Pediatric Angioedema Treatment & Management

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

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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]

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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.

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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.

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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.

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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.

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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

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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.

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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.

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