Pediatric Annals

Special Issue Article 

Angioedema

Divya Seth, MD; Deepak Kamat, MD, PhD, FAAP

Abstract

Angioedema is a localized swelling of the skin and submucosal tissues and is generally benign and self-limiting. However, it can be life threatening if angioedema involves the upper airway, resulting in airway obstruction. Airway protection would be critical and lifesaving in patients with angioedema irrespective of the underlying etiology. Detailed history and physical examination can help identify the underlying mechanism of angioedema in an individual patient (ie, mast-cell versus bradykinin-mediated angioedema). Treatment of angioedema depends on the underlying etiology. Mast cell-mediated angioedema is generally responsive to steroids, antihistamines, and epinephrine (when indicated), unlike bradykinin-mediated disease. [Pediatr Ann. 2019;48(12):e473–e478.]

Abstract

Angioedema is a localized swelling of the skin and submucosal tissues and is generally benign and self-limiting. However, it can be life threatening if angioedema involves the upper airway, resulting in airway obstruction. Airway protection would be critical and lifesaving in patients with angioedema irrespective of the underlying etiology. Detailed history and physical examination can help identify the underlying mechanism of angioedema in an individual patient (ie, mast-cell versus bradykinin-mediated angioedema). Treatment of angioedema depends on the underlying etiology. Mast cell-mediated angioedema is generally responsive to steroids, antihistamines, and epinephrine (when indicated), unlike bradykinin-mediated disease. [Pediatr Ann. 2019;48(12):e473–e478.]

Angioedema is a reversible, localized swelling of the skin or mucosal tissues that is caused by mediators that enhance vascular permeability.1 It affects deep dermal and subcutaneous tissues and typically involves the face and extremities. Occasionally, it may involve the submucosal tissue as in the oropharynx, which may be life threatening. The condition can be acute or recurrent. It characteristically occurs in nondependent areas and is asymmetrically distributed. It is often associated with urticaria but may occur in isolation or as a component of anaphylactic reaction. Angioedema is mediated by several mechanisms, including histamine and bradykinin. Diagnosis of the specific type of angioedema is essential for appropriate treatment.

Epidemiology

Angioedema affects both adults and children. In the United States, angioedema or allergic reactions account for more than 1 million emergency department visits annually.2

Results from a study in Denmark found that the prevalence of nonhereditary angioedema is 7.4% and the condition tends to becomes chronic in approximately 50% of patients who are affected.3 There is no clear race predilection; however, African Americans are more prone to develop angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema.4

Clinical Features

Angioedema is nonpruritic and nonpitting. It can involve any part of the body, although face, lips, larynx, extremities, and genitalia are more likely to be affected as the skin is more lax in these areas. Laryngeal involvement can vary from mild edema causing severe respiratory distress and asphyxiation. Involvement of the abdominal wall may present with severe abdominal pain, which could result in unnecessary surgical interventions.

Pathogenesis

Angioedema is mediated by vasoactive peptides (mainly histamine and bradykinin) that cause vasodilation and increased endothelial cell permeability, leading to extravasation of fluid into interstitial tissues. Thus, fluid collects asymmetrically in the affected areas.

Types of Angioedema

Two main types of angioedema can be distinguished: mast cell-mediated angioedema and bradykinin-mediated angioedema (Table 1). However, in most patients, the mechanism remains unclear.

Types of Angioedema

Table 1.

Types of Angioedema

Mast cell activation can result from immunological causes as well as direct activation. Mast cell mediators are released like histamine leukotrienes, which cause vasodilation and increased endothelial permeability. This leads to the development of angioedema, urticaria, and, in severe cases, anaphylaxis. Symptoms develop rapidly upon exposure to the offending agent. In immunoglobulin E (IgE)-mediated reactions, the allergen binds to the IgE, which is present on mast cells. This leads to cross-linking of IgE bound on mast cells and results in mast cell degranulation. Exposure to certain agents (anesthetics, contrast medium, and opiates) results in direct mast cell activation and release of mediators. In most cases of this type of angioedema, a chronologic relationship can be established between exposure to a trigger like food or insect bite and development of symptoms.5 Patients respond well to epinephrine, steroids, and antihistamines.

Bradykinin-mediated angioedema, on the other hand, results from overproduction of or inhibition of bradykinin degradation. Bradykinin is produced from high-molecular weight kinins in the presence of kallikrein, which is activated by mediators such as factor XII of the contact activation system. Bradykinin binds to receptors on the vascular endothelium, which causes vasodilation and increased vascular permeability as well as edema formation.6

C1 inhibitor (C1INH) regulates the production of bradykinin. If C1INH is deficient or dysfunctional, the contact activation system remains activated, which leads to excess bradykinin production.4 There is no associated urticaria and itching because mast cells are not involved. Thus, patients do not improve with epinephrine, steroids, or antihistamines. Gastrointestinal mucosa is often involved in these patients in addition to the typical locations of swelling.

ACEI therapy is the most common subtype of bradykinin-induced angioedema with the prevalence varying from 0.1% to 2.5%.4 Patients may develop symptoms immediately or they may be delayed to several years after starting ACEIs. ACEIs inhibit breakdown of bradykinin to inactive fragments. This results in accumulation of bradykinin as well as prolonged half-life. Occasionally, angioedema attacks may develop several weeks to years after stopping ACEI.7

Hereditary angioedema (HAE) is caused by mutations in the C1INH gene present on chromosome 11.8 The prevalence of HAE varies between 1:10,000 and 1:50,000 in the US.9 HAE is inherited in an autosomal dominant fashion. However, in 25% cases, there is a spontaneous mutation at the C1INH gene.5 Symptoms often begin in childhood and worsen during puberty. HAE can be divided into three subtypes: type 1 HAE (85% cases) is characterized by quantitative C1INH deficiency; type II HAE (15%) is a qualitative C1INH deficiency, where C1INH is normal in quantity but is dysfunctional; and type III primarily occurs in women and is associated with estrogen use or pregnancy. Type III HAE has been associated with a mutation in the factor XII gene. Estrogen can increase transcription of this gene.10

Patients with HAE1 and HAE2 have a similar clinical presentation. Patients experience recurrent episodes of swelling, which affects the skin, mucosa, intestinal tract, or abdominal viscera. There is no accompanying urticaria. Patients may sometimes develop a characteristic rash (eg, erythema marginatum) prior to the onset of angioedema. Attacks usually have a slow onset and may reach maximum intensity over several hours. The cutaneous swellings tend to be nonpruritic and are not usually painful; however, involvement of the abdominal viscera is extremely painful. Patients may present with hypotension, signs of bowel obstruction, and ascites, which may resemble surgical abdomen and could result in unnecessary surgical intervention.11 Swelling of the oral cavity may extend to involve the larynx and may be life threatening. Swelling episodes may be precipitated by minor trauma, particularly dental work,12 infection,13 or emotional stress.

Acquired C1INH deficiency is a rare cause of angioedema that tends to predominantly affect older patients. Clinical presentation is similar to patients with HAE. Type 1 acquired C1INH deficiency occurs due to increased consumption of C1INH by immune complexes. This can be seen in certain pathologic conditions such as lymphoproliferative disorder and/or autoimmune disease (such as monoclonal gammopathy or lymphomas), which may be seen in 15% of the cases.14 In patients with type II acquired C1INH deficiency, anti-C1INH autoantibodies inactivate C1INH, which leads to angioedema.14

Idiopathic Angioedema

Idiopathic angioedema is a term used to describe recurrent episodes of angioedema with or without associated urticaria of unknown etiology. Idiopathic angioedema may be classified into idiopathic histaminergic angioedema and idiopathic nonhistaminergic angioedema. The former may be associated with chronic urticaria. The following are etiologies that may be associated with idiopathic angioedema.

Infections. Infections have been associated with angioedema in children. In a study conducted on children with isolated angioedema, the authors identified infections (21%), allergic etiologies (14%), thyroid autoimmunity with normal thyroid function (8%), and nonsteroidal anti-inflammatory drug (NSAID) use (6%) as the most common causes of angioedema. Among infectious etiologies, common cold or viral infections, streptococcal pharyngitis, and urinary tract infection were more commonly associated with angioedema.15

Disorders with eosinophilia. Angioedema is associated with a peripheral eosinophilia in disorders such as hypereosinophilic syndrome (HES) and Gleich syndrome. A diagnosis of HES should be considered in patients with markedly elevated eosinophil counts (≥1,500 eosinophils/mcL). Angioedema may affect up to 15% of patients with HES. In these patients, angioedema may be mediated by vasodilator mediators released from eosinophils and/or mast cells.16 Patients with Gleich syndrome develop episodic angioedema, with or without urticaria, and have elevated serum eosinophil and IgM levels. The etiology of Gleich syndrome is unknown

Drugs. Certain drugs such as rocuronium, calcium channel blockers, and propofol17–19 can cause angioedema. However, the exact mechanism is not known.

Urticarial vasculitis. Patients with hypocomplementemic urticarial vasculitis can develop angioedema. The urticarial lesions are often painful and purpuric in this condition and may leave residual hyperpigmentation. Fever may be present.

Diagnosis

History

Detailed history should be obtained in patients presenting with angioedema. History should be aimed at identifying possible exposures such as insect stings, foods, or other ingestions prior to the onset of symptoms, as well as any previous episodes of angioedema.

Medication records should be reviewed for (1) ACEI or angiotensin-receptor blockers; (2) NSAIDs; (3) estrogen that can increase the frequency of attacks in patients with HAE); (4) calcium channel blockers; and (5) any new medications or significant increases in doses of medications.1

Patients who have HAE or acquired C1INH deficiency tend to develop recurrent orofacial angioedema after dental work or may have episodes of unexplained abdominal pain. Family history should be obtained to see if other family members have experienced episodes of cutaneous or laryngeal angioedema. However, family history is not always significant as 25% of patients with HAE have a new mutation.5

Laboratory Evaluation

Routine laboratory studies are normal in most cases of angioedema. Laboratory testing in these patients should be based on exposures to suspected trigger as well as the presence of other signs and symptoms. They may be helpful in the identification of any allergy, complement disorder, or other systemic conditions.

Isolated Angioedema

Complete blood count, including differential, basic chemistry panel with liver function tests, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and levels of the complement protein C4, should be obtained.

Patients who have low C4 levels should be evaluated for hereditary or acquired C1 inhibitor deficiency. C1INH deficiency or dysfunction leads to low C4 levels as C4 is normally cleaved by C1 complex during the classical complement pathway. This is exaggerated if C1INH is deficient. Thus, C4 level can be used as a screening test for deficiency of C1INH.

C1INH level and function should be obtained when patients are being evaluated for HAE or acquired C1 inhibitor deficiency (when there is lack of response to antihistamines or positive family history). CRP and ESR may be markedly elevated during infections (particularly bacterial) and inflammatory conditions.20 These conditions can sometimes be associated with angioedema.

Angioedema Associated with Urticaria/Anaphylaxis

Laboratory tests have limited value in evaluation of patients who present with angioedema associated with urticaria/anaphylaxis. Serum tryptase levels are usually elevated, which is suggestive of mast cell-mediated disease.21

However, when an allergic etiology is suspected, such as a food or drug allergy, patients should be evaluated by an allergy specialist and may need to be provided with epinephrine for self-injection. In these patients, skin prick test or serum tests for allergen-specific IgE antibodies should be obtained as suggested by the patient's history to identify the allergen.

Differential Diagnosis

Several conditions may mimic angioedema as shown in Table 2. In patients with contact dermatitis and cellulitis, the affected area is painful and erythematous. Head and neck tumors can cause protracted facial swelling and venous engorgement resulting in superior vena cava syndrome, which can also mimic angioedema of the face. Laryngeal edema may be seen in infections (eg, tonsillitis). Bowel wall edema could also result from inflammatory bowel disease, mesenteric infarction, vasculitis, and infections (eg, viral/bacterial).

Differential Diagnosis of Angioedema

Table 2.

Differential Diagnosis of Angioedema

Treatment

Because angioedema can progress rapidly and can be life threatening, airway protection is critical. Once the airway is stabilized, then further treatment can be guided by determining the underlying mechanism. When possible, history should be obtained to identify the cause of angioedema, family history, and past history of similar episodes. Short-term prophylaxis can be used prior to any surgical or dental procedure in patients with HAE. Long-term prophylaxis tends to be more suitable in patients who experience frequent attacks affecting their quality of life.

Upper Airway Management

Patients who present with angioedema of oral cavity including tongue, uvula, soft palate, or larynx must be promptly assessed for any signs of airway compromise. In such cases, mechanical intervention (intubation or cricothyrotomy/tracheotomy) would be lifesaving. However, in the absence of any airway compromise, treatment should be based on presumed etiology.

Angioedema with Anaphylaxis

Anaphylaxis should be promptly treated with intramuscular epinephrine. Adjuvant drugs include corticosteroids, which help to suppress inflammatory mediators. Antihistamines such as diphenhydramine help to reduce histamine-related effects such as itching. Intravenous fluids and oxygen should be used in patients with airway involvement and low blood pressure.

Mast Cell-Mediated Angioedema

Treatment of this type of angioedema includes using both H1 and H2 blockers as well as oral corticosteroids. These medications suppress the effects of histamine and other inflammatory mediators. The recommended dose of prednisone in children is 0.5 to 1 mg/kg/day, which can be tapered over 5 to 7 days.

Bradykinin-Mediated Angioedema (Hereditary Angioedema)

In patients with bradykinin-mediated angioedema, therapy should aim to prevent the production of bradykinin or reduce its effect (Table 3). Fresh-frozen plasma (FFP) provides C1INH and thus can be used to treat acute attacks. However, adverse effects are common and include hypersensitivity reactions as well as transmission of blood-borne pathogens even though the risk is low.

Medical Management of Hereditary Angioedema

Table 3.

Medical Management of Hereditary Angioedema

Attenuated androgens such as danazol stimulate production of C1INH by the liver, and help to reduce the frequency of attacks in most cases.22 Side effects are related to the androgenic effects of these drugs and can affect compliance.

Fibrinolysis inhibitors such as tranexamic acid have been shown to be effective in some patients.23 The mechanism of action involves decreased peripheral consumption of C1INH. However, fibrinolysis inhibitors are not effective in acute settings.

Bradykinin-mediated angioedema responds well to C1 inhibitor concentrate and other drugs that prevent the production or action of bradykinin. The latter includes ecallantide (kallikrein inhibitor)24 and icabitant (a bradykinin-B2-receptor antagonist).25

Various C1 inhibitor concentrate preparations are currently available. These include plasma-derived products and recombinant concentrates. Of these, Berinert and Ruconest are approved for treatment of acute attacks, whereas Cinryze is approved for prophylactic use. It has not been approved for acute attacks even though it has efficacy. Plasma-derived C1 inhibitor concentrates have been shown to be effective in treatment of angioedema attacks that occur at different sites. Patients start experiencing improvement in their symptoms after 30 to 120 minutes. There is complete resolution of symptoms over 24 hours. Treatment should be initiated earlier in the course of attack for maximal relief of symptoms.26

Acquired Angioedema

Management of acquired angioedema is similar to that of HAE. C1-inhibitor concentrates can be used for acute attacks, although occasionally high doses are required.27 Kallikrein or bradykinin receptor antagonists are also useful in these patients. Treatment of the underlying condition is also effective in prevention of attacks, and in some cases may normalize complement levels.28

Angiotensin-Converting Enzyme Inhibitor–Induced Angioedema

Treatment primarily involves stopping the ACEI and monitoring for improvement. Some patients may benefit from use of FFP. As in other cases, the airway must be protected if swelling involves the oral cavity.

Idiopathic, Recurrent Angioedema

Idiopathic, recurrent angioedema may show response to antihistamines in case of mast cell-mediated disease. Patients may require higher than recommended doses (2–4 times) to prevent further episodes. Non–mast cell-mediated disease does not respond to antihistamines. Such patients should be referred to an allergy specialist for further evaluation.

Summary

Angioedema typically affects the skin and mucosal tissues of the face, lips, mouth and throat, larynx, extremities, and genitalia, often in an asymmetric pattern. Angioedema can also affect the bowel wall and present as colicky abdominal pain. Angioedema may occasionally be life threatening. Immediate assessment and protection of the airway is essential in the patient with angioedema, affecting the larynx, tongue, mouth, or soft palate.

Two types of angioedema can be distinguished: mast cell-mediated angioedema (allergic reactions) and bradykinin-mediated angioedema (ACEI-induced angioedema, HAE). However, angioedema may be idiopathic in some cases.

The treatment of angioedema depends upon the severity and the underlying mechanism (mast cell- or bradykinin-mediated). Mast cell-mediated angioedema responds to antihistamines, and glucocorticoids, and in severe cases may require the use of epinephrine. In contrast, bradykinin-mediated angioedema responds to C1 inhibitor concentrate, FFP, and other agents that interfere with the production or action of bradykinin

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Types of Angioedema

Characteristics Mast Cell-Mediated Bradykinin-Mediated
Onset and duration Minutes to hours, symptoms resolve within 24–48 hours 24–36 hours, symptoms resolve within 2–4 days
Urticaria and anaphylaxis Yes No
Triggers Insect stings, food, medications (ie, NSAIDs) Medications (ie, ACE-I), hereditary angioedema, acquired angioedema
Family history of angioedema No Most cases
Response to antihistamines Yes No
Treatment Antihistamines, steroids, epinephrine Bradykinin pathway inhibitors (icatibant, ecallantide), C1 inhibitor concentrate, or plasma replacement

Differential Diagnosis of Angioedema

Disorder Clinical Manifestations
Contact dermatitis Pain, erythema, pruritus, and burning of the skin due to delayed hypersensitivity reaction. Resolution may be followed by peeling of skin
Cellulitis Infection of skin associated with erythema, pain, and fever
Autoimmune conditions (lupus, polymyositis) Persistent swelling of the face, periorbital areas associated with other systemic rheumatologic findings
Hypothyroidism Facial and lip swelling or generalized edema
Superior vena cava syndrome and tumors Edema of face and neck as well as venous engorgement related to head and neck tumors and lymphoma
Laryngeal edema Infections (tonsillitis, peritonsillar abscess) and pharyngeal foreign body
Bowel wall edema Inflammatory bowel disease, mesenteric infarction, vasculitis, infections (Yersinia, Campylobacter)

Medical Management of Hereditary Angioedema


Route of Administration Adverse Effects
Prophylaxis drug
Attenuated androgens Orally Virilising effects
C1 inhibitor concentrate Intravenous Subcutaneous Dysgeusia Hypersensitivity reactions, nasopharyngitis, and dizziness
Treatment
Icatibant Subcutaneous Rash, headache, fever
Ecallantide Subcutaneous Rash, headache, fever
C1 inhibitor concentrate Intravenous Thrombosis, headache, vertigo, diarrhea
Fresh-frozen plasma Intravenous Hypersensitivity reactions, fluid overload, bloodborne infections
Authors

Divya Seth, MD, is an Assistant Professor, Division of Allergy/Immunology, Wayne State University School of Medicine, Children's Hospital of Michigan. Deepak Kamat, MD, PhD, FAAP, is a Professor of Pediatrics, University of Texas Health Science Center at San Antonio.

Address correspondence to Deepak Kamat, MD, PhD, FAAP, Professor of Pediatrics, University of Texas Health Science Center at San Antonio, 7635 Hays Hill, San Antonio, TX 78256; email: kamatd@uthscsa.edu.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20191118-01

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