INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Angioedema and urticaria should be viewed as varying manifestations of the same pathologic process. Postcapillary venule inflammation results in fluid leakage and edema in both conditions. However, angioedema involves vessels in the layers of the skin below the dermis, while urticaria is localized superficial to the dermis. This results in varying clinical presentations.

The subdermal source of angioedema results in well-demarcated, localized, nonpitting edema. Urticaria is localized to the superficial portion of the dermis and is characterized by well-circumscribed wheals with raised erythematous borders and central blanching. These often coalesce to become giant wheals.

These conditions can occur together or separately. Recurrent episodes of one or both conditions for less than a 6-week duration are considered acute, whereas longer-lasting attacks are considered chronic.

Angioedema, with or without urticaria, is classified as allergic, hereditary, or idiopathic. Complications range from dysphonia or dysphagia to respiratory distress, complete airway obstruction, and death.

Pathophysiology

Angioedema involves vascular leakage beneath the dermis and subcutis. This response is mediated by vasoactive mediators, such as histamine, serotonin, and kinins (eg, bradykinins), which cause the arterioles to dilate while inducing a brief episode of vascular leakage in the venules, where the junction between the endothelial cells appears looser than in the capillaries and arterioles.

Frequency

United States

Approximately 15% of the general population is affected by recurrent idiopathic episodes. The most common kind does not have a discoverable cause.

Mortality/Morbidity

Morbidity and mortality are directly related to the severity of airway obstruction.

Race

No specific racial predilection exists.

Sex

Women tend to have more occurrences than men.

Age

Persons who are predisposed have an increase in frequency of attacks after adolescence, with the peak incidence occurring in the third decade of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• General history
• • Urticarial eruptions usually appear at intervals and are intensely pruritic.
  • Patients with angioedema or urticaria should be questioned in detail to identify the offending antigen (in cases of allergic angioedema).
  • Any family history or history of recurrent episodes with the use of particular agents must be sought.
• Drugs associated with urticaria and angioedema include the following:
• • Radiocontrast agents
  • Opiates
  • Dextran
  • Angiotensin-converting enzyme (ACE) inhibitors
  • Aspirin
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Common sources of antigens that cause urticaria and angioedema include the following:
• • Hymenoptera envenomations
  • Food allergies such as fresh berries, shellfish, fish, nuts, tomatoes, eggs, milk, chocolate, food additives, and preservatives
  • Local trauma (eg, dental procedure, tonsillectomy)
  • Exposure to water, sunlight, cold, or heat
  • Animal dander (from scales of shed skin)
  • Emotional stress
  • Post infection or illness, including autoimmune disorders such as thyroid autoimmunity and leukemia
• Chronic urticaria (increasingly associated with Helicobacter pylori bacteria)

Physical

• General examinations
• • Patients usually present with the acute onset of well-demarcated cutaneous edema of distensible tissues (eg, lips, eyes, earlobes, tongue, uvula).
  • The face, extremities, and genitalia are most commonly affected.
• Airway assessment
• • First, determine airway patency.
  • Severe attacks can herald the onset of systemic anaphylaxis, characterized initially by dyspnea.
• Gastrointestinal (GI): Massive edema of the subcutaneous tissue in the abdominal region may present with abdominal distention and signs consistent with bowel obstruction.

Causes

• Immunoglobulin E (IgE)-mediated angioedema/urticaria may result from antigen ingestion (eg, food, drug) or from parenteral exposure (eg, medications, Hymenoptera).
• Complement-mediated angioedema/urticaria:
• • This angioedema involves immune complex–mediated necrotizing cutaneous venulitis manifested as serum sickness.
  • It is characterized by fever, angioedema, arthralgias, urticaria, and palpable purpura.
• Hereditary angioedema
• • This type of angioedema is characterized by recurrent self-limited attacks involving the skin, subcutaneous tissue, upper respiratory tract, or GI tract. Attacks may last from several hours to 2-3 days.
  • GI or upper respiratory tract attacks may be precipitated by local trauma (eg, dental procedures, tonsillectomy).
• Idiopathic angioedema appears to manifest due to direct mast cell–releasing agents in certain compounds (eg, radiocontrast media, opiates, dextran).
• • Other drugs may precipitate attacks by effects on arachidonic acid metabolism (eg, aspirin, NSAIDs, any compounds that are cyclooxygenase inhibitors).
  • ACE inhibitors precipitate attacks by directly interfering with the degradation of bradykinin, thereby potentiating its biological effect.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Bullous pemphigoid
Contact edema
Localized edema
Ludwig angina
Morbilliform drug eruptions
Urticaria pigmentosa

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• No workup for either etiology exists in the ED.
• • Diagnosis of IgE-mediated angioedema usually is made historically; however, epicutaneous skin testing or radioallergosorbent tests for foods may be confirmatory.
  • Hereditary angioedema is characterized by low levels of C1 esterase inhibitor (C1INH) or elevated levels of dysfunctional C1 esterase inhibitor, as detected by an immune assay. Between attacks, low levels of C4 are noted.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Care is taken to maintain a patent airway. Nasopharyngeal intubation may be more feasible because of extreme lingual edema and oral obstruction. Initiation of steroids and subcutaneous epinephrine may be efficacious.

Emergency Department Care

• The initial goal of therapy is airway management. Most patients with mild acute angioedema may be treated the same way as those with an allergic reaction. Severe symptoms require steroids, H1 and H2 blockers, and subcutaneous epinephrine in addition to antihistamines.
• The most skilled person available must handle airway interventions because of the often massive degree of oral obstruction that is involved. Approaches to consider include nasopharyngeal intubation, endotracheal intubation (which is often difficult), and nasotracheal intubation, either blind or with fiberoptic assistance and cricothyrotomy.
• Patients with mild limited urticaria may be reassured that symptoms are self-limited, typically disappear within hours to days, and do not need to be treated if itching is not incapacitating.
• Chronic angioedema responds well to steroids and H2 blockers.
• Hereditary angioedema
• • Hereditary angioedema is more refractory to the use of subcutaneous epinephrine, antihistamines, and steroids.
  • Stanozolol, an anabolic steroid, and danazol, a gonadotropin inhibitor, may be used for the acute phase of an attack of hereditary angioedema.
  • Often, patients are given aminocaproic acid for maintenance replacement of C1INH to prevent attacks. C1INH replacement should be attempted during the acute phase. If C1INH concentrate is unavailable, fresh frozen plasma may be used in the interim.

Consultations

An immunologist may be of benefit when dealing with difficult cases in patients with an unknown history of angioedema. An immunologist also may be able to recommend treatment modalities for patients with hereditary angioedema after the airway has been secured.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medications used are aimed at blocking the effects of the mediators of the reaction (eg, histamine, serotonin).

Drug Category: Catecholamines

The smooth muscle that lines the airways is controlled by the sympathetic and parasympathetic nervous system. In the lungs, the parasympathetics serve as the primary constrictor, and stimulation of sympathetics leads to relaxation. The receptors of this tissue type are beta2-receptors.

Drug Category: Antihistamines

These agents prevent the histamine response in sensory nerve endings and blood vessels. They are more effective in preventing histamine response than in reversing it.

Drug Category: Histamine H2 Antagonist

These agents are reversible competitive blockers of histamine at the H2 receptors, particularly those in the gastric parietal cells where they inhibit acid secretion. The H2 antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents.

Drug Category: Glucocorticoids

These agents are used to treat idiopathic and acquired autoimmune disorders. In addition, they prevent or lessen delayed reactions.

Drug Category: Anabolic steroids

Immunosuppressive properties may improve clinical symptoms.

Drug Category: Antigonadotropic agents

These agents are shown to improve clinical symptoms.

Drug Category: Beta2-adrenergic Agonist Agent

These agents relieve reversible bronchospasm by relaxing smooth muscles of the bronchi.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• For patients with hereditary angioedema, follow-up with an immunologist is necessary.

Further Outpatient Care

• Patients whose symptoms are minor and show no progression after 4 hours of observation may safely be discharged home on a short course of steroids and antihistamines. Discontinue any medication that may have caused symptoms.

In/Out Patient Meds

• Patients with no systemic symptoms and localized angioedema without progression of symptoms may be discharged home on a short course (ie, 5 d) of antihistamines and oral steroids.
• For patients with documented H pylori infection and a history of chronic urticaria, an appropriate antibiotic combination for eradication may stop the urticarial eruptions.

Deterrence/Prevention

• To prevent angioedema from returning, the patient should avoid irritation of the affected area, known allergens, and temperature extremes.
• Individuals should never take medications that are not prescribed for them.

Complications

• Life-threatening airway obstruction (if swelling occurs in the throat)  
• Anaphylactic reaction

Prognosis

• Patients on ACE inhibitors for several years may still have an attack of angioedema at some point. Once a medication has been shown to be a causative agent of angioedema, the patient must be counseled to discontinue all similar medications indefinitely.

Patient Education

• A helpful resource for patients and their family members is the Hereditary AngioEdema Association.
• For excellent patient education resources, visit eMedicine's Allergy Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Hives and Angioedema.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to secure the airway is a pitfall.
• Failure to recognize the potentially progressive nature of angioedema and premature discharge from the ED is a pitfall.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Blumen IJ, Rodenberg H, eds. Principles of Medicine. 2^nd ed. 1994.
• Cooper KD. Urticaria and angioedema: diagnosis and evaluation. J Am Acad Dermatol. Jul 1991;25(1 Pt 2):166-74; discussion 174-6. [Medline].
• Gavras I, Gavras H. Are patients who develop angioedema with ACE inhibition at risk of the same problem with AT1 receptor blockers?. Arch Intern Med. Jan 27 2003;163(2):240-1. [Medline].
• Horan RF, Schneider LC, Sheffer AL. Allergic skin disorders and mastocytosis. JAMA. Nov 25 1992;268(20):2858-68. [Medline].
• Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol. Sep 2005;53(3):373-88; quiz 389-92. [Medline].
• Lewiston NJ. Bronchiectasis. In: Hillman, BC, ed. Pediatric Respiratory Disease. Philadelphia: WB Saunders; 1993:222-229.
• Price KS, Thomson DM. Localized unilateral periorbital edema induced by aspirin. Ann Allergy Asthma Immunol. Nov 1997;79(5):420-2. [Medline].
• Salomone J. Anaphylaxis and acute allergic reactions. In: Tintinalli JE, Keleg GD, eds. Emergency Medicine: A Comprehensive Study Guide. New York: McGraw-Hill; 1996:209-211.
• Sheehan C. Clinical Immunology: Principles of Laboratory and Diagnosis. Philadelphia: Lippincott-Raven Publishers; 1997:43-44, 140, 313.
• Stern M. Hereditary Angioedema Association. April 2001.

Article Last Updated: Sep 11, 2007