontrast-related urticaria/anaphylaxis is unknown. Incidence varies from 3.1% with newer, lower osmolar agents to 12.7% with previously established, higher osmolar agents. Atopy is a risk factor for urticaria developing after radiocontrast exposure. The physical urticarias may be induced both by direct stimulation of cell membrane receptors and by immunologic mechanisms.

Rule Out Physical Urticarias.

Unrecognized physical urticarias (see p. 189 ) may account for approximately 10% of all cases of CU. In one large study physical urticarias were present in 71% of patients with CU: 22% had immediate dermographism, 37% had delayed pressure urticaria, 11% had cholinergic urticaria, and 2% had cold urticaria.

The presence of physical urticaria should be ruled out by history and appropriate tests before a lengthy evaluation and treatment program is undertaken. Dermographism is the most common type of physical urticaria; it begins suddenly following drug therapy or a viral illness, persists for months or years, and clears spontaneously. Wheals that appear after the patient’s arm is stroked prove the diagnosis.

Thyroid Autoimmune Disease.

There is a significant association between CU and autoimmune thyroid disease (Hashimoto thyroiditis, Graves disease, toxic multinodular goiter). Thyroid autoimmunity was found in 12% of 140 consecutively seen patients with CU in one series; 88% were women. Most patients with thyroid autoimmunity are asymptomatic and have thyroid function that is normal or only slightly abnormal. Guidelines for evaluation and treatment of thyroid-related urticaria are presented in Box 6.6 .

Change of Environment.

Because the environment consists of numerous antigens, patients should consider a trial period of 1 or 2 weeks of separation from home and work, preferably with a geographic change.

Highly Restricted Diet.

A highly restricted diet may be attempted. Patients are fed lamb, rice, sugar, salt, and water for 5 days. The occurrence of new hives after 3 days suggests that foods have no role. If hives disappear, a new food is reintroduced every other day until hives appear.

Treatment of Occult Infections.

Patients occasionally respond to antibiotics even in the absence of clinical infection. Consider eradication of Helicobacter pylori in patients with infection.

Skin Biopsy.

Urticarial reactions display a wide spectrum of changes, ranging from a mild, mixed dermal inflammatory response to true vasculitis. Patients with hives that are characteristic of urticarial vasculitis should have a biopsy taken of the urticarial plaque. These hives burn rather than itch and last longer than 24 hours.

Dermal edema and dilated lymphatic and vascular capillaries occur. Increased numbers of neutrophils and eosinophils occur in patients with acute urticaria and in those with delayed pressure urticaria. Mast cell numbers are higher in the dermis of lesional and uninvolved skin of all patients with urticaria. Mononuclear infiltrates are more pronounced in cold urticaria and CU, when compared with other forms of CU.

Antihistamines.

For the majority of patients, acute and chronic urticaria may be controlled with antihistamines.

Epinephrine.

Severe urticaria or angioedema requires epinephrine. Epinephrine solutions have a rapid onset of effect but a short duration of action. The dosage for adults is a 1 : 1000 solution (0.2 to 1.0 mL) given either subcutaneously or intramuscularly; the initial dose is usually 0.3 mL. The epinephrine suspensions provide both a prompt and a prolonged effect (up to 8 hours). For adults, 0.1 to 0.3 mL of the 1 : 200 suspension is given subcutaneously.

Oral Corticosteroids.

Many patients with CU and angioedema will have little response to even a combination of H ₁ – and H ₂ -receptor blockers. Oral corticosteroids should be considered for these refractory cases. Because of toxicity, corticosteroids are reserved for antihistamine failures or the most severe cases. They are reliable and effective. They do not have the potential for drug-free remission. Prednisone 40 mg/day given in a single morning dose or 20 mg twice a day is effective in most cases. Another approach is to prescribe thirty 20-mg tablets. The patient receives 5 days each of 60 mg, 40 mg, and 20 mg, and the medication is taken once each morning. Others will respond to prednisone 20 mg every other day with a gradual taper.

Leukotriene Modifiers.

Leukotriene modifiers may provide improvement in some cases of antihistamine-resistant CU. Excellent safety, absence of required monitoring in the cases of montelukast and zafirlukast, and wide availability make leukotriene modifiers the preferred alternative agent. Montelukast, zafirlukast, and zileuton have been studied. Response may take days to weeks. Randomized controlled trials show zafirlukast and montelukast either singly or in combination with antihistamines are effective but several negative studies have also appeared. Montelukast was demonstrated to be effective for patients with NSAID-exacerbated CU. Patients with positive autologous serum skin test (ASST) results may predict better response to leukotriene modifiers. Experience in physical urticarias has also been promising.

Dapsone.

Small studies demonstrate excellent clinical response with dosages that vary from 25 mg/day to 100 mg/day. Response may be fairly rapid, but some patients require several weeks to notice improvement. Monitor for the predictable small decline in hemoglobin level. The drug is generally well tolerated. There is a possibility of sustained remission after stopping the drug. Obtain a glucose-6-phosphate dehydrogenase (G6PD) level to avoid more severe hemolytic anemia in G6PD-deficient patients.

Cyclosporine.

Cyclosporine might be an effective alternative in some CU patients unresponsive to conventional treatments and may be considered if leukotriene modifiers and dapsone fail. Patients with severe unremitting disease who respond poorly to antihistamines may respond to cyclosporine 4 mg/kg daily for 4 weeks. Patients requiring initially high doses of glucocorticosteroids and with a long clinical history are less amenable to cyclosporine treatment.

Mycophenolate Mofetil.

Mycophenolate mofetil (MMF) is a useful and well-tolerated second-line therapy for patients with autoimmune and chronic idiopathic urticaria in whom antihistamines and other therapeutic agents have failed. Combining MMF with oral prednisolone was helpful in gaining immediate control of the CU symptoms.

Intravenous Immunoglobulin.

Responses ranging from complete and lasting remission to modest transient benefit are reported. Response seems to be rapid. The optimal dose and number of infusions to attempt are unclear. Only case reports and short series of patients are reported.

Methotrexate.

Methotrexate may be considered in resistant cases of urticaria. Case reports and a small series of patients document benefit within 1 to 2 weeks of starting methotrexate. Because adverse effects may be serious and frequent monitoring is necessary, methotrexate should be reserved for intractable cases in which other alternative agents have failed. Methotrexate 10 to 15 mg weekly has been successful.

Topical Measures.

Itching is controlled with tepid showering, tepid oatmeal baths (Aveeno), cooling lotions that contain menthol (Sarna lotion), and topical pramoxine lotions (Itch-X). Avoid factors that enhance pruritus (e.g., taking aspirin, drinking alcohol, or wearing tight elasticized apparel or coarse woolen fabrics).

Omalizumab (Xolair).

Omalizumab, a recombinant humanized monoclonal antibody (IgG1κ) that selectively binds to human IgE, reduces the levels of free IgE and the high-affinity receptor for the Fc region of IgE (FcεRI), both of which are essential in mast cell and basophil activation. Omalizumab is indicated for chronic idiopathic urticaria in adults and children older than 12 years of age. It is administered 150 mg or 300 mg by monthly subcutaneous injections. The dosing for chronic idiopathic urticaria is not dependent on serum IgE or body weight.

Diagnosis.

A tongue blade drawn firmly across the patient’s arm or back produces whealing 2 mm or more in width in approximately 1 to 3 minutes (Darier’s sign), an exaggerated triple response ( Fig. 6.14 ).

• 1.
  

  A red line occurs in 3 to 15 seconds (capillary dilation).

  
  
• 2.
  

  Broadening erythema appears (axon reflex flare from arteriolar dilation).

  
  
• 3.
  

  A wheal with surrounding erythema replaces the red line (transudation of fluid through dilated capillaries).

Dermographism. A tongue blade drawn firmly across the arm elicits urticaria in susceptible individuals. This simple test should be considered for any patient with acute or chronic urticaria.

Unlike urticaria pigmentosa caused by cutaneous mastocytosis (CM; which also manifests dermographism – Darier’s sign), there is no increase in skin mast cell numbers.

Treatment.

Treatment is not necessary unless the patient is highly sensitive and reacts continually to the slightest trauma. Antihistamines are very effective. Nonsedating H ₁ antihistamines or hydroxyzine in relatively low dosages (10 to 25 mg daily one to four times a day) provides adequate relief. Some patients are severely affected and require continuous suppression. Use the lowest dose possible to stop itching. Many patients adapt to a low dose of hydroxyzine and do not feel sedated.