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- Krishnamurthy, A., Naguwa, S.M. & Gershwin, M.E. Clinic Rev Allerg Immunol (2008) 34: 250. doi:10.1007/s12016-007-8037-y
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Angioedema is a self-limited nonpitting edema generally affecting the deeper layers of the skin and mucous membranes. It is the result of increased vascular permeability causing the leakage of fluid into the skin in response to potent vasodilators released by immunologic mediators. Two main pathways are thought to be implicated in angioedema. The mast cell pathway in which preformed mediators, such as histamine, rapidly formed mediators, leukotrienes and prostaglandins, are released from mast cells through IgE or direct activation. This is the most common pathway among children, with food, medications, and infections commonly implicated. The second pathway is the kinin pathway, most notably affected by angiotensin-converting enzyme (ACE) inhibitors and hereditary forms of angioedema, which ultimately results in the formation of bradykinin, a potent vasodilator. Angioedema is being encountered with increasing frequency, particularly among children and is important to recognize and treat for its life-threatening associated manifestations such as anaphylaxis and airway obstruction. Although angioedema is still not fully understood, we have broadened our understanding of the possible causes and clinical course of angioedema. An understanding of these potential causes and mechanisms by which angioedema can occur may guide the clinician in determining the need for diagnostic testing and the extent of treatment.
Angioedema is a commonly encountered disease that can occur as the sole clinical finding or with associated urticaria. Prevalence in the United States is noted to be between 14% and 25%  with a large proportion of cases among children. Angioedema is an immunologic process causing a nonpitting edema in the deeper layers of the skin and mucous membranes. Two main immunologic pathways are implicated in angioedema—mast cell degranulation and the kinin pathway activation, both of which result in the release of potent vasodilators, which increase vascular permeability and result in capillary leakage with resultant tissue edema.
Although most cases require solely supportive treatment or removal of offending agents, angioedema is a potentially life-threatening condition that may be associated with anaphylaxis or airway compromise, and therefore necessitates prompt evaluation and treatment. Aside from hereditary angioedema, which remains rare but is often discussed in association with pediatric angioedema, manifestations and causes of angioedema among children is not comprehensively discussed in the literature. An understanding of the various causes of angioedema and the potential mechanisms by which angioedema may occur dictates the need for further diagnostic testing and guides for therapy.
Classic features of angioedema
Features of angioedema
Lasts 24–48 h
Rapid onset (minutes to hours)
Face, genital areas, extremities, bowel often affected
Angioedema and urticaria are common problems occurring in as many as 15% to 25% of the population at some time in their life and frequently encountered among children . Both genders and all racial groups are affected. Acute angioedema, defined as lasting less than 6 weeks, is thought to be more common among young people whereas chronic angioedema more commonly occurs among the 40–50 age group . Angioedema, in general, is more common among individuals with a history of atopic diseases such as asthma, food allergy, allergic rhinitis, or atopic dermatitis.
Angioedema may occur in conjunction with urticaria, but it may also be an isolated finding. In approximately 40% of patients presenting with angioedema, urticaria and angioedema occur in conjunction. Another 40% of patients present with urticaria alone whereas 20% of patients have angioedema but no urticaria . Studies suggest that patients with both urticaria and angioedema tend to have more severe and persistent symptoms that those without this combination.
When evaluating a child with angioedema, the hereditary forms of the disease must be included in the differential. In two-thirds of patients, the hereditary forms of angioedema will manifest during childhood, but it is important to note that overall hereditary forms are rare and account for only a small fraction of the cases of angioedema. The majority of angioedema seen among children is usually secondary to precipitating factors such as infection, food hypersensitivity, physical factors, or medications. One study of urticaria and angioedema among 54 children found that the most common etiology was infection, which was diagnosed in 58% of the children studied . Although the hereditary forms of angioedema remain rare, they are important for their life-threatening implications and recurrent nature. Laryngeal edema occurs frequently in this population with a lifetime incidence estimated at approximately 70% and a mortality rate estimated at 30–40% from obstruction of the upper airway . For this reason, early recognition and treatment is essential.
Angioedema arises from the release of vasoactive mediators causing tissue edema. Two main pathways are thought to be involved: mast cell degranulation and kinin formation. Mast cell degranulation results in the release of inflammatory mediators from mast cells such as histamine, leukotriene C and D, prostaglandin D2, and platelet-activating factor. These factors have potent vasoactive properties that result in the dilation of venules, which increases their permeability and causes tissue edema. Many different drugs and allergens can trigger this process through IgE mechanisms as detailed below. Certain drugs such as opiates, vancomycin, and radiocontrast media can also trigger mast cell degranulation directly through direct mechanisms not involving IgE . The second pathway leading to angioedema involves kinin formation. Kallikrein is an enzyme that converts kininogen to bradykinin, a vasoactive peptide. Bradykinin subsequently interacts with bradykinin receptors as a potent vasodilator that increases vascular permeability and causes tissue edema. Angiotensin-converting enzyme (ACE) inhibitors are the most notable example of triggering angioedema through this pathway.
Classification and Pathogenesis
Classification of angioedema can be thought of in terms of acute versus chronic and mast cell- versus kinin-mediated. Acute episodes of angioedema are generally defined as those occurring within a 6-week period, whereas episodes occurring over a longer period are designated as chronic. Clinically, mast cell-mediated angioedema and kinin-mediated angioedema can often be differentiated by whether urticaria is present. Mast cell angioedema is associated with urticaria and/or pruritis in 90% of cases, whereas in the kinin-mediated responses, urticaria is generally absent. Classifying angioedema accordingly can help guide the need for further diagnostic testing and therapy.
Mast Cell-Mediated Responses
Acute Allergic Angioedema
Causes of acute allergic angioedema
Peanuts, milk, eggs, fish, tree nuts, soy, wheat, crustaceans, shellfish, mollusks
Foods cross-reacting with latex (i.e., kiwi fruit, banana, avocado, chestnut)
Penicillin, bactrim, sulfa-derived drugs, cephalosporins, diuretics, sulfonylurea, dilantin, oral hypoglycemics, NSAIDs
Fire ants, insect venom
Latex substances, preservatives, formaldehyde, chemical irritants, flavor enhancers, colorants, radiocontrast media, opiates
Viral: herpes simplex, hepatitis B, coxsackie A and B, mononucleosis, upper respiratory infections, parvovirus
Bacterial: otitis media, sinusitis, dental abscesses, upper respiratory infections, urinary tract infections
Parasitic infections: Strongyloides, Ascaris, Filaria, Echinococcus
Dust mites, pollens, animal dander, molds
The onset of acute allergic angioedema depends upon prior sensitization of mast cells. IgE molecules are bound to dermal mast cells, and exposure to certain antigens for which the IgE molecules are specific results in the activation of cellular processes causing mast cell degranulation and release of mediators that increase vascular permeability. Although angioedema will generally resolve in 24 to 48 h, repetitive exposure or cross-reactive agents can result in recurrence. Skin testing may be helpful in demonstrating specific IgE-mediated hypersensitivity. There is no minimum age for skin testing, it is widely available and has a high negative predictive value, although a relatively low positive predictive value (i.e., a significant number of patients with a positive result may be asymptomatic). Serum IgE levels to foods (RAST test) or other possible allergens is an alternative to skin testing, although values vary among laboratories and it may be more expensive than skin testing.
Nonsteroidal antiinflammatory drugs (NSAIDs) are used extensively among children as analgesic and antipyretic agents. Hypersensitivity to NSAIDs can result in acute angioedema and is being observed with increasing frequency because of the widespread use of NSAIDs, even among children. Prevalence rates for acute angioedema from NSAIDs is noted between 0.1% and 0.3% with higher rates among those who use NSAIDs intermittently, as opposed to chronic use. One study of the average risk of urticaria/angioedema in a large cohort of patients was 1.1% among those who used NSAIDs chronically and 3.6% among those who used NSAIDs intermittently . Rates are substantially higher among asthmatics and other patients with a history of atopy. The incidence of facial angioedema and NSAID hypersensitivity among atopic children with asthma or allergic rhinitis was studied in a 10-year retrospective chart review of patients in an allergy clinic. Among these children, 41 of 1,007 (4.1%) experienced documented facial angioedema secondary to NSAIDs. The incidence of angioedema among this cohort was found to increase with age, 2% at less than 5 years of age compared with 21% in the 16 to 21 age group . Other predisposing factors for the development of angioedema in response to NSAIDs include female sex, family history, and a history of chronic urticaria.
Chronic angioedema is thought to be secondary to an autoimmune process in approximately 40% of patients, whereas the other 60% is considered to be idiopathic . The autoimmune process is thought to be the result of autoantibodies (IgG) to the IgE receptor on mast cells causing recurrent attacks of angioedema. These autoantibodies stimulate the release of histamine from basophils and mast cells. Episodes occur independently of external triggers and often recur months to years later. Of patients with chronic angioedema, 75% have symptoms for longer than a year, 50% have symptoms longer than 5 years, whereas 20% have symptoms for decades.
Chronic idiopathic angioedema in which recurrent attacks of angioedema occur without a specific cause is a diagnosis of exclusion. Idiopathic angioedema with life-threatening anaphylactic manifestations is termed idiopathic anaphylaxis. In idiopathic anaphylaxis, recurrent attacks of anaphylactoid reactions occur without identifiable precipitants. Idiopathic anaphylaxis can be classified into either idiopathic anaphylaxis generalized or idiopathic anaphylaxis with angioedema. Idiopathic anaphylaxis with angioedema presents with recurrent attacks of angioedema with upper airway compromise of the larynx, pharynx, or tongue, but without the other systemic symptoms of anaphylaxis . Idiopathic angioedema is perhaps the most common cause of recurrent angioedema. A recent prospective study of 220 adults found that among adults with idiopathic angioedema and idiopathic angioedema with urticaria, 80% and 40.5%, respectively, still had symptoms after 1 year indicating the recurrent and persistent nature of the disease .
Among children, infection is a common cause of angioedema. Viral infections such as herpes simplex, coxsackie A and B, hepatitis B, Epstein–Barr, and other viral illnesses such as upper respiratory tract infections, may result in angioedema and urticaria. The proposed mechanism is a type 3 immune complex-mediated hypersensitivity process in which viruses produce circulating immune complex resulting in anaphylatoxins causing IgE cross-linking releasing mast cell products. Bacterial infections associated with angioedema, particularly among children, may include otitis media, sinusitis, tonsillitis, upper respiratory tract infections, and urinary tract infections. Parasitic infections, although less common, should be considered on the differential including strongyloides, toxocara, and filarial . Insect bite/stings such as bee stings may also result in similar reactions.
Angioedema may also occur through nonimmunologic release of mast cell mediators. Most notably, radiocontrast media, opiates, and irradiation are thought to have a direct effect on mast cells resulting in the release of mediators. Physical factors are implicated in mast cell release, including heat, cold, pressure, solar, and vibration, and often results in an urticarial rash. Other medications are noted to produce reactions either through immunologic or direct release of mast cell mediators. These include beta-lactams, sulfonamides, insulin, dilantin and streptokinase.
Angioedema can also be observed in approximately 15% of patients with hypereosinophilic syndrome, either through mediators released from eosinophils that directly result in angioedema or eosinophil-released products that trigger mast cell degranulation. Urticarial vasculitis can also present with angioedema particularly in the low complement form of the disease.
Angiotensin-converting Enzyme and Angioedema
ACE inhibitors cause angioedema in 0.1–0.2% of patients treated with the drug . Given the large number of patients taking ACE inhibitors, approximately 40 million patients worldwide, it is the most common cause of acute angioedema seen in emergency rooms . ACE inhibitor-induced angioedema is more commonly seen among adults, given the target population of the medication, but occurs among children taking the medication as well. Half of the cases occur within a week of starting therapy, but may occur immediately after starting treatment or months to years later. All ACE inhibitors are equally likely to cause angioedema, as it appears to be a class effect, rather than a drug-specific effect, and is not dependant on the dose administered. There does appear to be a racial predilection as African-American patients are five times more likely to have angioedema from ACE inhibitors than Caucasian patients . Clinically, angioedema from ACE inhibitors has a predilection for facial areas, and urticaria is generally absent . Intestinal edema may also occur, presenting with symptoms of acute abdominal pain, diarrhea, and/or vomiting that may mimic an acute abdomen.
Hereditary angioedema (HAE) is a rare autosomal dominant disease affecting 1 in 50,000 . HAE reflects 1% of all angioedema cases. Despite the rarity of hereditary forms of angioedema, early recognition is important given the high morbidity and mortality of the disease without appropriate treatment. Hereditary angioedema is caused by the deletion, duplication, or mutation in the complement gene on chromosome 11 resulting in either a reduction in the C1 esterase inhibitor (C1-INH) concentration or decreased functional activity of the enzyme. Children classically present with recurrent episodes of angioedema. Of patients with HAE, 75% have cutaneous angioedema of an extremity as the first presenting sign of the disease . Other common symptoms include upper airway obstruction and dysphagia occurring in approximately 50% of the patients and recurrent colicky abdominal pain (40%) . The majority of patients have their first attack before the age of 5. Patients traditionally have milder symptoms in childhood with more severe presentation in adolescence after a precipitating event such as mechanical trauma, stress, exercise, injury, or alcohol consumption that leads to the diagnosis. Episodes may be less frequent than in adulthood with intestinal edema perhaps more common than laryngeal edema . Triggers for angioedema episodes include trauma, stress, infection, or medications. HAE is associated with several autoimmune diseases including thyroiditis, lupus, and Sjogren’s syndrome.
Type I HAE involves a quantitative defect in the C1 esterase inhibitor and occurs in 85% of patients with C1-INH levels decreased to 5–30% of the normal level . Type II involves a functional defect in C1-INH and occurs in the remaining 15%. C1-INH primarily degrades C1, a component of the classical complement pathway, to prevent excessive complement activation. It also inhibits the generation of other proteins in the fibrinolytic system, in particular, the enzyme kallikrein that transforms kininogen to kinins . Thus, a deficiency of this inhibitor results in increased levels of vasoactive mediators, in particular, bradykinin. Elevated bradykinin levels is thought to be the main cause of the swelling seen in HAE [4, 22, 23]. HAE type III clinically resembles the hereditary angioedema disorders but does not have a known C1-INH, complement, or kinin abnormality. It is described in women particularly in association with estrogen and pregnancy and may be an X-linked disorder, although the cause remains unknown [23, 24].
Hereditary and acquired angioedema—laboratory comparison
Type I hereditary angioedema
Type II hereditary angioedema
Type I acquired angioedema
Type II acquired angioedema
Normal to mildly decreased
Classification of angioedema
Chronic angioedema—idiopathic or autoimmune
Acquired C1 inhibitor deficiency
Angioedema with eosinophilia
Differential diagnosis of angioedema
Distinguishing clinical features
Painful, possible fever, prominent erythema. Peeling of skin upon resolution often occurs
Not usually transient. Other manifestations of hypothyroidism: Fatigue, weight gain, dry skin, brittle hair
Not usually transient. Generalized nonpitting edema. Longstanding history of thyroid disorder and/or acute event trigger
Heliotrope rash (violaceous rash) afflicting eyelids. Proximal muscle weakness
Contact facial dermatitis
Pruritis, scaling, pain, burning. May last longer than 24–48 h. Peeling of skin upon resolution often occurs
Usually associated with rosacea
Superior vena cava syndrome
Edema not transient, exacerbated by bending forward or lying down. Neck vein distension. Associated with ruddy color (rubor)
Tumors (head and neck, lymphoma)
Progressive swelling, not transient. Usually unilateral
Involves bilateral hands, Raynaud’s phenomenon usually present
Systemic lupus erythematous
Malar rash. Other manifestations of lupus
Peripheral blood eosinophilia, weight gain, fever
Recurrent facial edema, fissured tongue, facial nerve palsy occasionally occurs
Cheilitis granulomatosa (Miescher’s cheilitis
Recurrent episodes of angioedema. Eventual permanent enlargement of lip. Idiopathic
Several other conditions may produce similar clinical manifestations to angioedema and should be considered in the differential diagnosis, although angioedema is often distinguishable based on its rapid onset, distribution, and transient nature. Allergic contact dermatitis from cosmetics, topical drugs, or poison ivy can present similarly to angioedema, afflicting the facial areas with the skin surrounding the eyes being particularly susceptible . Facial cellulitis may present with facial edema as well, although there is often fever, very prominent erythema, and associated pain. Both facial cellulitis and contact dermatitis may be accompanied by skin peeling upon resolution; this does not occur in angioedema.
Hypothyroidism can also cause a puffiness of the face and lips similar to angioedema and in severe hypothyroidism manifesting as myxedema coma, one may see a generalized nonpitting edema. These conditions are generally not transient and are accompanied by other manifestations of a hypothyroid state such as cold intolerance, dry skin, or coarse, brittle hair.
Several connective tissue disorders such as systemic lupus erythematous, scleroderma, dermatomyositis, and Sjogren’s syndrome can manifest with facial and periorbital edema. Other cutaneous manifestations such as malar rash, photosensitivity, or the classic heliotropic (violaceous) rash in dermatomyositis may be seen.
Tumors of the head and neck, lymphoma, or superior vena cava syndrome may also cause edema of the face, neck, and upper extremities, but are usually progressive swelling rather than transient in nature. Superior vena cava syndrome is often marked by a ruddy color of the skin (rubor).
Angioedema of the gastrointestinal tract presents without cutaneous involvement with symptoms of nausea, vomiting, and abdominal pain that may mimic an acute abdomen. In children, in particular, this may easily be mistaken for acute appendicitis. Parasitic infections such as trichinosis may also present with abdominal pain, diarrhea, vomiting, and periorbital edema that may mimic angioedema, although significant myalgias are often present. Other more unusual conditions include cheilitis granulomatosa, or Miescher’s cheilitis, an idiopathic condition characterized by recurrent episodes of angioedema with resultant permanent lip enlargement.
Laboratory testing in angioedema
Confirm anaphylactic event
Elevated within 5–10 min after mast cell activation. Elevated 30 min to 1 h
Confirm anaphylactic event
Peaks after 1 h, elevated for up to 6 h
Confirm anaphylactic event
Urinary metabolite of histamine—elevated for several hours
Serum IgE antibody tests
Acute allergic angioedema
Can be obtained without delay
Acute allergic angioedema
Delay 4 weeks after anaphylactic event
Useful in patients without urticaria to rule out hereditary process
C1 esterase levels
Distinguish type I and type II HAE
Distinguish AAE and HAE
ESR, CBC, ANA, antithyroglobulin, antimicrosomal
Rule out an autoimmune etiology
Further laboratory testing is generally only needed for recurrent, unexplained episodes of angioedema, and in children with a strong family history suggestive of hereditary angioedema. Workup should include an evaluation for possible lymphoproliferative, connective tissue, autoimmune, thyroid, and hereditary disorders. An evaluation for a possible connective tissue disorder may include an erythrocyte sedimentation rate, antinuclear antibody, and complete blood count. Thyroid function tests and antithyroglobulin and antimicrosomal antibody may also be helpful given the association with thyroid disease and chronic angioedema . Complement levels are used to determine if hereditary angioedema is present. Hereditary angioedema shows a low C4 level during attacks; C1-INH level and function are used to distinguish type I versus type II HAE . Acquired angioedema clinically presents similar to hereditary angioedema and shows low C4 levels. The C1q levels are used to distinguish acquired angioedema from HAE. After the diagnosis of acquired angioedema, workup to rule out an underlying malignancy is needed.
Pharmacotherapeutic management of chronic angioedema
Management of chronic angioedema
Addition of Second Generation H1 Receptor Antagonist
Cetirizine, Fexofenadine, Loratadine
Addition of First Generation H1 Receptor
Addition of H2 or H1 plus H2 Receptor Antagonist
Doxepin, Cimetidine, Ranitidine
Add Leukotriene Receptor Modulator
Add oral corticosteroid
Prednisone 10–40 mg/day short course
Dermatology and/or allergy consult
Children with airway symptoms show rapid improvement with intravenous corticosteroids and histamines when compared to adults . It is unclear whether children are simply more responsive to such treatments or whether they have a slower progression of angioedema. More likely it is because of the causes of angioedema, which in children is usually because of food or other mast cell processes that respond better to steroid and antihistamine treatment, whereas in adults, medications are the most common cause, which generally responds to cessation of the drug.
In most cases of angioedema, avoidance of triggers may be the only treatment needed. The mainstay of medical treatment for outpatient management of angioedema is antihistamines. First generation H1 receptor blockers such as diphenhydramine are often used for their rapid onset of action. Second generation H1 receptor antagonists include loratadine and fexofenadine, and are generally preferred secondary to their nonsedating effects and less frequent dosing. If the H1 receptor blocker or second generation H1 receptor antagonists are not adequate for the control of symptoms, the addition of an H2 receptor antagonist such as cimetidine or doxepin, a tricyclic antidepressant with potent H1 and H2 blocking ability, may be helpful [30, 31]. Leukotriene modulators such as montelukast may be helpful in certain patients in terms of reducing swelling and hives and may have a role in the prevention of attacks in the chronic setting [3, 32]. Patients unresponsive to antihistamine treatment may require a short term of low dose oral corticosteroids. Children with a history of urticaria and angioedema should be prescribed and parents taught to use an epinephrine autoinjector. Patients should also be instructed to wear a medical alert bracelet, as well as educated that they may experience recurrent symptoms and instructed on the action to take in such situations.
The efficacy of antihistamines and steroids that are used in mast cell-associated angioedema has not been documented to be effective in angioedema caused by kinin-mediated processes such as ACE-induced angioedema. In ACE inhibitor-induced angioedema, for example, cessation of medication use is crucial, as recurrence with continuation has been well documented. With discontinuation of the drug, symptoms generally resolve within 24 to 48 h. Angiotensin receptor blockers do not affect bradykinin and theoretically should not result in angioedema; they may serve as a good alternative to ACE inhibitors.
In HAE, treatment involves treating acute edematous attacks, short-term prophylaxis, and long-term prophylaxis. In an emergency situation, acute attacks are optimally treated with C1-INH concentrate or fresh frozen plasma, which contains C1-INH concentrate. Prophylactic treatment is via androgens or antifibrinolytics. In pediatric patients, antifibrinolytic agents are the first choice for long-term prophylaxis given the more favorable safety profile when compared to androgens . If antifibrinolytics are ineffective, then attenuated androgens such as danazol and stanazol can be used. The mechanism by which attenuated androgens act is not fully understood although the efficacy in relieving symptoms has been well established. Among adults, danazol reduced the risk of at least one acute episode from 94% to 2.2% over a 28-day period and reduced the frequency of attacks from monthly to one every 10 months . These androgen derivatives notably increase the levels of C4, but they likely have other additional effects as some patients respond before their C4 levels have normalized . Androgens are noted to cause side effects such as weight gain, menstrual irregularities, headaches, hirsutism, tremor, and libido changes. Of particular concern in children are the effects on linear growth, virilization, delay of menarche, and effects on the liver. To limit potential adverse effects, the lowest effective dose should be used. Short-term prophylaxis is needed for procedures such as head and neck surgeries, most notably dental procedures or tonsillectomy in children. Antifibrinolytic agents or attenuated androgens in higher doses may be used; alternatively, C1-INH concentrate may be necessary in a patient with severe attacks in prior situations.
Angioedema is encountered with increasing frequency particularly among children, and it is important to recognize and treat to prevent life-threatening manifestations such as airway obstruction or anaphylaxis. The most common forms of angioedema in children are secondary to mass cell degranulating processes and are self limiting, requiring only a thorough history and possible skin-prick testing to discover external triggers such as food, infection, or medications. There is likely a genetic basis to at least some forms of angioedema but, unlike autoimmune disease, these have not been mapped. In addition, the role of subpopulations of immune cells in the inflammatory response is also poorly described, again, unlike autoimmunity [35–43].
More comprehensive laboratory testing is necessary only for recurrent unexplained episodes of angioedema or in children with a family history of the disease. Although angioedema is still not fully understood, we have made advances in our understanding of the possible causes and clinical course of angioedema. An understanding of these potential mechanisms by which angioedema can occur as well as the chronicity of the angioedema can help guide the clinician in determining the extent of diagnostic testing and the need for acute and prophylactic treatment.