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Urticaria

(Hives; Wheals)

by Robert J. MacNeal, MD

Urticaria are migratory, well-circumscribed, erythematous, pruritic plaques on the skin.

Urticaria also may be accompanied by angioedema, which results from mast cell and basophil activation in the deeper dermis and subcutaneous tissues and manifests as edema of the face and lips, extremities, or genitals. Angioedema can be life-threatening if airway obstruction occurs because of laryngeal edema or tongue swelling.

Pathophysiology

Urticaria results from the release of histamine, bradykinin, kallikrein, and other vasoactive substances from mast cells and basophils in the superficial dermis, resulting in intradermal edema caused by capillary and venous vasodilation and occasionally caused by leukocyte infiltration.

The process can be immune mediated or nonimmune mediated.

Immune-mediated mast cell activation includes

  • Type I hypersensitivity reactions, in which allergen-bound IgE antibodies bind to high-affinity cell surface receptors on mast cells and basophils

  • Autoimmune disorders, in which antibodies to an IgE receptor functionally cross-link IgE receptors and cause mast cell degranulation

Nonimmune-mediated mast cell activation includes

  • Direct nonallergic activation of mast cells by certain drugs

  • Drug-induced cyclooxygenase inhibition that activates mast cells by poorly understood mechanisms

  • Activation by physical or emotional stimuli; mechanism is poorly understood but possibly involves the release of neuropeptides that interact with mast cells

Etiology

Urticaria is classified as acute (< 6 wk) or chronic (> 6 wk); acute cases (70%) are more common than chronic (30%).

Acute urticaria (see Some Causes of Urticaria) most often results from

  • Type I hypersensitivity reactions

A presumptive trigger (eg, drug, food ingestion, insect bite or sting, infection) occasionally can be identified.

Chronic urticaria most often results from

  • Idiopathic causes

  • Autoimmune disorders

Chronic urticaria often lasts months to years, eventually resolving without a cause being found.

Some Causes of Urticaria

Cause

Suggestive Findings

Diagnostic Approach

Acute urticaria

Contact or inhaled allergens (eg, latex, animal saliva, dust, pollen, molds, dander)

Onset within minutes or hours after contact with offending agent

Clinical evaluation

Sometimes allergy testing

Drug effects

  • Cyclooxygenase inhibition (eg, aspirin, NSAIDs)

  • Direct mast cell release (eg, opioids, vancomycin, succinylcholine, curare, radiocontrast agents)

  • IgE mediated (any prescription, OTC, or herbal drug)

  • Increased bradykinin levels (ACE inhibitors)

Urticaria within 48 h of drug exposure

Angioedema common with ACE inhibitors

Clinical evaluation

Sometimes allergy testing

Emotional or physical stimuli

  • Adrenergic (stress, anxiety)

  • Cholinergic (sweating, eg, while taking a warm bath, while exercising, or during episodes of fever)

  • Cold

  • Delayed pressure

  • Exercise

  • Focal pressure (dermatographism)

  • Heat

  • Sunlight (solar urticaria)

  • Vibration

Onset typically within seconds or minutes of offending stimulus

Clinical evaluation, including reproducible response to suspected stimulus

Infections

  • Bacterial (eg, group A streptococci, Helicobacter pylori)

  • Parasitic (eg, Toxocara canis, Giardia lamblia, Strongyloides stercoralis, Trichuris trichiura, Blastocystis hominis, Schistosoma mansoni)

  • Viral (eg, hepatitis A, B, or C; HIV; CMV; EBV; enterovirus)

Symptoms of systemic infection*

Testing for specific suspected underlying infection

Resolution of urticaria after eradication of the infection

Ingested allergens (eg, peanuts, nuts, fish, shellfish, wheat, eggs, milk, soybeans)

Urticaria within minutes or hours after ingestion of offending agent

Clinical evaluation

Sometimes allergy testing

Insect bites or stings ( Hymenoptera venom)

Urticaria within seconds or minutes after insect bite or sting

Clinical evaluation

Serum sickness

Urticaria with or without fever, polyarthralgias, polyarthritis, lymphadenopathy, proteinuria, edema, and abdominal pain within 7–10 days after parenteral administration of a biologic-based drug or substance

Clinical evaluation

Transfusion reactions

Urticaria usually within a few minutes after initiating blood product transfusion (or switching to a new unit of blood product)

Clinical evaluation

Chronic urticaria

Autoimmune disorders (eg, SLE, Sjögren syndrome, autoimmune thyroid disease, cryoglobulinemia, urticarial vasculitis)

Evidence of systemic autoimmune disease, including hypothyroidism or hyperthyroidism (autoimmune thyroiditis); hepatitis, renal failure, and polyarthritis (cryoglobulinemia); malar rash, serositis, and polyarthritis (SLE); dry eyes and dry mouth (Sjögren syndrome); cutaneous ulcers or hypopigmented lesions after resolution of urticaria (urticarial vasculitis)

TSH measurement

Thyroid autoantibodies (eg, thyroid peroxidase antibodies, antimicrosomal antibodies)

Cryoglobulin titers

Rheumatologic serologies (eg, ANA, RF, anti-SS-A, anti-SS-B, anti-Sm, anti-RNP, anti-Jo-1)

Skin biopsy (cryoglobulinemia, urticarial vasculitis)

Cancer (typically GI, lung, lymphoma)

Signs of underlying cancer (eg, weight loss, night sweats, abdominal pain, cough, hemoptysis, jaundice, lymphadenopathy, melena)

Specific to the type of suspected underlying cancer

Chronic idiopathic urticaria

Occurrence of daily (or almost daily) wheals, and itching for at least 6 wk, with no obvious cause

Diagnosis of exclusion

Drugs (same as those causing acute urticaria)

Unexplained urticaria in a patient chronically taking prescription, OTC, or herbal drugs

Clinical evaluation

Sometimes allergy testing

Resolution with stoppage of offending drug

Emotional or physical stimuli (same as those causing acute urticaria)

Urticaria typically within seconds or minutes of offending stimulus

Clinical evaluation, including reproducible response to suspected stimulus

Endocrine abnormalities (eg, thyroid dysfunction, elevated progesterone level)

Heat or cold intolerance, bradycardia or tachycardia, hyporeflexia or hyperreflexia

Patients taking progesterone-containing oral contraceptives or hormone replacement therapy or those with cyclic urticaria that appears during the 2nd half of the menstrual cycle and resolves with menstruation

Clinical evaluation

TSH measurement

Systemic mastocytosis (urticaria pigmentosa)

Presence of small pigmented papules that turn into wheals with mild trauma (eg, gentle stroking)

Possible concomitant anemia, abdominal pain, easy flushing, and recurrent headaches

Skin biopsy

Serum tryptase level

*Patients should be asked about recent travel to a developing country.

ANA = antinuclear antibodies; CMV = cytomegalovirus; EBV = Epstein-Barr virus; RF = rheumatoid factor; TSH = thyroid-stimulating hormone.

Evaluation

Because there are no definitive diagnostic tests for urticaria, evaluation largely relies on history and physical examination.

History

History of present illness should include a detailed account of the individual episodes of urticaria, including distribution, size, and appearance of lesions; frequency of occurrence; duration of individual lesions; and any prior episodes. Activities and exposures during, immediately before, and within the past 24 h of the appearance of urticaria should be noted. Clinicians specifically should ask about recent exercise; exposure to potential allergens (see Some Causes of Urticaria), insects, or animals; new laundry detergent or soaps; new foods; recent infections; or recent stressful life events. The patient should be asked about the duration between any suspected trigger and the appearance of urticaria and which particular triggers are suspected. Important associated symptoms include pruritus, rhinorrhea, swelling of the face and tongue, and dyspnea.

Review of systems should seek symptoms of causative disorders, including fever, fatigue, abdominal pain, and diarrhea (infection); heat or cold intolerance, tremor, or weight change (autoimmune thyroiditis); joint pain (cryoglobulinemia, SLE); malar rash (SLE); dry eyes and dry mouth (Sjögren syndrome); cutaneous ulcers and hyperpigmented lesions after resolution of urticaria (urticarial vasculitis); small pigmented papules (mastocytosis); lymphadenopathy (viral illness, cancer, serum sickness); acute or chronic diarrhea (viral or parasitic enterocolitis); and fevers, night sweats, or weight loss (cancer).

Past medical history should include a detailed allergy history, including known atopic conditions (eg, allergies, asthma, eczema) and known possible causes (eg, autoimmune disorders, cancer). All drug use should be reviewed, including OTC drugs and herbal products, specifically any agents particularly associated with urticaria (see Some Causes of Urticaria). Family history should elicit any history of rheumatoid disease, autoimmune disorders, or cancer. Social history should cover any recent travel and any risk factors for transmission of infectious disease (eg, hepatitis, HIV).


Physical examination

Vital signs should note the presence of bradycardia or tachycardia and tachypnea. General examination should immediately seek any signs of respiratory distress and also note cachexia, jaundice, or agitation.

Examination of the head should note any swelling of the face, lips, or tongue; scleral icterus; malar rash; tender and enlarged thyroid; lymphadenopathy; or dry eyes and dry mouth. The oropharynx should be inspected and the sinuses should be palpated and transilluminated for signs of occult infection (eg, sinus infection, tooth abscess).

Abdominal examination should note any masses, hepatomegaly, splenomegaly, or tenderness. Neurologic examination should note any tremor or hyperreflexia or hyporeflexia. Musculoskeletal examination should note the presence of any inflamed or deformed joints.

Skin examination should note the presence and distribution of urticarial lesions as well as any cutaneous ulceration, hyperpigmentation, small papules, or jaundice. Urticarial lesions usually appear as well-demarcated transient swellings involving the dermis. These swellings are typically red and vary in size from pinprick to covering wide areas. Some lesions can be very large. In other cases, smaller urticarial lesions may become confluent. However, skin lesions also may be absent at the time of the visit. Maneuvers to evoke physical urticaria can be done during the examination, including exposure to vibration (tuning fork), warmth (tuning fork held under warm water), cold (stethoscope or chilled tuning fork), water, or pressure (lightly scratching an unaffected area with a fingernail).


Red flags

The following findings are of particular concern:

  • Angioedema (swelling of the face, lips, or tongue)

  • Stridor, wheezing, or other respiratory distress

  • Hyperpigmented lesions, ulcers, or urticaria that persist > 48 h

  • Signs of systemic illness (eg, fever, lymphadenopathy, jaundice, cachexia)


Interpretation of findings

Acute urticaria is nearly always due to some defined exposure to a drug or physical stimulus or an acute infectious illness. However, the trigger is not always clear from the history, particularly because allergy may develop without warning to a previously tolerated substance.

Most chronic urticaria is idiopathic. The next most common cause is an autoimmune disorder. The causative autoimmune disease is sometimes clinically apparent. Urticarial vasculitis sometimes is associated with connective tissue disorders (particularly SLE or Sjögren syndrome). In urticarial vasculitis, urticaria is accompanied by findings of cutaneous vasculitis; it should be considered when the urticaria are painful rather than pruritic, last > 48 h, do not blanch, or are accompanied by vesicles or purpura.


Testing

Usually, no testing is needed for an isolated episode of urticaria unless symptoms and signs suggest a specific disorder (eg, infection).

Unusual, recurrent, or persistent cases warrant further evaluation. Referral for allergy skin testing should be done, and routine laboratory tests should consist of CBC, blood chemistries, liver function tests, and thyroid-stimulating hormone (TSH). Further testing should be guided by symptoms and signs (eg, of autoimmune disorders) and any abnormalities on the screening tests (eg, hepatitis serologies and ultrasonography for abnormal liver function tests; ova and parasites for eosinophilia; cryoglobulin titer for elevated liver function tests or elevated creatinine; thyroid autoantibodies for abnormal TSH).

Skin biopsy should be done if there is any uncertainty as to the diagnosis or if wheals persist > 48 h (to rule out urticarial vasculitis).

Clinicians should not recommend the patient do an empiric challenge (eg, “Try such and such again and see whether you get a reaction”) because subsequent reactions may be more severe.


Treatment

Any identified causes are treated or remedied. Implicated drugs or foods should be stopped.

Nonspecific symptomatic treatment (eg, taking cool baths, avoiding hot water and scratching, wearing loose clothing) may be helpful.

Drugs

Antihistamines remain the mainstay of treatment. They must be taken on a regular basis, rather than as needed. Newer oral antihistamines often are preferred because of once-daily dosing and because some are less sedating. Appropriate choices include

  • Cetirizine 10 mg once/day

  • Fexofenadine 180 mg once/day

  • Desloratadine 5 mg once/day

  • Levocetirizine 5 mg once/day

Older oral antihistamines (eg, hydroxyzine 10 to 25 mg q 4 to 6 h; diphenhydramine 25 to 50 mg q 6 h) are sedating but inexpensive and sometimes quite effective.

Systemic corticosteroids (eg, prednisone 30 to 40 mg po once/day) are given for severe symptoms but should not be used long term. Topical corticosteroids or topical antihistamines are not beneficial.

Patients with chronic idiopathic urticaria often do not respond to antihistamines or other drugs commonly used. Omalizumab, a monoclonal antibody that can suppress certain allergic reactions, may help relieve symptoms, but experience with this use is limited.


Angioedema

Patients who have angioedema involving the oropharynx or any involvement of the airway should receive epinephrine 0.3 mL of 1:1000 solution sc and be admitted to the hospital. On discharge, patients should be supplied with and trained in the use of an auto-injectable epinephrine pen.


Geriatrics Essentials

The older oral antihistamines (eg, hydroxyzine, diphenhydramine) are sedating and can cause confusion, urinary retention, and delirium. They should be used cautiously to treat urticaria in elderly patients.

Key Points

  • Urticaria can be caused by allergic or nonallergic mechanisms.

  • Most acute cases are caused by an allergic reaction to a specific substance.

  • Most chronic cases are idiopathic or result from autoimmune disease.

  • Treatment is based on severity; nonsedating antihistamines and avoidance of triggers are first-line options.

  • Topical corticosteroids and topical antihistamines are not beneficial.

  • Concomitant systemic symptoms require a thorough evaluation for the etiology.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • ANECTINE, QUELICIN
  • CRINONE
  • VANCOCIN
  • No US brand name
  • XYZAL
  • CLARINEX
  • ALLEGRA
  • XOLAIR
  • VISTARIL
  • ZYRTEC
  • No US trade name
  • RAYOS
  • ADRENALIN

* This is a professional Version *