AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

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

• Hereditary type 1 (HAE1)
• Hereditary type 2 (HAE2)
• Acquired type 1 (AAE1) (very rare; only a few reported cases)
• Acquired 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 HAE deserve special attention. In 1876, Milton described the first case. 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. HAE 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 HAE cases, serum levels of C1 inhibitor (C1INH) are decreased to approximately 30% of reference range values. In contrast, about 15% of patients with HAE 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. 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 nearby the reactive center of the C1INH gene.

The structural abnormalities in the C1INH genes in patients with HAE 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

AAE1 is related to the immune complex and is usually linked to an underlying lymphoproliferative disorder. During the disease process, it 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 functions. No underlying disorder is apparent. AAE1 and AAE2 are very rare in the pediatric population.

Recently, a new form of HAE, HAE type 3 (HAE3), has been described. In HAE3, C1INH function and complement components are normal.² Essential features of HAE3 include (1) a long history of recurrent skin swelling, attacks of abdominal pain, or episodes of upper airway obstruction; (2) familial occurrence, exclusively in female members of the family; (3) no history of urticaria in the patient or other family members; (4) normal C1INH and C4 concentrations in the plasma; and (5) a failure to respond to antihistamines, corticosteroids, or C1INH concentrate.

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.

Pathophysiology

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

The cause of angioedema in patients with HAE 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 kininlike 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 HAE, 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 HAE. 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 HAE.

Studies in the function of C1INH have helped further the understanding of angioedema's 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 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 human beings by factor XIIa.

HAE type III 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 FXII (Hageman factor), as a possible cause of HAE type III.⁴ Transcription of F12 is positively regulated by estrogens, which may explain why only women are affected by HAE type III.

Frequency

United States

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.

Alternatively, the frequency rate of HAE diseases is currently unknown. Current estimates suggest that the disease affects 1 in 10,000-50,000 persons. An estimated 5,000-25,000 patients in the United States have HAE1.

The exact frequency of HAE2 is unknown, but the ratio of HAE1 to HAE2 is 85:15.

No epidemiologic data are available for acquired C1INH deficiency because these patients have only been described in case reports. In the past 5 years, the number of spontaneous mutations in newly diagnosed HAE cases has increased 50%, indicating the need for more accurate epidemiologic data.

No epidemiologic data are currently available regarding patients with HAE3.

International

International frequency is similar to US frequency.

Mortality/Morbidity

• Mortality may occur because of laryngeal swelling and subsequent asphyxiation. In the past, the mortality rate for attacks involving the upper airways exceeded 25%.
• Urticaria-associated angioedema is generally self-limited in pediatric patients. In patients with HAE, 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.

Race

No racial differences are known.

Sex

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

Age

• Urticaria-related angioedema has no known age differences.
• HAE is more common beyond the teenaged years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• If the patient has urticaria-associated angioedema, occurrence coincides with the cause of urticaria.
• Hereditary angioedema (HAE) accounts for only 0.4% of cases of urticaria but is associated with a high mortality rate.
• • The initial manifestations of HAE in children occurred at a median age of 4.8 years (range, 3-9.7 y).
  • HAE attacks are characterized by episodic angioedema that usually involves the extremities. Swelling is usually brawny and is not associated with urticaria or pruritus. Patients also have episodic attacks of severe abdominal pain that are sometimes associated with vomiting but are not associated with diarrhea; they persist until the angioedema attacks subside. Abdominal pain may resemble that of acute abdomen. Occasionally, attacks are precipitated by trauma, particularly the injection of an anesthetic (eg, in dental procedures, during tooth extraction). Attacks may be life threatening. Approximately one half of patients with HAE have attacks precipitated by trauma; interestingly, the other half do not.
  • HAE attacks generally last 1-4 days. Swelling of the extremities is typically painless. Abdominal attacks due to edema in the submucosa and serosa of the bowel wall are often associated with nausea, vomiting, and severe pain. Edema of the upper airway may result in asphyxiation.
  • Only 25% of patients provide a positive family history.
  • The disease may be present in childhood, but for reasons that are still not fully defined, it often becomes more severe at the time of puberty.
  • 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.
• Many patients have a family history 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 location of swelling may be characteristic in some forms of angioedema. For instance, in HAE1 and HAE2, swelling can occur in the extremities, abdomen, throat, and other organs. Airway swelling can be fatal. Abdominal swelling usually involves pain, vomiting, and diarrhea. Symptoms (angioedema attacks) occur by age 13 in most HAE cases and may increase in severity after puberty. Angioedema episodes may spontaneously occur or may be triggered by physical trauma or even emotional stress. HAE2 or HAE3 may present like HAE1.
• The acquired form of angioedema (AAE1 or AAE2) may present like classic HAE, 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 HAE. 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.
• Swelling of the gastrointestinal mucosa results in nausea, vomiting, diarrhea, and severe pain that can mimic a surgical emergency.
• Subcutaneous swelling is disfiguring but is not erythematous, pruritic, or painful.
• During attacks, angioedema remains limited to the area in which it begins.
• Symptoms last 1-4 days, and most patients have one or more attacks per month, leaving them unable to engage in normal social activities for 20-100 days a year.
• 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.
• Onset usually follows trauma such as surgery, dental manipulation, an accident, or mental stress. In HAE2, attacks occur more often with sex hormone fluctuation.
• Onset is usually in adolescence, with more severe symptoms associated with menses.

Physical

• 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 HAE 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.⁵
• A generalized, nonpruritic skin rash (erythema marginatum) may be observed in 8% of children prior to the onset of an angioedema attack. 
• Onset usually follows trauma such as surgery, dental manipulation, an accident, or mental stress.
• 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%.
• Abdominal pain eventually becomes a major symptom in 93% of patients.
• Patients do not have typical urticarial wheals but exhibit targetlike lesions. Severe airway edema accounts for the almost 30% mortality rate in untreated patients.
• Fewer than 5% of patients taking ACE inhibitors 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.

Causes

• HAE is an autosomal dominant condition.
• 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.
• Acquired forms of angioedema are commonly associated with lymphoproliferative disorders or malignancy. They are relatively uncommon in pediatric patients. Patients who are using ACE inhibitors, which are uncommonly in children, may experience episodic swelling of the tissue due to the accumulation of bradykinin.
• In HAE3, a fluctuation of sex hormones has been speculated to precipitate HAE attacks.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

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, in contrast to the acute stretching of tissue observed in angioedema.

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

Acute contact dermatitis: The patient has a history of contact with sensitizing agents. It is always accompanied by intense pruritus.

Idiopathic scrotal edema in children: The etiology is unknown, but swelling is limited to the scrotal area. Rarely, it causes systemic symptoms.

Rosenthal-Melkersson syndrome: Recurrent facial edema, recurrent peripheral facial nerve palsy, and remarkable fissuring of the tongue are characteristic.

Laryngeal swelling due to anaphylaxis: Patients most likely have a history of intense allergic diathesis. It could 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. Patients with hereditary angioedema (HAE) usually have a history of abdominal pain and unexplained diarrhea. Family history helps identify HAE.

Surgical abdomen: Severe pain caused by HAE can be difficult to distinguish from conditions leading to surgical abdomen. Conditions 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.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• 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 diagnostic workup for urticaria-related angioedema is the same for urticaria.
• Perform 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 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 CBC count with differential, C-reactive protein level, and erythrocyte sedimentation rate if the patient's history indicates underlying vasculitis or inflammatory diseases.
• In laboratory findings, 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. 
• 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.

Imaging Studies

• Ultrasonography of the GI tract may help differentiate between HAE and conditions of surgical abdomen.
• In HAE, ascites and edema of the intestinal walls are present in more than 80% of patients during acute attacks.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• 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 purpose. C1INH concentrate for prophylaxis, especially before surgery, has been used.
• Treatment of an episode 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.
  • The use of C1INH for an acute attack of hereditary angioedema (HAE) has been reported.
  • 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 HAE patients felt the epinephrine injection was effective during acute attack.⁵
  • Cautious sedation with antihistamines may be beneficial. These patients may be frightened when airway symptoms or difficulty in swallowing occurs because 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.
  • Ultrasonography of the abdomen may be useful when differential diagnosis is needed.
•  Treatment strategies for angioedema
• • HAE1 and HAE2: C1INH concentrate administration is preferred for acute treatment and has recently received US Food and Drug Administration (FDA) approval in the United States. 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.
  • Acquired angioedema type 1 (AAE1): Diagnosis and treatment of underlying lymphoproliferative disease often eliminates the root cause. Antifibrinolytics, such as tranexamic acid and epsilon-aminocaproic acid, may be administered for possible prevention of episodes. Androgen may be helpful.
  • AAE2: Antifibrinolytics, such as tranexamic acid and epsilon-aminocaproic acid, may be administered for possible prevention of episodes. Immunosuppressive therapy may be successful.
  • Idiopathic angioedema: Antihistamines are primarily used. Dehydroepiandrosterone 1-thyroxine is used for thyroid dysfunction. Prednisone therapy may be considered.
  • Nonhistaminergic angioedema (INAE): Consider antifibrinolytics such as tranexamic acid and epsilon-aminocaproic acid.
  • Allergic angioedema: Avoid the substance that causes the allergic reaction. Antihistamines and adrenaline (epinephrine, possibly the self-injector EpiPen) are used in case of emergency.
  • ACE inhibitor–induced angioedema: The medication is either suspended or changed. 
• Investigational new drugs for HAE therapy 
• • Three new compounds, the plasma kallikrein inhibitor Dx-88 (Dyax Corp./Genzyme), the bradykinin B2 receptor antagonist Icatibant (Jerini AG), and the recombinant human C1INH (Pharming Group NV) are under investigation at present as potential therapies for HAE.
  • • Dx-88 is a recombinant peptide of 7054 kDa produced in Pichia pastoris for treatment of HAE. Three clinical studies with Dx-88 have been completed.⁶ A fourth is currently underway. In these completed studies, all types of attacks were successfully treated by either intravenous or subcutaneous administration of Dx-88. The safety profiles appear good, except for one case of anaphylactoid reaction.
    • Icatibant is a potent, specific, and selective peptidomimetic bradykinin B2-receptor antagonist. Two clinical trials showed a significant reduction in the time to onset of symptom relief.⁷ Significant reduction of symptom severity was also achieved. Overall, the results are encouraging. Side effects have not been reported.
    • Recombinant human C1 inhibitor (rhC1INH) has been developed by the Pharming Group NV. It was produced in the milk of transgenic rabbits. A favorable safety profile and biologic activity were proved in a phase 1 study.⁸ The efficacy in treating angioedema was assessed in an open-label study. The symptom relief was more rapid compared with the control group. No patient experienced side effects or symptom relapse. A randomized, double-blind study is currently in progress.
  • Any agent confirmed to be effective would significantly change the future treatment of HAE.

Surgical Care

• Tracheostomy is used in severe cases of laryngeal edema to maintain the airway.

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 HAE and other similar conditions and initiation of proper prophylaxis for patients is appropriate.
• Abdominal ultrasonography by a radiologist may be useful in acute attack.

Activity

• Patients should be told that an acute HAE 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.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Treatment of urticaria-related angioedema is the same as that for urticaria. Drug therapy for hereditary angioedema (HAE) may be for preventive measures 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

Currently, numerous products for the treatment of HAE are in trial, including genetically engineered a recombinant C1 esterase inhibitor, a kallikrein inhibitor (Dx-88), and a bradykinin B2-receptor antagonist. They will be reported in detail when clinical data become available.

Drug Category: Androgens

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

Drug Category: Antifibrinolytic agents

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.

Drug Category: Complement replacement agents

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. Symptoms may worsen because the plasma also contains sufficient substrate to the enzyme that is to be replaced. A change in response to this treatment probably results 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.

Drug Category: C1-Inhibitors (C1 esterase inhibitors)

Recently FDA-approved and indicated for routine prophylaxis against angioedema attacks. Derived from human plasma. Investigational use for prevention prior to the scheduled or unscheduled surgery or for treating an acute attack.

Drug Category: Sympathomimetic agents

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Supportive care in angioedema: Patients with acquired C1INH deficiency often have malignancy, especially lymphoproliferative disorder. Management of the underlying disorder should be a priority.
• Fluid replacement: When a major loss of fluid from the vascular compartment occurs, replacement with physiologic intravascular fluids is necessary to prevent shock.
• Pain control: When an episode of abdominal colic occurs, narcotics may be required to relieve pain.

Further Outpatient Care

• Fluid replacement and pain control should be the same as with inpatient care.

In/Out Patient Meds

• Prescribe synthetic attenuated androgens such as danazol, stanozolol, and oxandrolone.
• Consider antifibrinolytic agents, fresh frozen plasma (FFP), or vapor-heated C1INH concentrate.

Deterrence/Prevention

• Preparation for surgery, dental procedures, and childbirth includes androgens, FFP, or vapor-heated C1INH concentrate.
• Patients should avoid trauma and contact sports.

Complications

• Sudden onset of severe laryngeal edema can lead to death.
• Severe abdominal pain may sometimes subject the patient to surgery.

Prognosis

• Severe airway edema accounts for almost a 30% mortality rate in untreated patients.

Patient Education

• 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 excellent patient education resources, visit eMedicine's Allergy Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Hives and Angioedema.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Special Concerns

• Pregnancy and delivery are always a medical concern for patients with hereditary angioedema (HAE). However, in a large-scale follow-up study, danazol apparently did not result in any adverse effects.⁹ The baby demonstrated mild signs of virilization. These results confirm that 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. Therefore, 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 Web site.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Agostoni A, Aygoren-Pursun E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. Sep 2004;114(3 Suppl):S51-131. [Medline].
2. Patel NN, Patel DN. Hereditary angioedema with normal C1 inhibitor. Am J Med. Nov 2008;121(11):949-51. [Medline].
3. Visy B, Fust G, Varga L, et al. Sex hormones in hereditary angioneurotic oedema. Clin Endocrinol (Oxf). Apr 2004;60(4):508-15. [Medline].
4. Cichon S, Martin L, Hennies HC, Müller F, Van Driessche K, Karpushova A. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet. Dec 2006;79(6):1098-104. [Medline].
5. Huang SW. Results of an on-line survey of patients with hereditary angioedema. Allergy Asthma Proc. Mar-Apr 2004;25(2):127-31. [Medline].
6. Williams A, Baird LG. DX-88 and HAE: a developmental perspective. Transfus Apher Sci. Dec 2003;29(3):255-8. [Medline].
7. van Doorn MB, Burggraaf J, van Dam T, et al. A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. J Allergy Clin Immunol. Oct 2005;116(4):876-83. [Medline].
8. Kunschak M, Engl W, Maritsch F. A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema. Transfusion. Jun 1998;38(6):540-9. [Medline].
9. Herrmann G, Schneider L, Krieg T. Efficacy of danazol treatment in a patient with the new variant of hereditary angio-oedema (HAE III). Br J Dermatol. Jan 2004;150(1):157-8. [Medline].
10. Bork K. Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations. Immunol Allergy Clin North Am. Nov 2006;26(4):709-24. [Medline].
11. Bowen T, Cicardi M, Farkas H, et al. Canadian 2003 International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema. J Allergy Clin Immunol. Sep 2004;114(3):629-37. [Medline].
12. Cicardi M, Agostoni A. Hereditary angioedema. N Engl J Med. Jun 20 1996;334(25):1666-7. [Medline].
13. Cicardi M, Bergamaschini L, Cugno M. Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience. J Allergy Clin Immunol. Apr 1991;87(4):768-73. [Medline].
14. Cichon S, Martin L, Hennies HC, et al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet. Dec 2006;79(6):1098-104. [Medline]. [Full Text].
15. Davis AE 3rd. The pathophysiology of hereditary angioedema. Clin Immunol. Jan 2005;114(1):3-9. [Medline].
16. Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun. May 19 2006;343(4):1286-9. [Medline].
17. Donaldson VH. Hereditary angioneurotic edema. In: Current Therapy in Allergy, Immunology and Rheumatology. 5^th ed. St Louis, MO: Mosby; 1996:75-8.
18. Farkas H, Harmat G, Fust G. Clinical management of HAE in children. J Allergy Clin Immunol. 2004;114(3):S108-113.
19. Farkas H, Harmat G, Fust G, Varga L, Visy B. Clinical management of hereditary angio-oedema in children. Pediatr Allergy Immunol. Jun 2002;13(3):153-61. [Medline].
20. Icabant:HOE 140, JE 049, JE049. Drugs RD. 2004;5:343-8.
21. Martinez-Saguer, Rusicke E, Aygoren-Pursun, et al. Clinical manifestation and therapy in children with HAE: A prospective follow-up. J Allergy Clin Immunol. 2004;114 (3):S107-108.
22. Weiler CR, van Dellen RG. Genetic test indications and interpretations in patients with hereditary angioedema. Mayo Clin Proc. Jul 2006;81(7):958-72. [Medline].

Article Last Updated: Nov 3, 2008