URTICARIA, ANGIOEDEMA, AND ANAPHYLAXIS
Approximately 1 in 5 people will experience urticaria. Urticaria may be more common in atopic individuals and is usually classified as acute or chronic; however, the majority of cases are acute lasting from hours to a few weeks. Chronic urticaria is defined as episodes of urticaria lasting for more than 6 weeks; however, all urticaria begins in an acute phase. Occasionally, acute urticaria is associated with deeper less well-demarcated edema referred to as angioedema.
Allergic angioedema can be associated with anaphylaxis including life-threatening bronchoconstriction and hypotension. The eyelids and lips are most typically affected by angioedema. The cause of acute urticaria may be identified and generally self-limiting; the cause of chronic urticaria may be determined in only 5% to 20% of cases.
Urticaria, also called hives or wheals, is a common and distinctive cutaneous reaction pattern involving the superficial dermis. It is usually transient, demonstrating localized edema caused by dilatation and increased permeability of the capillaries and marked by the development of wheals. A wheal or hive is a welldemarcated, erythematous or white, nonpitting, edematous papule or plaque that is usually pruritic. The lesions are polymorphous and often form annular, arciform, or polycyclic plaques (Figures 18-1
). The lesions change shape and size during the few hours or days they are present. Urticaria can be acute or chronic, and the physical urticarias depend on an external or exogenous factor. Chronic urticaria is defined as episodes of urticaria lasting for more than 6 weeks; however, all urticaria begins in an acute phase.
Angioedema (angioneurotic edema) is a hive-like swelling caused by increased vascular permeability in the subcutaneous tissue of the skin and mucosa and submucosal layers of the respiratory and gastrointestinal (GI) tracts. Hives and angioedema can occur simultaneously and may have the same etiology. Angioedema is usually located on the eyes, as seen in Figure 18-3
, and mouth (Figure 18-4
) but may also occur on the hands and feet or in the throat. Laryngeal edema does not usually occur with urticaria or simple angioedema. There are multiple syndromes of angioedema including idiopathic, allergic, and medication-induced angioedema; hereditary angioedema (HAE); and acquired angioedema (AAE). The presence or absence of hives is used to characterize the different syndromes of angioedema.
3. Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly after contact with an allergy-causing substance.
FIGURE 18-1. Large edematous plaques of urticaria. (From Elder, D. E. (2012). Atlas and synopsis of Lever’s histopathology of the skin. Philadelphia, PA: Wolters Kluwer.)
a. Most cases of acute urticaria are IgE-mediated type I hypersensitivity reactions. Circulating antigens such as foods, drugs, or inhalants react with cell membrane-bound IgE to release histamine. IgE antigen on the mast cell surface unites with the antigen of food, drug, stinging insect venom, or pollen and causes an immediate and large release of histamine and other vasoactive mediators from mast cells.
b. Complement-mediated acute urticaria may be caused by administration of whole blood, plasma, immunoglobulins, and drugs or by insect stings. Type III hypersensitivity reactions occur with deposition of insoluble immune complexes in vessel walls (Arthus reactions). The complexes are composed of IgG or IgM, the trapped complexes activate complement, and the process releases histamine from mast cells. A frequent reason for acute urticaria is viral infections of the upper respiratory tract, which increases mast cell reactivity.
FIGURE 18-2. Typical hives of different sizes. (From Anderson, M. K. (2012). Foundations of athletic training. Philadelphia, PA: Wolters Kluwer.)
FIGURE 18-3. Urticaria with angioedema around the eyes. (From Goodheart, H. P. (2003). Goodheart’s photoguide of common skin disorders (2nd ed.). Philadelphia, PA: Lippincott Williams & Wilkins.)
Nonimmunologic release of histamine occurs when pharmacologic mediators, such as acetylcholine, opiates, polymyxin B, or strawberries, react directly with
cell membrane-bound mediators to release histamine. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can cause nonimmunologic release of histamine; these patients may have a history of allergic rhinitis or asthma. The physical urticarias may be induced by both direct stimulation of cell membrane receptors and immunologic mechanisms.
FIGURE 18-4. Angioedema of the lip, tense swelling of the dermis and subcutaneous tissue. (Neville, B., Damm, D., White, D., & Waldron, W. (1991). Color atlas of clinical oral pathology. Philadelphia, PA: Lea & Febiger. Used with permission.)
Patients with history of hives lasting more than 6 weeks may be classified as having chronic urticaria. The lesional morphology is similar to acute hives, any skin surface can be affected, and the lesions last less than 24 hours. Angioedema occurs in 50% of cases of chronic urticaria. Chronic urticaria patients are likely to exhibit physical urticaria, is usually nonallergic, and is usually idiopathic. Angioedema associated with chronic urticaria is different from HAE in that it rarely affects the larynx. Table 18-2
displays the clinical classification of urticaria/angioedema.
A partial list of the etiologic classification of urticaria is found in Table 18-3
a. Most cases of angioedema are idiopathic. Angioedema will often occur with hives, and angioedema without wheals is seen with drug reactions and C1 inhibitor deficiency.
b. Severe allergic type I immediate hypersensitivity IgE-mediated reactions can cause acute angioedema. Angioedema can occur with other symptoms of anaphylaxis including hypotension and respiratory distress.
c. Drugs such as contrast dyes, NSAIDs, aspirin, indomethacin, and ACE inhibitors can cause angioedema with nonimmunologic mechanism.
d. AAE results from an acquired C1 inhibitor deficiency considered to be an autoimmune disease. HAE is an inherited C1 inhibitor deficiency and results from lack of the functional C1 esterase inhibitor.
a. Immediate-type hypersensitivity reactions may occur locally or systemically causing mild symptoms or sudden death from anaphylactic shock. Food allergies, including allergy to tree nuts and peanuts, and crustaceans are common causes of serious anaphylactic reactions. Other common causes include antibiotics, especially penicillins; other drugs and chemicals, including radiographic contrast agents; and hymenoptera stings.
TABLE 18-2 Clinical Classification of Urticaria
Ordinary urticaria (acute and chronic)
Exercise-induced urticaria (anaphylaxis)
30 min to 2 h except delayed pressure urticaria that may last longer than 2 h
TABLE 18-3 Etiologic Classification of Urticaria
Fish, shellfish, nuts, eggs, strawberries, cow’s milk, wheat, and yeast
Salicylates, benzoates, penicillin, and sulfites
Penicillin, aspirin, sulfonamides, and drugs that cause a nonimmunologic release of histamine (morphine, codeine, dextran, polymyxin, curare, quinine)
Chronic bacterial infections (sinus, dental, urinary tract), fungal infections, viral infections (hepatitis B prodrome, infectious mononucleosis, coxsackie), intestinal worms, and malaria
Pollens, mold spores, animal dander, house dust, and aerosols
Systemic lupus erythematosus, hyperthyroidism, autoimmune thyroid disease, carcinomas, lymphomas, leukocytoclastic vasculitis, polycythemia vera, rheumatic fever, and transfusion reaction
Physical stimuli (physical urticarias)
Listed in Table 18-4
Nonimmunologic contact urticaria
Plants (nettles), animals (caterpillars, jellyfish), and medications (cinnamic aldehyde, dimethyl sulfoxide)
Ammonium persulfate used in hair bleach, chemicals, foods, textiles, wood, saliva, cosmetics, perfumes, and bacitracin
Mastocytosis, dermatitis herpetiformis, pemphigoid, and amyloidosis
Pregnancy and premenstrual flare (progesterone)
Hereditary angioedema, familial cold urticaria, and vibratory urticaria
1. Estimates of the lifetime occurrence of urticaria range from less than 1% to as high as 30% of the population. Hives can occur at any age, is a worldwide disease, and may be more common in atopic patients.
2. Angioedema frequently occurs with acute urticaria, which is more common in children and young adults. Chronic urticaria is more common in women in the third to fifth decades of life; there is no consensus on the prevalence of chronic urticaria.
3. Most cases of angioedema are idiopathic. It can occur at any age but is most common in the 40- to 50-yearold age group, women being more affected than men. Angiotensin-converting enzyme inhibitors (ACEIs) are the number one drug cause of acute angioedema; the incidence may be higher in Black Americans. HAE affects between 1 in 10,000 and 1 in 50,000 persons and begins in late childhood or early adolescence.
4. True incidence of anaphylaxis is unknown; lifetime prevalence is 1% to 2% for the population as a whole.
D. Pathologic processes
There are several types of stimuli that cause urticaria, which include immunologic, nonimmunologic, physical, and chemical. Several are listed in Table 18-3
2. The mast cell is the primary effector cell in urticaria. Release of mast cell mediators causes inflammation and mast cell degranulation that results in the release of histamine and inflammatory mediators, as well as an accumulation and activation of other cells including eosinophils, neutrophils, and, possibly, basophils. Histamine causes endothelial cell contraction that allows vascular fluid to leak between the cells through vessel walls, causing tissue edema and wheal formation.
3. When histamine is injected into the skin, there is vasodilation causing local erythema, a peripheral flare characterized by erythema beyond the border of local erythema (axon reflex), and a wheal produced by leakage of fluid from the postcapillary venules.
4. Angioedema is a hive-like swelling in the subcutaneous tissue of skin, mucosa, and submucosal layers of the respiratory and GI tracts. The reaction is similar to that of urticaria in the upper dermis. Hives and urticaria may have the same etiology and often occur simultaneously.
5. Anaphylaxis can be mediated by immunologic (IgEmediated and non-IgE-mediated [e.g., IgG and immune complex complement-mediated]) and nonimmunologic factors, which include events resulting in sudden mast cell and basophil degranulation in the absence of immunoglobulins.
E. Considerations across the life span
1. Urticaria, angioedema, and anaphylaxis can occur at any age.
The diagnosis of urticaria is often one of exclusion. It is essential to rule out the presence of serious illnesses of which recurring hives and/or edema can be a symptom. Examples of such illnesses may include hepatitis, hyperthyroidism, lymphomas, lupus, and cancers of the rectum, kidneys, and GI tract.
A. History and physical examination
1. History and physical exams are the most important parts of the initial evaluation and should include an evaluation of the following factors.
a. Association with any specific substance or activity: drug ingestion or exposure; respiratory infection; food and drink; exposure to pollens and chemicals; physical location of work, travel, hobby, or home; and medications, supplements, or homeopathic compounds.
b. Appropriate description of the character of the primary lesion in urticaria is important, usually an edematous and erythematous papule or plaque.
c. Location of the lesions—itchy lesions that come and go, located anywhere on the skin.
d. Length of response—individual hives do not usually last for more than 24 hours. Note time of onset, appearance, day, year, and season. Duration of individual lesions: less than 1 hour, physical urticaria and typical hives; less than 24 hours, typical hives; longer than 25 hours, and that burn or resolve with purpura require a biopsy to exclude urticarial vasculitis.
Assessment of previous incidence of symptoms related to common causes of urticaria. Table 18-3
lists possible causes. Drugs are common causes in adults, and viral respiratory or streptococcal infections are common causes in children.
f. Evaluation of recent exposure to possible allergens.
Assessment of common subtypes of urticaria (Table 18-2
h. Evaluate the role that occupation can play in establishing the diagnosis of urticaria.
i. Differentiation of angioedema from urticaria is of utmost importance related to the life-threatening possibilities associated with angioedema. Urticarial lesions are superficial and widespread, while lesions associated with angioedema are deep, and the eyelids and lips are the areas most typically affected. Urticaria and angioedema frequently occur at the same time. Any patient with recurrent angioedema or abdominal pain without wheals should be evaluated for HAE.
j. Evaluate for physical urticaria by stroking the arm with a tongue blade to test for dermatographism. This may indicate one of the physical urticarias.
k. Anaphylaxis almost always involves the skin and/or mucous membranes with a combination of erythema, urticaria, angioedema, or pruritus. Adults will present with cutaneous and respiratory symptoms and children may show more respiratory symptoms.
B. Skin findings
A wheal or hive is a well-demarcated, erythematous or white, nonpitting, edematous papule or plaque that is usually pruritic. The lesions of urticaria change shape and size during the few hours or days they are present. The central area (wheal) can be pale compared to the surrounding erythematous area (flare). Wheals are sharply marginated and predominantly flat topped. Their color varies from light pink to dark red depending on the amount of fluid present between the skin surface and the underlying dilated vascular bed. Wheals frequently have a dimpled surface because of the anchoring effect of hair follicles as fluid fills the papillary dermis surrounding them. The physical urticarias have unique characteristics and are outlined in Table 18-4
a. The evolution of urticaria is dynamic and lesions are transient.
b. Hives result from local capillary vasodilation and dermal edema; the edema is in the superficial dermis.
c. Lesions vary in size from 2 to 4 mm seen in cholinergic urticaria up to a giant hive that may cover an entire extremity.
d. Lesions will be round, oval, polycyclic, or incomplete rings. Color may be solid red or white, or white in center with red border. Purpura within individual lesions may indicate urticarial vasculitis.
TABLE 18-4 The Physical Urticarias
Irregular, pruritic wheals
Burning, deep swelling
Diffuse, tender swelling
Various light wavelengths
Wheezing, dizziness, and syncope
Familial cold urticaria
Change in skin temperature from cold air
Tremor, headache, arthralgia, and fever
Essential cold urticaria
Wheezing and syncope
General overheating of the body
Papular, pruritic wheals
Syncope, diarrhea, vomiting, salivation, and headaches
Papular, pruritic wheals
Vibrating against skin
Exercise; in some cases, ingestion of certain foods
Respiratory distress and hypotension
e. Thicker plaques with fluid in dermis and subcutaneous tissue are considered angioedema.
f. Hives are generally ITCHY; however, intensity may vary.
g. Purpura within a wheal may indicate urticarial vasculitis and will need biopsy.
2. The reaction of angioedema is deeper than wheals and produces more diffuse swelling. The swelling is painful and burning but not pruritic.
a. Lips, palms, soles, trunk, limbs, and genitalia are commonly affected.
b. There may be involvement of respiratory or GI tracts producing dyspnea, dysphagia, abdominal pain, and diarrhea.
c. Angioedema may develop as a result of trauma.
3. The physiologic responses to the release of anaphylaxis mediators include smooth muscle spasm in the respiratory and GI tracts, vasodilation, increased vascular permeability, and stimulation of sensory nerve endings.
a. These physiologic events lead to some or all of the classic symptoms of anaphylaxis: flushing; urticaria/angioedema; pruritus; bronchospasm; laryngeal edema; abdominal cramping with nausea, vomiting, and diarrhea; and feeling of impending doom.
C. Differential diagnosis
1. Urticarial stage of bullous pemphigoid
2. Dermatitis herpetiformis
3. Drug eruptions
4. Erythema multiforme
5. Papular urticaria
6. Polymorphic eruption of pregnancy
7. Urticaria pigmentosa
8. Urticarial vasculitis
D. Diagnostic tests
1. Complete blood count (CBC) with differential.
2. Liver and thyroid function tests.
3. Urine analysis.
4. Erythrocyte sedimentation rate (ESR).
5. If the history provides evidence that warrants additional tests, consider test for hepatitis A, B, and C; infectious mononucleosis; thyroid antibodies; and antinuclear antibody (ANA).
6. Biopsy for urticarial lesions with purpuric center or for lesions that last for more than 36 hours to evaluate for urticarial vasculitis. Also, biopsy if there is fever, arthralgia, elevated ESR, or petechiae.
7. Sinus x-rays may be considered for evaluation of chronic urticaria if there is a corresponding history.
8. If HAE is suspected, C4 level can be a screening test.
III. COMMON THERAPEUTIC MODALITIES
A. Systemic therapy for urticaria and associated angioedema
1. First-line therapy is (nonsedating) second-generation H1 antagonists to inhibit mast cell mediators.
a. Cetirizine 10 mg nightly or twice daily
b. Loratadine 10 mg daily or twice daily
c. Fexofenadine 120 to 180 mg daily
2. First-line therapy may include first-generation H1 (sedating) antihistamines and/or H2 receptor antagonists if symptoms are not controlled after a week or two of treatment.
a. Diphenhydramine 10 to 25 mg four times daily.
b. Hydroxyzine HCl 10 to 25 mg four times daily.
c. Doxepin 10 to 25 mg nightly.
d. H2 receptor antagonists include cimetidine 400 mg twice daily, ranitidine 150 mg twice daily, or famotidine 20 mg twice daily.
3. Second-line therapy may include systemic corticosteroid.
a. Prednisone 0.5 to 1 mg/kg daily for short course may provide relief for severe cases.
4. Third-line therapy may include leukotriene receptor agonists and can be combined with antihistamines.
a. Montelukast 10 mg daily
b. Zafirlukast 20 mg twice daily
c. Zileuton 600 mg four times a day
5. Treatment of choice for angioedema associated with anaphylaxis is epinephrine given intramuscularly (IM) (1:1,000 solution) when intravenous is not available. Diphenhydramine 50 mg can also be given IM. The IM route is better and more quickly absorbed than subcutaneous.
B. Nonpharmacologic interventions
1. Identify and eliminate underlying cause.
a. Avoid common triggers such as aspirin, NSAIDs, food additives, heat, and alcohol.
b. Whether urticaria is acute or chronic, consider stopping vitamins, laxatives, antacids, toothpaste, cigarettes, cosmetics and all toiletries, chewing gum, household cleaning solutions, and aerosols.
c. Chronic hives are not caused by food allergies; however, some individuals find that hives are worsened after eating certain foods. Consider stopping fruits, tomatoes, nuts, eggs, shellfish, chocolate, milk, cheese, bread, diet drinks, and junk food.
2. Avoid eliciting stimuli.
a. Take cool showers or baths, apply cool compresses (except with cold urticaria), wear loose fitting clothes, and avoid strenuous activity.
b. Swimming in cold water is the most common cause of severe cold urticaria reaction. Patients should be advised never to jump into a cold body of water, and water activities should be done under supervision.
c. Strategies to reduce stress can be helpful.
C. Medication therapy monitoring
1. The role of pharmacotherapy is symptom management, and control of pruritus is critical in helping patients find relief.
2. Antihistamine therapy usually starts with nonsedating antihistamines; however, if symptoms are not managed well, sedating antihistamines will be needed.
3. All patients, especially the elderly, should be educated on possible side effects including sedation, dry mouth, urine retention, and dizziness.
4. Start with low dose to monitor tolerance.
D. Other nursing interventions
1. Discuss skin care with patients recommending emollients and bathing not too hot or cold.
2. Emollients with anti-itch properties such as menthol, phenol, and pramoxine can be helpful especially for spot treatment and comfort.
3. Quality-of-life issues for patients with chronic urticaria should be acknowledged and addressed especially around relief of pruritus. Disease management needs to be prompt, and an individual approach is necessary due to the complex nature of urticaria. In addition, the management must be a close working cooperation with the patient.
4. When the cause of acute urticaria is promptly avoided, symptoms resolve rapidly. Reassure patients with acute urticaria that most cases resolve within 6 weeks; patients are often frustrated and fearful especially with chronic urticaria. The evolution from acute to chronic urticaria is not well understood, and the prognosis for resolution after 6 months is unclear.
E. Complementary alternative medicine
1. Certain foods can act as natural antihistamine:
a. Foods high in vitamin C such as carrots, mangoes, spinach, and tomatoes.
b. Foods high in vitamin A such as oranges, lemons, tangerines, limes, and grapefruit.
c. Pineapples can also be considered as an alternative and natural antihistamine. Bromelain is an enzyme found in high concentration in pineapple. Adding pineapples to daily diet can act as an alternative way to prevent and treat hive outbreaks.
IV. HOME CARE AND FOLLOW-UP
Patients with chronic urticaria may need referral to allergist, immunologist, or urticaria specialist if the cause cannot be found and the urticaria is interfering with quality of life. Allergy testing may be helpful for urticaria evaluation, but it is imperative for individuals who have had an anaphylactic episode. In general, patients with urticaria can be cared for on an outpatient basis unless their urticaria is severe and does not respond to antihistamine therapy or if they progress to laryngeal angioedema and/or anaphylactic shock or have comorbidities that require inpatient therapy.