Urticaria & Angioedema

Urticaria (also known as hives) is characterized by severely pruritic raised erythematous, circumscribed lesions resulting from mast-cell activation and subsequent release of histamine and other vasoactive mediators that lead to increased vascular permeability of postcapillary venules and subsequent edema, erythema, and pruritus. Although urticaria can last for days to weeks, each urticarial lesion typically lasts less than 24-48 hours and does not leave a bruise or mark. Urticaria may develop during or following viral and bacterial infections, especially in pediatric patients.

(Source: Exanthematous Drug Eruptions. N Engl J Med 2012.)

Urticaria can be classified as acute or chronic, depending on the duration of symptoms:

• Acute urticaria (duration, <6 weeks) may have an identifiable cause, such as foods, medications (including antibiotics, aspirin, or nonsteroidal anti-inflammatory drugs [NSAIDs]), insect stings, underlying disorders (infections, Helicobacter pylori, and parasitic diseases), and malignancy (see table below).

• Chronic urticaria (duration, >6 weeks) typically does not have an underlying allergic basis; often an etiology is not found, and it is considered chronic spontaneous or chronic idiopathic urticaria (CIU):

  • CIU is associated with autoimmune disorders such as Hashimoto thyroiditis (autoimmune hypothyroidism); evidence suggests that the urticaria may be caused by autoantibodies directed against mast cells in the skin in about half of patients with CIU.

  • CIU is considered a benign and self-limiting condition and is not associated with tissue-destructive activity.

  • Nonimmunologic causes of urticaria include physical urticarias (e.g., cold-induced, pressure-induced, exercise-induced, vibration-induced, and cholinergic urticaria).

Angioedema is similar to urticaria but affects the deep dermis and subcutaneous tissue and leads to nonpitting swelling. Angioedema tends to be localized, asymmetric, and often affects the face, extremities, and genitalia. Angioedema can be mast-cell-mediated or bradykinin-mediated. This section addresses mast-cell- or histamine-mediated angioedema. Bradykinin-mediated angioedema is not associated with urticaria or other histamine-mediated symptoms.

Causes

The following table lists the possible causes of urticaria and angioedema:

(Source: Northwestern University Allergy-Immunology Syllabus 2012: Residents and Students. Providence, RI: Oceanside Publications. Copyright © 2012, OceanSide Publications, Inc. with permission.)

Evaluation

• On physical exam, urticarial lesions may be present if a flare is ongoing. Ask patients for photographs of the rash to differentiate urticaria from other skin eruptions (e.g., eczema or contact dermatitis).

• In chronic urticaria, screening tests may be indicated if a systemic disorder is suspected.

  • Specific lab tests depend on clinical suspicion but may include complete blood count (CBC) with differential, chemistry panel, liver function tests, thyroid-stimulating hormone (TSH), erythrocyte sedimentation rate (ESR), and antinuclear antibodies (ANA).

• In isolated angioedema without urticaria, a C4 level is the best screening test for hereditary angioedema. However, in rare cases, patients with hereditary angioedema can have normal C4 levels. Therefore, if clinical suspicion is high, lab testing for C1 inhibitor level and function should also be measured to screen for this condition.

• Skin biopsies may be considered to evaluate for urticarial vasculitis if the hives are atypical (nonblanching, painful, purpuric, last >24 hours) or are associated with systemic symptoms (e.g., fever, uveitis, glomerulonephritis, or arthritis).

Treatment

• If a trigger is identifiable, avoidance is the first step.

• Aspirin and NSAIDs should be avoided because they can cause or exacerbate urticaria and angioedema. A selective COX-2 inhibitor (e.g., celecoxib) can be considered if needed for pain/anti-inflammatory properties. Acetaminophen can often be tolerated at lower doses.

• Antihistamines (preferably second-generation, long-acting, nonsedating histamine-1 blockers [e.g., cetirizine or fexofenadine]) are the mainstay of treatment.

  • Higher doses (2-4 times the FDA-approved dose) are often required to control symptoms.

  • Other treatment options include doxepin, hydroxyzine, and montelukast.

  • Histamine-2 blockers can also be considered.

• In the short term, oral glucocorticoids can be used to control symptoms but only for limited duration due to the adverse effect profile. Long-acting nonsedating antihistamines should be used in conjunction with glucocorticoids to prevent recurrence once glucocorticoids are discontinued.

• Omalizumab is a monoclonal antibody that targets IgE and is approved for use in chronic idiopathic urticaria refractory to high-dose antihistamines in patients aged 12 years and older.

Types of Angioedema

Angioedema can be mast-cell-mediated or bradykinin-mediated (see the previous section on histamine-mediated angioedema). Patients with histamine-mediated angioedema typically present with urticaria and pruritus.

Bradykinin-mediated angioedema is not associated with urticaria or other histamine-mediated symptoms. Angiotensin converting enzyme (ACE)-inhibitor-induced angioedema is the most common cause of bradykinin-mediated angioedema in adults, and therefore, not covered in this pediatric review. Similarly, acquired angioedema is most commonly diagnosed after the fourth decade of life, and is not covered.

(Source: Angioedema: Classification, Management and Emerging Therapies for the Perioperative Physician. Indian J Anaesth 2016.)

Hereditary Angioedema

• Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by a deficiency or dysfunction of functional C1 esterase inhibitor (C1-INH) that leads to excessive production of the vasoactive mediator bradykinin. This causes episodic increases in vascular permeability and angioedema.

• HAE is not associated with urticaria, and an alternate diagnosis should be considered if hives are a prominent feature of presentation.

• HAE accounts for only a small fraction of cases of angioedema.

• The three subtypes of HAE are as follows:

  • type I (deficient production; C1-INH level <30% of normal)

  • type II (dysfunctional protein; C1-INH is detectable but has reduced function)

  • hereditary angioedema with normal C1-INH (previously known as type III; factor XII mutation can be present in some patients, but overall pathogenesis remains unclear)

• C4 is the best test to screen for HAE because it is low at baseline in approximately 96% of patients and during most attacks (in 99% of patients). C1-INH functional and quantitative levels can help differentiate between type I and type II HAE (see table below).

(Source: Hereditary Angioedema. N Engl J Med 2008.)

HAE treatment options for acute attacks include the following:

• plasma C1-inhibitor concentrate (available in intravenous [IV] and subcutaneous preparations but only IV preparation is FDA approved for acute attacks)

• kallikrein inhibitors (subcutaneous ecallantide)

• bradykinin-receptor B2 antagonists (subcutaneous icatibant)

• anabolic steroids (e.g., danazol or stanozolol) have slower onset of action; used less often now that more-specific, targeted treatments are available

• fresh frozen plasma carries a risk of worsening angioedema; used less often now that more-specific, targeted treatments are available

HAE prophylaxis options include the following:

• purified C1-inhibitor concentrate, available for prevention of attacks in an IV and subcutaneous preparation

• subcutaneous lanadelumab (human monoclonal antibody targeting plasma kallikrein)

• attenuated androgens (adverse effects limit use; contraindicated in growing children and pregnant/lactating women)

• antifibrinolytics (generally less effective)

• oral berotralstat (plasma kallikrein inhibitor); FDA approved in December 2020

(Reprinted from 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema. Allergy Asthma Clin Immunol 2010. Copyright [2010] with permission from Elsevier.)