Pediatric Angioedema 

Updated: Aug 08, 2017
Author: Shih-Wen Huang, MD; Chief Editor: Harumi Jyonouchi, MD 

Overview

Background

Angioedema is a subcutaneous extension of urticaria, resulting in deep swelling within subcutaneous sites. In contrast, urticaria results from transient extravasation of plasma into the dermis, causing a wheal characterized by tense edema with or without redness.

Angioedema can occur with generalized urticaria if the tissue swelling has indistinct borders around the eyelids and lips. In addition, when the swelling of urticaria extends to the face, hands, feet, and genitalia, the clinical manifestation may be called angioedema. As many as 50% of children who have urticaria exhibit angioedema, with swelling of the hands and feet.

Classification of angioedema

Based on the current clinical understanding of angioedema, dividing cases into the following types is useful:

  • Hereditary angioedema type 1 (HAE1)

  • Hereditary angioedema type 2 (HAE2)

  • Hereditary angioedema type 3 (HAE3)

  • Acquired angioedema type 1 (AAE1) (very rare; only a few reported cases)

  • Acquired angioedema type 2 (AAE2) (very rare; only a few reported cases)

  • Nonhistaminergic angioedema (INAE) (may occur in approximately 1 of 20 angioedema cases)

  • Idiopathic angioedema

  • Allergic angioedema (most common form)

  • ACE inhibitor–induced angioedema (4-8% of cases)

Hereditary angioedema (HAE) accounts for only 0.4% of angioedema cases; however, the specific diagnostic tests and high mortality rate associated with hereditary angioedema deserve special attention.

In 1876, Milton described the first case of hereditary angioedema. Six years later, Quincke introduced the term angioneurotic edema to describe this disease. Later, Osler described the disease as episodic bouts of well-circumscribed nonpitting subepithelial edema that primarily involved the extremities, larynx, face, and abdomen.

Hereditary angioedema is an autosomal dominant disease usually associated with a positive family history of angioedema. However, numerous cases are due to a new mutation of the gene.

In approximately 80-85% of hereditary angioedema cases, serum levels of C1 inhibitor (C1INH) are decreased to approximately 30% of reference range values. In contrast, about 15% of patients with hereditary angioedema have reference range levels of antigenic, but mostly nonfunctional, C1INH. Missing or nonfunctional C1INH leads to failure in controlling the enzymatic activity of C1, resulting in lower levels of the early-acting complement components C4 and C2 because of overconsumption.

No close relationship between plasma C1INH levels and the severity of attacks has been noted. Some patients with very low C1INH levels have few attacks, whereas others with much higher levels of C1INH have much more severe disease.

HAE1 (low levels of functional C1INH) may be due to a wide range of gene mutations. In HAE2 (reference range or even increased levels of antigenic but nonfunctional C1INH), different point mutations have been described within or near the reactive center of the C1INH gene (SERPING1). (See the image below.)

The mechanism of angioedema resulting from C1-este The mechanism of angioedema resulting from C1-esterase inhibitor deficiency.

The structural abnormalities in the SERPING1 genes in patients with hereditary angioedema have been found to be very heterogeneous. More than 150 mutations have been reported in unrelated patients. Agostino et al have reported on the details of genetic analysis.[1]

HAE3 is the most recently described type of hereditary angioedema. In HAE3, C1INH function and complement components are normal.[2] Mutations in the gene that encodes coagulation factor XII (Hageman factor) have been found in some patients with HAE3.

Essential features of HAE3 include the following:

  • A long history of recurrent skin swelling, attacks of abdominal pain, or episodes of upper airway obstruction

  • Familial occurrence, exclusively in female members of the family

  • No history of urticaria in the patient or other family members

  • Normal C1INH and C4 concentrations in the plasma

  • Failure to respond to antihistamines, corticosteroids, or C1INH concentrate

AAE1 is usually linked to an underlying lymphoproliferative disorder. Complement-activating factors, idiotype/anti-idiotype antibodies, or other immune complexes associated with the underlying disorder destroys the function of C1INH. The onset of angioedema can precede other symptoms of a lymphoproliferative disease; thus, exploring the possibility of underlying malignancy in cases of AAE1 is vital.

AAE2 is associated with autoantibodies that directly inhibit C1INH function. No underlying disorder is apparent. AAE1 and AAE2 are very rare in the pediatric population.

INAE angioedema is angioedema without urticaria. Patients usually do not respond to H1 blockers (antihistamines). Parasites, infections, and autoimmune diseases are not present.

The idiopathic form of angioedema may be associated with swelling, hives that persist longer than 6 weeks, or both. Thyroid dysfunction should be considered.

Allergic angioedema is characterized by swelling, hives, or both in reaction to environmental factors such as food, an insect sting or bite, cold, heat, latex, or a drug. Usually, these environmental factors provoke histamine release that leads to swelling, hives, or both.

Angioedema can also be caused by ACE inhibitors (eg, captopril, enalapril, genzapril, quinapril, ramipril) used to treat high blood pressure. Swelling may begin a few hours to years after first starting the medication.

For other discussions on angioedema, see the overview topics Acquired Angioedema and Hereditary Angioedema.

Pathophysiology

The pathophysiology of urticaria-associated angioedema is fully discussed in Urticaria.

The cause of angioedema in patients with hereditary angioedema is still unknown. One hypothesis involves persistent activation of C1, resulting in ongoing cleavage of the next 2 components of the complement cascade, C4 and C2. According to this hypothesis, cleaved C2 is acted on by other proteolytic enzymes (possibly plasmin), generating a kinin-like molecule that causes angioedema. Involvement of local mediators is virtually uncertain.

A second hypothesis is that angioedema attacks are caused by activation of the kinin-generating system, which involves cleavage of high-molecular-weight kininogen by activated kallikrein with attendant formation of bradykinin. Bradykinin is believed to be responsible for angioedema episodes.

In hereditary angioedema, 2 phenotypic variants have been described. HAE1 may be due to a wide range of gene mutations, resulting in either a lack of messenger RNA transcription or transcription in abnormal messenger RNAs that are not translated into a stable protein. In HAE2, different point mutations have been described within or near the reactive center, resulting in different dysfunctional proteins.

AAE is due to the production of a C1INH-consuming factor by malignant cells. In fact, most cases of acquired C1INH-deficient angioedema have been associated with the presence of a lymphoid or other malignancy. In rare cases, C1INH deficiency could be due to consumption by the immune complex during the course of an autoimmune disease. Another type of C1INH deficiency is the result of monoclonal or oligoclonal production of antibodies that appear to recognize C1INH and destroy its functional activity.

The fluctuations in sex hormone levels at the beginning of adolescence, in the perimenopausal period, during pregnancy, or during the use of oral contraceptives can precipitate edematous attacks in hereditary angioedema. One study indicated that the number of attacks was significantly higher in females with high progesterone levels (≥4 nmol/L); a significantly lower attack frequency was noted in patients with a higher (40 nmol/L) sex hormone–binding globulin (SHBG) level.[3] Thus, monitoring these 2 hormonal levels may be useful in predicting attacks in patients with hereditary angioedema.

Studies on the function of C1INH have helped further the understanding of angioedema pathophysiology. C1INH controls activation of the complement system by inhibiting the esterase activity of C1r and C1s in the classic pathway and the esterase activity of mannan-binding lectin serine peptidase 2 (MASP2) in the mannose-binding lectin pathway.

The second major physiological role of C1INH is now believed to be regulation of the contact system, where it intervenes and inhibits activated coagulation factor XII and kallikrein. In addition to these 2 major functions, C1INH inhibits factor XI, plasmin, and the tissue plasminogen activator (tPA). The relevance of these activities in vivo remains controversial. However, convincing in vivo evidence supports the activation of plasminogen in humans by factor XIIa.

HAE3 has been exclusively observed in women, in whom it appears to be correlated with high estrogen levels (eg, pregnancy, the use of oral contraceptives). One report proposed 2 missense mutations (ie, c.1032C→A and c.1032C→G) in F12, the gene that encodes human coagulation factor XII (Hageman factor), as a possible cause of HAE3.[4] Transcription of F12 is positively regulated by estrogens, which may explain why only women are affected by HAE3.

Another extensive family study of HAE3 was reported. In this family a missense mutation Thr309Lys was identified in the factor XII gene with a heterozygotic pattern.[5] This mutation was also identified in the mother of the patient, her daughter, and her son.

Along with the 5 German and French families that have been reported for HAE3, a large Italian family was also reported from Canada.[6] A missense mutation in F12 was present in the 3 affected female subjects of this family who had estrogen-dependent inherited angioedema.

In addition, these affected females have polymorphisms associated with lower levels of both aminopeptidase and angiotensin-1 converting enzyme, the major enzymes responsible for bradykinin degradation. Thus, multiple genes may contribute to estrogen-dependent or estrogen-associated angioedema, leading to the observed heterogeneity of clinical features.

Etiology

Hereditary angioedema (HAE) is an autosomal dominant condition. In approximately 50% of cases, clinical manifestations may appear during childhood.[7] Risk factors for HAE episodes include trauma, such as surgery, dental manipulation, or accidents. Episodes of HAE are the result of unopposed complement activation and/or activation of the kinin generating system due to the C1INH deficiency.

In HAE type 3, a fluctuation of sex hormones has been speculated to precipitate HAE attacks.

In 2010, the international consensus algorithm for the diagnosis, therapy, and management of HAE was updated.[8] The consensus approach is only an interim guide to HAE, which is a complex disorder. This consensus should be replaced as soon as possible with large phase lll and IV clinical trials, meta-analyses, and database registry validation of approaches, including quality-of-life and cost-benefit analyses, followed by large head-to-head clinical trials and then evidence-based guidelines and standards for HAE disease management.

Diagnosis and treatment of HAE with normal C1 inhibitor (originally reported as HAE type 3) was recently reviewed by Bork.[9] Most of the patients were women. In many of the affected women, oral contraceptives, hormone therapy containing estrogens, and pregnancies triggered the clinical symptoms. Recently, in some families, mutations in the coagulation factor Xll (Hageman factor) gene were detected in the affected persons.

Acquired forms of angioedema are commonly associated with lymphoproliferative disorders or malignancy. They are relatively uncommon in pediatric patients. The known cause of angioedema has been increasingly reported in clinical practice. Therefore, it is prudent to consider those possibilities when inciting agents are used on patients.

Patients taking ACE inhibitors, which are rarely used in children, may experience episodic angioedema. The cause of acquired angioedema in patients using ACE inhibitors is believed to be the accumulation of bradykinin, which is subject to breakdown by ACE. ACE inhibitors help build up bradykinin levels in the tissue.

A severe case of angioedema was reported in a patient who received treatment with rituximab for rheumatoid arthritis.[10] Angioedema was reported after intravitreal bevacizumab was injected into the eye for the treatment of cystoid macular edema. The angioedema recurred when the patient received the same drug in the other eye later. It was the first report of a systemic reaction with this agent.[11]

Angioedema was reported in a female when she had the first exposure to hair dye. It contained paraphenylenediamine (PPD). Related compounds have been used in black henna tattoos, are widely used.[12]

Bedbug (insect family Cimicidae) infestation is now known to cause systemic reactions, including angioedema. Thus, an integrated pest management strategy should be used to eliminate infestation.[13]

Epidemiology

Urticaria-associated angioedema occurs in nearly 50% of children who have urticaria. Because urticaria occurs in 2-3% of children, urticaria-associated angioedema is estimated to occur in 1-2% of the general population.

The frequency rate of hereditary angioedema diseases is currently unknown. Current estimates suggest that the disease affects 1 in 10,000-50,000 persons. An estimated 5,000 to 25,000 patients in the United States have HAE1. The exact frequency of HAE2 is unknown, but the ratio of HAE1 to HAE2 is 85:15. In the past 5 years, the number of spontaneous mutations in newly diagnosed hereditary angioedema cases has increased 50%, indicating the need for more accurate epidemiologic data.

No epidemiologic data are available for acquired C1INH deficiency because these patients have only been described in case reports. No epidemiologic data are currently available regarding patients with HAE3.

Race-, sex-, and age-related demographics

No racial differences are known in most forms of angioedema. However, African Americans are at increased risk for ACE inhibitor–related angioedema.

Urticaria-related angioedema has no known sex differences. Hereditary angioedema is an autosomal dominant disorder and affects both sexes. HAE3 has been exclusively reported in females; the influence of an X-linked gene on the generation of vasoactive peptides has been speculated.

Urticaria-related angioedema has no known age differences. Clinical manifestations of hereditary angioedema are more common beyond the teenaged years.

Prognosis

Urticaria-associated angioedema is generally self-limited in pediatric patients. In patients with hereditary angioedema, the onset of symptoms frequently occurs during the teenage years. Morbidity varies from case to case. In some patients, acute attacks occur once every several years, whereas attacks in others occur several times a year. Morbidity changes after therapy begins.

Sudden onset of severe laryngeal edema can lead to death. In the past, the mortality rate for attacks involving the upper airways exceeded 25%. Severe abdominal pain may sometimes subject the patient to unnecessary surgery.

Patient Education

The following aspects of patient education should be considered:

  • Patients should be closely monitored by specialists for lifelong care

  • Patients should be careful to avoid trauma

  • Patients should wear a MedicAlert bracelet or carry an identification card at all times

  • Patients should keep up with prophylactic medication

More information is available from the Hereditary Angioedema Association.

For patient education information, see the Allergy Center and Skin, Hair, and Nails Center, as well as Hives and Angioedema.

 

Presentation

History

Hereditary angioedema is characterized by episodic attacks that generally last 1-4 days. Attacks typically involve the extremities, the abdomen, or the throat.

The extremities are the most common site of attacks. Swelling is usually brawny and is not associated with urticaria, pruritus, or pain.

Abdominal attacks are due to edema in the submucosa and serosa of the bowel wall and are often associated with nausea, vomiting, and severe pain, but not with diarrhea. Abdominal pain may resemble that of acute abdomen.

Episodes involving the throat are the most dangerous manifestation of angioedema. Edema of the upper airway may progress rapidly and result in asphyxiation.

Angioedema episodes may occur spontaneously or may be triggered by trauma, particularly the injection of an anesthetic (eg, in dental procedures, during tooth extraction), or even emotional stress. Approximately one half of patients with hereditary angioedema have attacks precipitated by trauma; interestingly, the other half do not.

In hereditary angioedema, initial manifestations occur in children at a median age of 4.8 years (range, 3-9.7 y). Angioedema attacks occur by age 13 in most hereditary angioedema cases and may increase in severity after puberty. Attacks occur more often with sex hormone fluctuation, with more severe symptoms associated with menses.

Only 25% of patients provide a positive family history. However, patients may have a family history of abdominal pain and unexplained diarrhea or of sudden death from asphyxia. In the past, the mortality rate for attacks involving the upper airways exceeded 25%. Patients live with the constant threat of life-threatening laryngeal obstruction.

The acquired form of angioedema (AAE1 or AAE2) may present like classic hereditary angioedema, except for the age of onset. Usually, this type of angioedema occurs in the fourth decade of life or later. Because it is an acquired defect, a family history is negative for angioedema.

The idiopathic form of angioedema may cause swelling anywhere in or on the body and may be accompanied by urticaria (hives).

Swelling due to nonhistaminergic angioedema (INAE) may occur anywhere, including the face, arms, legs, genitalia, throat, and abdomen, although abdominal symptoms are far less common than in those with hereditary angioedema. Furthermore, symptoms do not change with menstrual period or pregnancy.

Allergic angioedema may cause swelling, most often in the face and throat. Urticaria (hives) is often present. If the condition persists longer than 6 weeks, it is considered chronic idiopathic urticaria and is not a classic allergic reaction.

In patients with ACE-inhibitor–induced angioedema, swelling may occur just about anywhere, including the throat, face, lips, tongue, hands, feet, genitalia, and intestines. Urticaria (hives) is very rare in this form of angioedema. A recent report describes a patient who used ACE-inhibitors for 3 years who suddenly developed penile angioedema.[14]

Three cases of small bowel angioedema were reported after the patients were given intravenous iodinated contrast media. It is most evident in the venous phase of the CT images. None of the patients would require specific treatment.[15]

Physical Examination

If a patient has urticaria-related angioedema, lesions appear as large swellings with indistinct borders around the eyelids and lips. They may also appear on the face, trunk, genitalia, and extremities. The face, hands, and feet are involved in 85% of patients; other areas are involved in 15%. As many as 50% of children with urticaria exhibit angioedema with swelling of the hands and feet.

Patients with hereditary angioedema have associated repeated attacks of swelling of extremities, face, and throat accompanied by abdominal pain. Edematous swelling of the skin is not accompanied with itching but causes an unpleasant sensation of distension within the involved lesion.[16]

A generalized, nonpruritic skin rash (erythema marginatum) may be observed in 8% of children prior to the onset of an angioedema attack.

Angioedema manifests as a diffuse brawny swelling of the extremities in 75% of patients, abdominal pain in 52%, and swelling of the face and throat in 30%. Patients do not have typical urticarial wheals but exhibit targetlike lesions. Abdominal pain eventually becomes a major symptom in 93% of patients. Severe airway edema accounts for the almost 30% mortality rate in untreated patients.

Angioedema associated with ACE inhibitors affects fewer than 5% of patients taking these drugs. Affected patients experience episodic swelling of the lip or face, or tissue swelling on any part of the body; it is not usually accompanied by pruritus or pain.

Evidence of impaired sense of smell in hereditary angioedema has been reported. Using 3-stages Sniffin'-Sticks kit, Perricone et al observed a significant decrease in olfactory function observed in patients with hereditary angioedema compared with controls, as measured by threshold, discrimination, and identification (TDI) scores. Anosmia was present only in hereditary angioedema patients (3.3%). In addition, reduction of olfactory function in these cases seems to correlate with complement C4 and CH50 levels. This suggests that immune and genetic mechanisms might play a role in this defect.[17]

 

DDx

Diagnostic Considerations

A variety of other diagnostic possibilities should also be considered in children with possible angioedema.

For other discussions on angioedema, see the overview topics Acquired Angioedema and Hereditary Angioedema.

Cellulitis

Usually, this is caused by gram-positive bacterial infection. Pain and fever are common.

Erysipelas

This is caused by group A beta streptococci. Tenderness, fever, and redness are common.

Lymphedema

Chronic thickening of tissues occurs in lymphedema. This contrasts with the acute stretching of tissue observed in angioedema.

Collagen vascular disorders

Patients with systemic lupus erythematosus (SLE) or other collagen vascular disorders should have a history of systemic illness, indicating the presence of vasculitis. Laboratory findings reflect features of chronic inflammatory conditions.

Acute contact dermatitis

In acute contact dermatitis, the patient has a history of contact with sensitizing agents. The rash is always accompanied by intense pruritus.

Idiopathic scrotal edema in children

The etiology of this disorder is unknown, but swelling is limited to the scrotal area. Rarely, it causes systemic symptoms.

Rosenthal-Melkersson syndrome

In this rare neurologic disorder, recurrent facial edema, recurrent peripheral facial nerve palsy, and remarkable fissuring of the tongue are characteristic. Onset is in childhood or early adolescence.

Laryngeal swelling due to anaphylaxis

Most patients have a history of intense allergic diathesis. The anaphylaxis may be caused by ingestion of food, drugs, insect sting, or latex allergy. Idiopathic anaphylaxis, which is rare in children, may occasionally cause difficulty in the differential diagnosis.

Surgical abdomen

Severe pain caused by hereditary angioedema can be difficult to distinguish from conditions leading to surgical abdomen. The latter include intestinal obstruction and appendicitis. In addition, Crohn disease may cause chronic pain and diarrhea. History and physical examination should be helpful to distinguish those conditions with the aid of imaging studies.

Angioedema with eosinophilia

A total of 11 patients were reported from Japan. They were reported selectively in young females. The common features are angioedema with eosinophilia (eosinophil count of 7,839 +/- 6,008). Serum C-reactive protein and immunoglobulin E levels remained normal. They improved within 8 weeks, even without corticosteroid therapy.[18]

Differential Diagnoses

 

Workup

Approach Considerations

The diagnostic workup for urticaria-related angioedema is the same for urticaria. Perform an immunoglobulin E (IgE) antibody skin test or radioallergosorbent test (RAST) if the history is suggestive of a rash caused by foods, drugs, insect venom, or latex.

Obtain a bacterial culture with sensitivity if the patient has a history of fever and sore throat.

Obtain a thyroid profile, antithyroid microsomal antibodies, and antithyroglobulin antibody if the patient has a strong family history of thyroid disorder or symptoms of hypothyroidism; this is more frequent in females. However, patients are often euthyroid.

Measure C1 inhibitor (C1INH) and C3 and C4 levels if the patient has a family history of angioedema.

Obtain stool for ova and parasites if the patient reports ingestion of poorly cooked meats or travel in unsanitary areas.

Perform antinuclear antibody testing and urinalysis with microscopic examination if the patient may have arthritis, photosensitivity, or other signs or symptoms of collagen vascular disease.

Obtain a complete blood cell count (CBC) with differential, C-reactive protein level, and erythrocyte sedimentation rate if the patient's history indicates underlying vasculitis or inflammatory diseases.

Other Tests

Acquired angioedema (AAE) is characterized by low functional C1INH levels, low C4 levels, and C3 levels within the reference range. Concentration of C1q is often very low.

Plasma levels for the diagnosis of hereditary angioedema (HAE) include the following:

  • C4 level less than 14 mg/L (diagnostic)

  • C1q level greater than 77 mg/L

  • C1INH (antigenic) level less than 199 mg/L (diagnostic)

  • C1INH (functional) level less than 72% of the reference range (diagnostic)

The summary of complement profiles in different forms of angioedema is as follows:

  • HAE1: C1INH levels are low; C4 levels are almost always low and can be used as the first step of screening; C1, C3, and C1q levels are all within the reference range. These changes are seen in both hereditary and spontaneous mutation conditions.

  • HAE2: C1INH levels may be normal or elevated but are dysfunctional; C1, C3, and C1q levels are within the reference range, but C4 levels are almost always low.

  • HAE3: The complement profile is normal.

  • AAE1: C1INH and C4 levels are low. C1q levels are usually, but not always, reduced.

  • AAE2: The findings are the same as in AAE1. Autoantibody testing may be appropriate.

  • Idiopathic angioedema: The complement profile is normal.

  • Nonhistaminergic angioedema (INAE): The complement profile is normal.

  • Allergic angioedema: The complement profile is normal.

  • ACE inhibitor–induced angioedema: The complement profile is normal.

Prothrombin fragment (F1 + 2) and D-dimer levels may have an important diagnostic value. A study in 28 patients with C1INH deficiency during acute attacks and remission, in 35 patients without C1INH deficiencies during abdominal colic, and in 20 healthy subjects found high levels of these biomarkers during acute angioedema attacks in patients with C1INH deficiency.[19]

Ultrasonography

Ultrasonography of the GI tract may help differentiate between HAE and conditions of surgical abdomen.

In hereditary angioedema, ascites and edema of the intestinal walls are present in more than 80% of patients during acute attacks.

 

Treatment

Approach Considerations

Farkas advised that management of hereditary angioedema (HAE) in pediatric patients differs in many respects, is different from the management of adults. He recommends prompt control of edematous attacks, short-term prophylaxis, and intermittent therapy as the primary means for the management of pediatric HAE.

Currently, antifibrinolytics, attenuated androgens, and C1INH replacement therapy are used for the treatment of children with HAE. Antifibrinolytics are recommended for long-term prophylaxis because of their favorable safety profiles, but efficacy may be lacking. Attenuated androgens administered in the lowest effective dose are another option. C1INH replacement therapy is also effective and safe for children. Regular monitoring and follow-up of patients is highly recommended.[7]

Episodes of acute subcutaneous angioedema affecting the extremities in patients with known HAE are called peripheral attacks. In the past, those patients are considered to be of limited clinical significance. One report indicated aggressive treatment with recombinant human C1INH rapidly altered the outcome of the patients compared with conservative management.[20]

A case of acquired angioedema can cause severe abdominal pain mimicking an acute surgical abdomen. This disorder is strongly associated with chronic lymphocytic leukemia and other indolent lymphoplasmacytic disorders.[21]

Two recent review articles addressing the diagnosis and treatment of angioedema worldwide[22] and an outlined, stepwise management of HAE patients in the emergency department[23] should be of great assistance to clinicians when they approach patients with HAE.

For other discussions on angioedema, see the overview topics Acquired Angioedema and Hereditary Angioedema.

Preventive Measures

Ideally, episodes of swelling should be prevented with long-term or short-term prophylaxis. Once an angioedema episode occurs, mediators that increase vascular permeability have already been released, and intervention measures can only (possibly) reduce the severity or duration of the attack. Therefore, treatment is aimed at preventing attacks.

Successful pharmacologic approaches have included prevention of the activation of kinin-releasing enzymes or increasing the blood level of normal C1INH. Androgens and antifibrinolytic agents are frequently used to achieve this goal. C1INH concentrate (Cinryze) for IV prophylaxis, especially before surgery, has been used.[24]

In June 2017, the FDA approved the first subcutaneous C1 esterase inhibitor (Haegarda) for prevention of HAE attacks in patients aged 12-72 years. Approval was based on the phase 3 COMPACT trial (n=90), which showed C1-INH 60 IU twice weekly SC reduced the median number of HAE attacks by 90% compared with placebo. The study also showed use of rescue medication was reduced by >99% versus placebo.[37]

Treatment of Acute Angioedema

Minor episodes of subepithelial swelling need no treatment, but the patient with edema of the face and neck should be closely observed for spread of edema and signs of airway involvement. When hoarseness or other signs of a compromised airway occur, an otolaryngologist should be consulted for possible tracheostomy. This procedure is usually not needed but is sometimes a life-saving measure.

Berinert is a freeze-dried C1 esterase inhibitor derived from human plasma.[25] This agent was approved in the United States for treatment of acute abdominal attacks and facial swelling in adolescents and adults in September 2009. Berinert was also approved for acute treatment of laryngeal HAE in January 2012. Use was expanded to include children younger than 12 years in July 2016. Its long half-life may provide an extended a period of protection, even after the symptoms of an attack have subsided.[26]

The recombinant C1 esterase inhibitor (rhC1-INH), Ruconest, was approved by the Food and Drug Administration (FDA) in July 2014. It is indicated for adolescents and adults to treat acute attacks of HAE. Effectiveness was not established in patients with HAE that involved laryngeal attacks. Approval was supported by a phase 3 trial (n=75) that showed relief of symptoms of HAE attacks was achieved faster with rhC1-INH compared with placebo as assessed by patient questionnaire and visual analog scale.[27]

In December 2009, ecallantide (Kalbitor) was approved by the FDA for treating acute HAE attacks. During attacks, unregulated plasma kallikrein activity results in excessive bradykinin generation, resulting in swelling, inflammation, and pain. Ecallantide is a potent, selective, reversible inhibitor of plasma kallikrein, thereby reducing the conversion of kininogen to bradykinin. In April 2014, the FDA expanded approval of ecallantide to children aged 12 years or older.

Cicardi et al observed significantly better outcome scores in patients treated for acute attacks of angioedema with ecallantide compared with placebo.[28] This was a double-blind, placebo-controlled trial in 71 patients.

Another treatment that may be beneficial is an oropharyngeal spray of a 1:1000 dilution of racemic epinephrine (0.2-0.3 mL). However, one study indicated that fewer than 27% of patients with HAE considered that the epinephrine injection was effective during acute attack.[16]

Icatibant (Firazyr), a selective bradykinin B2 receptor antagonist, was approved by the US Food and Drug Administration for treatment of acute attacks HAE in adults. Approval was based on 3 double-blind, randomized, controlled clinical trials known as For Angioedema Subcutaneous Treatment (FAST) 1, 2, and 3.[29, 30]

Cautious sedation with antihistamines may be beneficial. These patients may be frightened when airway symptoms or difficulty in swallowing occurs, especially if they have witnessed affected relatives die during such episodes.

When an episode of abdominal colic occurs, symptomatic treatment with narcotics may be required to relieve pain. These patients may become addicted.

When a major loss of fluid from the vascular compartment occurs, replacement with physiologic intravenous fluid may aid in recovery. The degree of hemoconcentration may boost hematocrit (Hct) or leukocyte counts.

Treatment Strategies for Hereditary Angioedema

C1INH concentrate administration is preferred for acute treatment of HAE1 and HAE2 and has recently received US Food and Drug Administration (FDA) approval in the United States.[31] Androgens such as danazol and oxandrolone are used for possible prevention of episodes. Hypotension accompanied by abdominal symptoms may require fluid replacement therapy. The combination of meperidine (Demerol) and prochlorperazine (Compazine) suppositories (and possibly dicyclomine to relieve abdominal pain and vomiting) is useful.

Trials by Birjmohun et al documented the effects of short-term and long-term danazol treatment on healthy volunteers and patients with HAE (10 females and 7 males).[32] Short-term danazol treatment in healthy volunteers was associated with a reduction in high-density lipoprotein cholesterol levels without a significant effect on endothelial function or coagulation parameters.

In contrast, patients with HAE treated for more than 2 years with danazol had increased activation of coagulation. However, no significant difference in high-density lipoprotein cholesterol levels or carotid intima-media thickness (CIMT) was noted when compared with matched healthy controls.

Treatment Strategies for Acquired Angioedema

Diagnosis and treatment of underlying lymphoproliferative disease often eliminates the root ppressivcause of type 1 acquired angioedema (AAE1). Antifibrinolytics, such as tranexamic acid and epsilon-aminocaproic acid, may be administered for possible prevention of episodes. Androgen may be helpful. A case report of treatment of acquired angioedema with icatibant was recently reported in a single patient.[33]

A potentially life-threatening laryngeal edema in a patient with AAE that was nonresponsive to standard therapy with plasma-derived C1INH was successfully relieved with subcutaneous injection of icatibant within 2 hours and a complete recovery was achieved within 12 hours. Potential exists for using the same therapy on an outpatient basis in such patients.

For type 2 acquired angioedema, antifibrinolytics, such as tranexamic acid and epsilon-aminocaproic acid, may be administered for possible prevention of episodes. Immunosue therapy may be successful.

Treatment Strategies for Other Forms of Angioedema

Idiopathic angioedema

Antihistamines are primarily used. Dehydroepiandrosterone 1-thyroxine is used for thyroid dysfunction. Prednisone therapy may be considered.

Nonhistaminergic angioedema

Consider antifibrinolytics such as tranexamic acid and epsilon-aminocaproic acid for patients with nonhistaminergic angioedema.

Allergic angioedema

Avoid the substance that causes the allergic reaction. Antihistamines and adrenaline (epinephrine, possibly given by auto-injector [EpiPen]) are used in case of emergency.

ACE inhibitor–induced angioedema

In patients who develop angioedema after being placed on ACE inhibitor therapy, the medication is either suspended or changed.

Activity

Patients with HAE should be told that an acute attack could lead to a potentially fatal outcome. Direct patients as follows:

  • No contact sports are allowed

  • If surgery or dental procedures are necessary, the patient should be evaluated for prophylactic management

  • The patient should wear a MedicAlert bracelet or carry an identification card at all times

Consultations

Consultation with an otolaryngologist for possible tracheostomy may be necessary in cases with severe laryngeal edema.

Consultation with allergists for workup to differentiate between hereditary angioedema and other similar conditions and initiation of proper prophylaxis for patients is appropriate.

Abdominal ultrasonography by a radiologist may be useful in acute attack.

Patients with acquired C1INH deficiency often have malignancy, especially lymphoproliferative disorder. Management of the underlying disorder should be a priority.

Pregnancy and Delivery

Pregnancy and delivery are always a medical concern for patients with HAE. In one study, a woman treated during the last 8 weeks of pregnancy showed no side effects, but her female newborn had transient signs of virilization.[34] Thus, danazol, even when it is administered at low doses and late in pregnancy (ie, after sexual differentiation of the fetus) can still interfere with normal female external genital phenotype. A careful evaluation appears to be appropriate when attenuated androgens are proposed for pregnant women with HAE.

For more information, see the Hereditary Angioedema Association.

 

Medication

Medication Summary

Treatment of urticaria-related angioedema is the same as that for urticaria.[35] Drug therapy for hereditary angioedema (HAE) may be preventive or for the treatment of an acute attack. Few pediatric cases have been reported. Minor episodes of subepithelial swelling need no treatment, but patients with edema of the face and neck should be closely observed for spreading and for signs of airway involvement. Airway involvement can be a true medical emergency in this disorder.

Androgens

Class Summary

Oral androgens have provided the most successful preventive therapy. Synthetic attenuated androgens (eg, danazol, oxandrolone) taken prophylactically increase the serum concentration of C1 inhibitor (C1INH), presumably by enhancing the function of the C1INH gene (SERPING1). When danazol is used prophylactically in adolescents or preadolescents, the concentration of C1INH and C4 are increased in the plasma.

Danazol

This agent increases levels of C4 component of complement and reduces attacks associated with angioedema. In HAE, danazol increases level of deficient C1 esterase inhibitor.

Oxymetholone (Anadrol-50)

Oxymetholone is an anabolic and androgenic derivative of testosterone formulated for oral administration. It is a synthetic attenuated androgen with relatively few adverse effects.

Oxandrolone (Oxandrin)

Oxandrolone is considered one of the safer anabolic steroids available. It has gained orphan drug status to treat Turner syndrome, constitutional delayed growth or puberty of boys, and alcoholic hepatitis, and has recently been used to treat AIDS-wasting syndrome. Hepatotoxicity (more commonly observed in the group receiving 17 alpha alkylated androgen) has not been observed. Oxandrolone may prevent HAE in cases where other androgens were ineffective.

Antifibrinolytic Agents

Class Summary

These agents have been successfully used as preventive therapy. The effect may depend on physiologic or pathologic enhancement of plasminogen activation in blood, which may promote activation of C1INH.

Aminocaproic acid (Amicar)

Aminocaproic acid is an antifibrinolytic agent used for immediate short-term treatment of angioedema. It inhibits fibrinolysis via the inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. It is widely distributed. The half-life is 1-2 hours. For the inhibition of angioedema, several days of treatment may be required. Hepatic metabolism is minimal. This agent can be used orally or intravenously.

It is thought to prevent extensive edema formation after the onset of an attack. Even if the patient has bouts of intestinal edema, symptoms are markedly ameliorated.

Tranexamic acid (Cyklokapron)

Tranexamic acid is used for immediate short-term treatment. It inhibits fibrinolysis by displacing plasminogen from fibrin. It also prevents extensive edema formation and helps ameliorate intestinal symptoms.

Blood Products

Class Summary

Fresh frozen plasma (FFP) is used for treatment of acute attacks. Replacement therapy is logical in the case of an ongoing attack. Numerous reports indicate that FFP may relieve an episode of edema; on the other hand, symptoms may worsen because FFP also contains sufficient substrate to the enzyme that is to be replaced.

The differences in response to this treatment probably result from differences between the onset of symptoms and the time of an attack. When patient arrives at the emergency department (ED), the attack has probably been underway for a number of hours or more than a day. Some believe that early administration of FFP may worsen edema.

Fresh frozen plasma (FFP)

Plasma is the fluid compartment of blood containing many components essential to the complement cascade (ie, C1 esterase inhibitor).

Sympathomimetic Agents

Class Summary

These agents directly or indirectly stimulate adrenergic receptors. They are used as supportive emergency treatment for airway edema.

Epinephrine (Adrenalin)

An oropharyngeal spray of 1:1000 racemic epinephrine helps reduce edema, especially in the upper airway (eg, laryngeal edema).

Kallikrein Inhibitor

Class Summary

This agent elicits specific kallikrein inhibitor activity resulting in bradykinin reduction. It is useful for treating acute episodic attacks. The package insert carries a black box warning because a small subset of patients may have anaphylactic reactions to the drug. It must be administered by medical personnel capable of treating anaphylaxis.

Ecallantide (Kalbitor)

A human plasma kallikrein inhibitor, ecallantide binds to plasma kallikrein and blocks its binding site. It reduces conversion of kininogen to bradykinin. Ecallantide is indicated for acute attacks of HAE in adults and children aged 12 years or older. It is available as injectable solution, at 10 mg/mL per single-use vial.

Bradykinin Receptor Antagonists

Class Summary

Bradykinin receptor antagonists such as icatibant inhibit bradykinin from binding the B2 receptor and thereby treat the clinical symptoms of an acute attack. Recommended dose of icatibant is 30 mg SC in the abdominal area. It is available as a single-use, prefilled syringe, which delivers a dose of 30 mg (10 mg/mL). Safety and efficacy has not been established in patients younger than 18 years.

Icatibant (Firazyr)

Icatibant is a bradykinin B2 receptor antagonist indicated for acute attacks of HAE.

Serine Proteinase Inhibitors (serpins)

Class Summary

Depending on the particular brand, these concentrates are used for routine prophylaxis against angioedema attacks and as treatment for acute attacks.

C1 inhibitor human (Berinert, Cinryze, Haegarda)

C1 inhibitor is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). It regulates activation of pathway for complement and intrinsic coagulation, as well as the fibrinolytic system. It binds to and neutralizes substrates that activate these systems, thereby suppressing activity.

Cinryze (IV) and Haegarda (SC) are indicated for routine prophylaxis against angioedema attacks in adolescents and adults. Berinert is indicated for the treatment of acute abdominal, facial, or laryngeal attacks of hereditary angioedema (HAE) in adults and children.

C1 esterase inhibitor recombinant (Ruconest)

Recombinant C1 esterase inhibitor is from the milk of genetically modified (transgenic) rabbits. It restores the level of functional C1-esterase inhibitor in a patient's plasma, thereby treating the acute attack of swelling. It is indicated for adolescents and adults to treat acute attacks of HAE. Efficacy for treatment of laryngeal attack was not established.