BORISLAV STOEV, DO,
Resident, Department of Emergency Medicine, York Hospital, York, Pa.
MICHAEL A. BOHRN, MD,
Associate Residency Program Director, Clinical Assistant Professor, Department of Emergency Medicine, York Hospital, York,
Pa.
Angioedema is the transient (24-48 hours) swelling of areas in the deep dermis or subcutaneous tissue of the skin, mucosal
membranes, or both. Swelling is a result of increased permeability of the postcapillary venules and is typically nonpruritic
but may be painful or burning. It also seems to show predilection for areas of lax skin, especially the face, lips, tongue,
mouth, and genitalia.
Angioedema was first described formally by John Milton in 1876 and published in the Edinburgh Medical Journal.1 In 1888, William Osler described hereditary angioedema by studying its occurrence within a single family through 5 generations.2 More recently, in 1963, Donaldson and Evans showed the absence of serum inhibitor of C1 esterase in hereditary angioedema.3
Worldwide, the prevalence of hereditary angioedema is estimated at 1 in 50,000-150,000 persons. Approximately 15% of the US
population is believed to be affected by recurrent episodes of angioedema. Women have been thought to have higher rates of
hereditary angioedema, although this may be true mainly for type 3 hereditary angioedema. The occurrence of ACE-inhibitor
angioedema is probably higher than the typical rates, listed as 0.1%-0.2%. Results of the Omapatrilat Cardiovascular Treatment
Assessment Versus Enalapril (OCTAVE) trial, which included over 25,000 patients, showed rates of 0.68% for enalapril and 2.17%
for omapatrilat. Additionally, the rates of angioedema were much higher than previous estimates in the specific groups of
smokers (3.93%) and African Americans (5.54%).4
Differential diagnosis
Many conditions may present in similar fashion to angioedema, although most have specific clinical characteristics that allow
accurate diagnoses. Conditions that may cause similar symptoms include facial cellulitis, acute contact allergic or photodermatitis,
Crohn's disease of the mouth or lips, dermatomyositis, facial lymphedema, tumid discoid lupus, Ascher syndrome, Melkersson-Rosenthal
syndrome, and superior vena cava syndrome.5
Hereditary angioedema
Hereditary angioedema (HAE) is characterized by random swelling of the hands and feet, and frequently the face, tongue, and
genitalia. Some patients present with severe abdominal pain secondary to bowel wall swelling. This pain is usually spasmodic
with each peristaltic wave. An attack can last from several hours to several days and is generally not life-threatening unless
it involves the airway, with asphyxiation being the leading cause of death. Several exacerbating factors have been identified
including trauma, heat, cold, and emotional stress (angioneurotic). HAE is often not recognized when GI or other less obvious
symptoms are the predominant features.
Hereditary angioedema is an autosomal dominant disorder of C1 esterase inhibitor deficiency. The gene has been mapped to chromosome
11. Type 1 is characterized by low levels of normal functioning C1 inhibitor protein (85% of patients with HAE), while in
type 2 the concentration of this protein is normal but is functionally impaired (15% of patients with HAE). C1 esterase inhibitor
is a serine protease, and it controls the activity of the complement system. Failure of C1 inhibitor leads to unchecked activation
of the C1 with consumption of complement components C2 and C4 and production of vasoactive peptides and vasodilation. The
kallikrein system is also unchecked, which results in the production of bradykinins causing angioedema.6
Diagnosis
is based on a history of episodic occurrence of nonpruritic swelling involving the skin, GI, and upper respiratory tracts
that frequently starts in childhood but can present later in life. Family history can be contributory. Routine laboratory
studies are usually normal with frequent leukocytosis with GI episodes. Complement 2 and 4 levels are the most reliable indicators
of the condition since they are decreased in both type 1 and type 2 HAE.
Treatment
of acute exacerbations includes fluid replacement if severe volume contraction is present. Special attention should be paid
to laryngeal involvement that might require intubation or tracheostomy. HAE is more refractory than allergy-related angiodema
to the use of corticosteroids and SC epinephrine. Commercially available C1 esterase inhibitor is available for infusion,
or fresh-frozen plasma can be used to replace the missing C1 inhibitor protein.7 Prophylactic treatment with androgenic agents, such as danazol (Danocrine) and stanozolol (Winstrol), has been shown to
reduce attacks by increasing C4 complement levels. Most common side effects include arterial hypertension, hepatic toxicity,
lipid profile changes, and virilization in women that can be minimized by using the smallest effective dosage. Treatment for
children must take into account age-related anatomic and physiologic differences.8 Other prophylactic agents for HAE include aminocaproic acid (Amicar).
Acquired angioedema
Acquired angioedema (AAE) is a rare condition that is set apart from HAE by the absence of family history of angioedema. The
clinical presentation is the same and consists of painless, nonpruritic swelling of the skin and mucosal surfaces.
AAE is classified into type 1 and type 2. The first type is associated with the presence of other diseases including multiple
myeloma, chronic lymphocytic leukemia, Waldenstm's macroglobulinemia, non-Hodgkin's lymphoma, and infections with Helicobacter pylori. The production of complement-activating factors, antibodies, and immune complexes by the associated diseases destroys the
function of C1 inhibitor and results in angioedema. In type 2, for unknown reasons, there is a subpopulation of B cells that
secretes autoantibodies to C1 inhibitor protein.
Diagnosis
is made with the history of the associated diseases and laboratory studies that show decreased levels of C1 inhibitor, C1,
C2, and C4 complement. A positive immunoblot assay for cleavage products of C1 inhibitor protein is available for type 2.6
Treatment
is supportive in acute exacerbations with the goal of treating the underlying disorder. Therapy significantly reduces future
attacks but does not eliminate them completely. For type 2 AAE, plasmapheresis and cyclophosphamide immunosuppressive therapy
directed at decreasing autoantibody production may be effective.
ACE-inhibitor-associated angioedema
The antihypertensive drugs known as ACE inhibitors (ACEIs) were developed from a hypotension-inducing substance found in the
venom of the Brazilian pit viper (Bothrops jararaca) during the 1970s. Since then, their use has been shown to reduce mortality in patients who have hypertension or congestive
heart failure and in those who are at high risk for cardiovascular events.
ACEI–associated angioedema is a rare, potentially life-threatening side effect of treatment with ACEIs. Reactions range from
mild swelling of the face, hands, feet, or bowel to life-threatening airway compromise. The most common sites of involvement
are the lips, tongue, and face.9 The highest incidence is during the first month of treatment with an ACEI, but the majority of cases occur past the first
month and up to years later.10 The exact mechanism of ACEI-associated angioedema remains to be elucidated. Angiotensin converting enzyme inactivates bradykinin,
and the inhibition of this process could contribute to angioedema.
Treatment
includes advanced airway management with intubation or cricothyroidotomy as indicated. Discontinuing use of the offending
ACEI is important, and administration of complement C1 inhibitor or fresh-frozen plasma can be beneficial. This angioedema
is a class effect, so discontinuation of the ACEI and avoidance of other drugs from the same class should prevent any further
attacks. Angiotensin receptor blockers (ARBs) may be an alternative for patients with ACEI-associated angioedema, as the rate
of angioedema in patients taking ARBs is not significantly increased over that observed in the general public and appears
to be less that the rate in those taking ACEIs.11 However, there have been several reports of ARB-associated angioedema, which may occur at a higher rate than previously
expected. Recently, the American Academy of Emergency Medicine issued a clinical practice guideline on the initial evaluation
and management of patients presenting with acute urticaria or angioedema. The guideline advises that ARBs not be considered
a safe alternative for patients who have experienced ACEI angioedema.12
Angioedema associated with allergic reactions
Angioedema from allergic reactions is the most commonly seen form of angioedema and often manifests in association with urticaria.
The pathophysiology for angioedema and urticaria is similar as both are a result of the release of histamine and other inflammatory
mediators. A key difference is the location of the edema. With angioedema, swelling involves tissues deep to the dermis, while
urticaria involves swelling of tissues superficial to the dermis. Also, the lesions of angioedema are not typically associated
with pruritis.6
Diagnosis
is made on clinical presentation. Most angioedema from allergic reactions is due to exposure to certain foods, medications
or drugs, chemicals, insect bites, environmental conditions, transfusions, or other medical conditions.13 As with other forms of angioedema, the face, lips, mouth, and extremities are primarily affected. Associated edema of the
larynx is an immediate life threat and the most common cause of death with this type of reaction. Patients often complain
of hoarseness, dysphagia, or the sensation of a lump in the throat and may have overt stridor. Uvular edema is felt to be
a marker for concurrent laryngeal edema. Other clinical findings are more directly related to urticaria and generalized histamine
release. Bronchospasm, rhinitis, conjunctivitis, tachycardia, hypotension and distributive shock, and GI symptoms may also
be present.
Treatment
includes careful attention to airway management, with intubation or other techniques for securing the airway being of paramount
importance. Epinephrine, SC, 0.3 mg using 1:1000 dilution, or IV, 0.1 mg using 1:10,000 dilution, is the primary medical treatment
for severe reactions.13 For cases of anaphylactic shock, continuous IV infusion of epinephrine, 1-10 mcg/min, can be used. In patients with severe
reactions who are currently taking beta-blocker agents, glucagon infusion is a possible treatment option, allowing bypass
of beta receptors for clinical effect.14
Additional critical treatments include IV fluids utilizing normal saline or lactated Ringer's solution. Hypotension due to
anaphylaxis will generally respond to this treatment. Care should be used when administering epinephrine and large volumes
of IV fluids to elderly patients, to those with cardiac problems including coronary artery disease, and to patients with current
chest pain. Epinephrine may be lifesaving in these situations and should not be withheld in a life-threatening emergency,
but the risks and benefits of individual clinical situations must be evaluated.13,15,16 H1 antihistamine agents such as diphenhydramine (Benadryl), 25-50 mg, are important and can be given IV or po. H2-blockers such as cimetidine (Tagamet), 300 mg, can also be added to the treatment regimen. A synergistic effect between H1-and H2-blockers may exist, and this appears to account for greater efficacy when both agents are used with severe anaphylaxis.17 Corticosteroids such as methylprednisolone (Medrol), 125 mg IV, or prednisone, 60 mg po, may help resolve the acute episode
but are felt to be most effective in preventing recurrent or rebound symptoms, despite a relative lack of specific evidence
to support their use.18 Nebulized beta-agonists such as albuterol (Proventil, Ventolin) may help with bronchospasm resistant to epinephrine.15 Avoidance of any known triggers such as nuts or shellfish is key to preventing future episodes, and prescribing self-injectable
epinephrine (EpiPen) is also wise in appropriate situations.13,19
Angioedema associated with eosinophilia
Angioedema-associated eosinophilia (Gleich's syndrome) is a rare form that is also associated with severe swelling of the
face, lips, mouth, tongue, and extremities. Symptoms typically are intermittent, with severe exacerbations that usually respond
to systemic corticosteroid treatment. Molecular mechanisms of this syndrome are unclear, but IV immunoglobulin (IVIG) has
also been reported as a potential therapy for acute exacerbations.20
Drs Stoev and Bohrn disclose that they have no financial relationship with any manufacturer in this area of medicine.
REFERENCES
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11. Johnsen SP, Jacobsen J, Monster TB, et al. Risk of first-time hospitalization for angioedema among users of ACE inhibitors
and angiotensin receptor antagonists. Am J Med. 2005;118(12):1428-1429.
12. Palmer M, Rosenbaum S. Clinical Practice Guideline of the American Academy of Emergency Medicine (AAEM): initial evaluation
and management of patients presenting with acute urticaria or angioedema. http://www.aaem.org/positionstatements/clinical_practice_guidelines.php. Accessed October 1, 2007.
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report—second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 2006;47(4):373-380.
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Drugs mentioned in this article
Albuterol (Proventil, Ventolin)
Aminocaproic acid (Amicar)
Cimetidine (Tagamet)
Danazol (Danocrine)
Diphenhydramine (Benadryl)
Enalapril (Vasotec)
Epinephrine (EpiPen)
IV immunoglobulin (IVIG)
Methylprednisolone (Medrol)
Prednisone
Stanozolol (Winstrol)
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