AUTHOR INFORMATION

Section 1 of 11

Authored by Shih-Wen Huang, MD, Medical Director of Allergy Service, Professor, Department of Pediatrics, Division of Immunology and Infectious Diseases, University of Florida College of Medicine

Shih-Wen Huang, MD, is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Edited by C Lucy Park, MD, Director, Allergy and Asthma Center, Associate Professor, Department of Pediatrics, University of Illinois at Chicago; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; John Wilson Georgitis, MD, Consulting Staff, Lafayette Allergy Services; David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville; and Harumi Jyonouchi, MD, Associate Professor, Department of Pediatrics, Division of Pulmonary, Allergy/Immunology, and Infectious Diseases, UMDNJ-New Jersey Medical School

Author's Email:	Shih-Wen Huang, MD
Editor's Email:	C Lucy Park, MD

eMedicine Journal, November 23 2005, VOLUME 6, Number 11

INTRODUCTION

Section 2 of 11

Background: Angioedema is the 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. Up to 50% of children who have urticaria exhibit angioedema, with swelling of the hands and feet.

A pure form of angioedema, also known as hereditary angioedema (HAE), accounts for only 0.4% of cases. Its specific diagnostic tests and associated high mortality 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 involve the extremities, larynx, face, and abdomen.

The condition is now known as an autosomal dominant trait. HAE is characterized by decreased C1 inhibitor (C1INH) activity in the blood that is approximately 30% of reference range values. About 15% of patients with HAE, however, have reference range levels of antigenic C1INH, but it is mostly nonfunctional. Missing or nonfunctional C1INH does not block the enzymatic activity of C1, leading to lower levels of the early-acting complement component C4 and C2.

Two types of HAE exist. Type 1 HAE (low antigenic and functional C1INH levels) may be due to a wide range of gene mutations. In type 2 HAE (reference range or even increased antigenic levels of C1INH caused by the presence of nonfunctional protein), different point mutations have been described within or nearby the reactive center.

The structural abnormalities in the C1NIH genes in patients with HAE have found to be very heterogeneous. More than 150 mutations have been reported in unrelated patients. The details of genetic analysis could be found in the Proceedings of the Third C1 Esterase Inhibitor Deficiency Workshop and Beyond (Agostoni, 2004).

Recently, a new form of HAE has been described in which C1 inhibitor function and complement components are normal (HAE III). Essential features of HAE III are (1) a long history of recurrent skin swelling, attacks of abdominal pain, or episodes of upper airway obstruction; (2) familiar occurrence, exclusively in female members of the family; (3) no history of urticaria in the patient or other family members; (4) normal C1 inhibitor and C4 concentrations in the plasma; and (5) failure of treatment with antihistamines, corticosteroids, or C1 inhibitor concentrate.

Angioedema may be acquired (AAE). AAE is rare in pediatric ages, but it is worth noting that AAE is found mainly in association with lymphoproliferative disorders or occasionally with autoimmune, neoplastic, or infectious diseases. In a broader term, AAE also includes various other types of secondary C1INH deficiency, angioedema caused by certain antihypertensive medications, urticaria-associated angioedema, and idiopathic angioedema.

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, perhaps plasmin, generating a kininlike molecule that causes the angioedema. Involvement of a local mediator is virtually uncertain. A second hypothesis is that angioedema attacks are the consequence of activation of the kinin-generating system, with cleavage of high-molecular-weight kininogen by activating kallikrein with attendant formation of bradykinin. Bradykinin is believed to be responsible for angioedema episodes.

For HAE, 2 phenotypic variants have been described. Type 1 HAE may be due to a wide range of gene mutations, leading to either lack of transcription of messenger RNA or to transcription in abnormal messenger RNAs that are not translated into a stable protein. In type 2 HAE, different point mutations have been described within or near the reactive center, resulting in different dysfunctional proteins.

In the acquired form of HAE, angioedema 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 lymphoid or other malignancy. In rare cases, deficiency of C1INH could be due to consumption by antigen-antibody 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. A recently study indicated the number of attacks was significantly higher in females with high progesterone levels (>4 nmol/L) and a significantly lower attack frequency was noted in patients with a higher (40 nmol/L) sex hormone binding globulin (SHBG) level. Thus, the monitor of these two hormonal levels may be useful in the prediction of attacks in HAE.

Frequency:

• In the US: 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.

  On the other hand, no estimate of frequency is known for HAE disease. Current estimates suggest that the disease affects 1 in 10,000-50,000 persons. An estimated 250-400 patients in the United States have type 1 HAE.

  The exact frequency of type 2 HAE is unknown, but the ratio of type 1 to type 2 is 85:15.

  No epidemiologic data are available for acquired C1INH deficiency because these patients only appear in case reports. In the past 5 years, an increase of about 50% has occurred in the number of spontaneous mutations in those with newly diagnosed angioedema. This suggests that more accurate epidemiologic data are needed.

  No epidemiologic data are currently available on the patients with HAE III.

• Internationally: 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. For patients with HAE disease, onset occurs frequently during the teenage years.

• Morbidity varies from case to case. In some cases, acute attacks occur once every several years, while others occur several times a year. Morbidity changes after therapy begins.

Race: No racial differences are known.

Sex:

• No known sexual differences exist for urticaria-related angioedema.

• HAE is an autosomal dominant disorder and affects both sexes.

• HAE III has been reported exclusively in females. In this group, it has been speculated the influence of an X-linked gene on the generation of vasoactive peptides.

Age:

• No known age differences exist for urticaria-related angioedema.

• HAE is more prone to occur after the teenage years.

CLINICAL

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History:

• If the patient has urticaria-associated angioedema, occurrence coincides with the cause of urticaria.



• HAE accounts for only 0.4% of cases of urticaria, but it 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 usually involving the extremities. Swelling is usually brawny and not associated with urticaria or pruritus. Patients also have episodic attacks of severe abdominal pain, sometimes associated with vomiting but usually not associated with diarrhea until attacks subside. Abdominal pain may resemble that of acute abdomen. Occasionally, attacks are precipitated by trauma, particularly the injection of anesthetic, as in dental procedures or during tooth extraction. Attacks may be life threatening. About half of patients with HAE have attacks precipitated by trauma, but, interestingly, the other half do not.

  • Attacks of HAE generally last 1-4 days. Swelling of the extremities is typically painless. Abdominal attacks from 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 exists between plasma C1NH levels and the severity of attacks; some patients with very low C1NH levels have few attacks, whereas others with much higher levels of C1NH 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 in constant dread of life-threatening laryngeal obstruction.



• Swelling of the gastrointestinal mucosa results in nausea, vomiting, diarrhea, and severe pain that can mimic a surgical emergency.



• Subcutaneous swelling is disfiguring but 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 angiotensin-converting enzyme (ACE) inhibitors is believed to be the accumulation of bradykinin, which is subject to breakdown by ACE. ACE inhibitor helps build up bradykinin levels in the tissue.



• Onset usually follows trauma such as surgery, dental manipulation, an accident, or mental stress. In type III HAE, attacks occurred more at the time sex hormone fluctuated.



• 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%.

• Up to 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 was not accompanied with itching but caused an unpleasant sensation of distension within the involved lesion (Huang, 2004).



• Eight percent of children may present with a generalized, nonpruritic skin rash (erythema marginatum) prior to the onset of an edematous attack.

• Onset usually follows trauma such as surgery, dental manipulation, an accident, or mental stress.



• It 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 usually not accompanied by itching or pain.

Causes:

• HAE is an autosomal dominant condition.



• Risk factors for HAE include trauma, such as surgery, dental manipulation, or accidents. Episodes of HAE are the result of unopposed complement activation due to the deficiency of C1INH.



• Acquired forms of C1INH are commonly associated with lymphoproliferative disorders or malignancy. They are relatively uncommon in pediatric aged patients. Patients who are on ACE inhibitors, which are uncommonly used in children, may experience episodic swelling of the tissue due to the accumulation of bradykinin.



• In type III HAE, it has been speculated that fluctuation of sex hormones may precipitate attacks of swelling.

DIFFERENTIALS

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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 HAE usually have 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

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Lab Studies:

• Plasma levels for the diagnosis of HAE include the following:


• • C4 less than 104 mg/L (to be diagnostic)
  
  
  
  • C1q greater than 77mg/L
  
  
  
  • C1INH (antigenic) less than 199 mg/L (diagnostic)
  
  
  
  • C1INH (functional) 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 by 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 esterase inhibitor and C3 and C4 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, and erythrocyte sedimentation rate if the patient's history indicates underlying vasculitis or inflammatory diseases.



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



• In the laboratory studies, acquired angioedema (AAE) is characterized by low functional C1INH, low amounts of C4, and normal amounts of C3. Concentration of C1q is often very low.

TREATMENT

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Medical Care:

• Preventive measures


• • Ideally, episodes of swelling should be prevented with long-term prophylaxis or short-term prophylaxis.

  • Once an episode of edema occurs, mediators of the increased vascular permeability have already been released, and the severity or duration of the attack can possibly only be reduced. 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. Recently, the use of C1INH concentrate for prophylaxis, especially before surgery, has been reported.
  
  
  
• Treatment of an episode of acute edema


• • 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 sometimes it is a life-saving measure.

  • The use of C1INH for an acute attack of 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, a recent study indicated that fewer than 27% of HAE patients felt the epinephrine injection was effective during acute attack.

  • 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.

  • An ultrasound study of abdomen may be useful when differential diagnosis is needed.
  
  
  

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.

• An imaging study by radiologist for abdominal ultrasound may be useful in acute attack.

Activity:

• Patients should be told that an acute HAE attack could lead to a potentially fatal outcome, and they should do the following:


• • 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 11

Treatment of urticaria-related angioedema is the same as that for urticaria. Drug therapy for HAE may be for preventive measures or for the treatment of an acute attack. Few reports of pediatric cases exist. Minor episodes of subepithelial swelling need no treatment, but the patient 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, a number of new products are available for the treatment of HAE in trial, including genetically engineered recombinant C1 esterase inhibitor, kallikrein inhibitor (DX-88) and 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 Name	Danazol (Danocrine) -- Increases levels of C4 component of complement and reduces attacks associated with angioedema. In hereditary angioedema, danazol increases level of deficient C1 esterase inhibitor.
Adult Dose	200 mg/d PO initially; if abdominal discomfort recurs, increase to 400 mg/d PO for 1-2 mo; once symptoms are controlled, reduce dose to 200 mg/d PO; continue attempt to titrate downward to minimum effective dose Many patients ultimately take only 50-100 mg PO qd or qod; may double the daily dose for anticipated surgery or dental procedures 4-5 d prior to and for several d afterward
Pediatric Dose	Presurgical prophylaxis for adolescents or preadolescents: 200 mg PO qd initiated 1 wk prior to surgery that may aggravate edema and continued 4-5 d postoperatively; withdraw drug gradually
Contraindications	Documented hypersensitivity; seizure disorders; hepatic or renal insufficiency; lactation; conditions influenced by edema; undiagnosed genital bleeding; porphyria
Interactions	Decreases insulin requirements and increases effects of anticoagulants; may increase carbamazepine levels
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in renal, hepatic (elevated SGOT, SGPT, hepatomegaly), or cardiac insufficiency and seizure disorders; may cause weight gain, hypomenorrhea, hirsutism, altered libido, myalgia, muscle cramps, anxiety, and dizziness

Drug Name	Stanozolol (Winstrol) -- Synthetic androgen with immunosuppressive properties. Increases levels of C1 esterase inhibitor and C4 component of the complement. Its effects are believed to be identical to that of danazol, but it has fewer adverse effects. This drug is no longer available in the US.
Adult Dose	2 mg/d PO; adjust dose in anticipation of surgery or because of severe abdominal pain
Pediatric Dose	Not established; limited data suggest: <6 years: 1 mg/d PO 6-12 years: 2 mg/d PO Dose can be adjusted according to symptoms and adverse effects
Contraindications	Documented hypersensitivity; nephrosis; breast or prostate cancer
Interactions	Increases hypoprothrombinemic effects of PO anticoagulants and hypoglycemic effects of insulin and sulfonylureas
Pregnancy	X - Contraindicated in pregnancy
Precautions	May cause peliosis hepatitis, liver cell tumors, and blood lipid changes with increased risk of arteriosclerosis; caution in cardiac, renal, or hepatic disease (ie, may increase SGOT, SGPT) or epilepsy; may increase PT; phallic or clitoral enlargement, hirsutism, gynecomastia, acne, edema, nausea, vomiting, and diarrhea may occur May cause weight gain, hypomenorrhea, hirsutism, altered libido, myalgia, muscle cramps, anxiety, and dizziness Caution in pediatric patients because of the possibility of premature epiphyseal closure, precocious sexual development in males, and virilization in females

Drug Name	Oxymetholone (Anadrol-50) -- Anabolic and androgenic derivative of testosterone in PO formulation. Synthetic attenuated androgen with relatively few adverse effects.
Adult Dose	Not established; limited data suggest dose 0.5-1 mg/kg/d PO; dose adjustment may be contemplated depending on the patient's condition
Pediatric Dose	Not established; limited case reports describe positive response
Contraindications	Documented hypersensitivity; carcinoma of breast or prostate; nephrosis
Interactions	May increase effects of PO anticoagulants and insulin
Pregnancy	X - Contraindicated in pregnancy
Precautions	May cause peliosis hepatitis, liver cell tumors, and blood lipid changes with increased risk of arteriosclerosis; caution in cardiac, renal, or hepatic disease (ie, may increase SGOT, SGPT) or epilepsy; may increase PT; phallic or clitoral enlargement, hirsutism, gynecomastia, acne, edema, nausea, vomiting, and diarrhea may occur May cause weight gain, hypomenorrhea, hirsutism, altered libido, myalgia, muscle cramps, anxiety, and dizziness Caution in pediatric patients because of the possibility of premature epiphyseal closure, precocious sexual development in males, and virilization in females

Drug Name	Oxandrolone (Oxandrin) -- Considered to be one of the safer anabolic steroids available and has gained orphan drug status to treat Turner syndrome, constitutional delayed growth or puberty of boys, and alcoholic hepatitis. Recently it has been used to treat AIDS wasting syndrome. Hepatotoxicity more commonly observed in the group receiving 17 alpha alkylated androgen has not been observed. Successful prevention of HANE is reported with oxandrolone when other androgens were ineffective.
Adult Dose	Not established; limited data suggest 2.5 mg PO tid initially; may adjust dose to response
Pediatric Dose	Not established; limited data suggest 0.1 mg/kg/d PO initially; may adjust dose to response
Contraindications	Documented hypersensitivity; carcinoma of prostate or breast; nephrosis; hypercalcemia
Interactions	May increase effect of warfarin or PO hypoglycemic agents; may increase fluid retention when coadministered with glucocorticoids
Pregnancy	X - Contraindicated in pregnancy
Precautions	May cause peliosis hepatitis, liver cell tumors, and blood lipid changes with increased risk of arteriosclerosis; caution in cardiac, renal, or hepatic disease (ie, may increase SGOT, SGPT) or epilepsy; may increase PT; phallic or clitoral enlargement, hirsutism, gynecomastia, acne, edema, nausea, vomiting, and diarrhea may occur May cause weight gain, hypomenorrhea, hirsutism, altered libido, myalgia, muscle cramps, anxiety, and dizziness Caution in pediatric patients because of the possibility of premature epiphyseal closure, precocious sexual development in males, and virilization in females

Drug Category: Antifibrinolytic agents -- Used successfully as preventive therapy. Effect may depend on physiologic or pathologic enhancement of plasminogen activation in blood, which may promote activation of C1INH.

Drug Name	Aminocaproic acid (Amicar) -- Antifibrinolytic agent used for immediate short-term treatment. Thought to prevent extensive edema formation after onset of an attack. Even if the patient has bouts of intestinal edema, symptoms are markedly ameliorated.
Adult Dose	4-5 g IV over 1 h initially, followed by 1 g/h IV for 8 h; dilute IV solution to obtain concentration of 1 g/50 mL Length of treatment may be adjusted depending on response of patient
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; evidence of active intravascular clotting process; because aminocaproic acid can be fatal in patients with disseminated intravascular coagulation (DIC), differentiate between hyperfibrinolysis and DIC
Interactions	Coadministration with estrogens may cause increase in clotting factors, leading to a hypercoagulable state
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in cardiac, hepatic, or renal disease; rapid infusion may induce hypotension, bradycardia, or arrhythmia; may cause thrombophlebitis; muscle necrosis has been reported in a rare instance with prolonged high dose (ie, 30 g/d)

Drug Name	Tranexamic acid (Cyklokapron) -- Used for immediate short-term treatment. It also prevents extensive edema formation and helps amelioration of intestinal symptoms.
Adult Dose	2 g/d IV until patient improves PO tranexamic acid has also been studied for long-term prophylaxis
Pediatric Dose	1.5 g/d IV until patient improves
Contraindications	Documented hypersensitivity; evidence of active intravascular clotting process; because aminocaproic acid can be fatal in patients with DIC, differentiate between hyperfibrinolysis and DIC
Interactions	Coadministration with sympathomimetics may increase risk of cerebral vasospasm or ischemia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal deficiency or thrombotic diseases

Drug Category: C1-esterase inhibitors -- A vapor-heated treated C1INH derived from human plasma can be used for prevention prior to the scheduled or unscheduled surgery or for treating an acute attack. Currently not approved in the United States, but clinical trials have been planned. Several reports in Europe already confirm the usefulness of these agents.

Drug Name	C1-esterase inhibitor, human (investigational) -- Vapor-heated treated concentrate from human plasma or recombinant forms are currently investigational in the United States. Used for preoperative prophylaxis or for acute treatment. When administered promptly at the onset of an attack, symptoms regress in 30-90 min.
Adult Dose	C1 esterase inhibitor from human plasma concentrate Prophylaxis: 500-1000 U IV for 2h prior to surgery Acute treatment: 500-1000 U IV Dose can be increased significantly depending on history and seriousness of previous attacks
Pediatric Dose	Not established; 1 case report describes 2300 U IV administered to a 15-year-old prior to a tonsillectomy with good results; patient also received danazol
Contraindications	Documented hypersensitivity
Interactions	Unknown
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Investigational agent; monitor for infusion-related adverse effects (eg, phlebitis, hypotension, anaphylaxis); monitor to prevent fluid overload; derived from human pooled plasma, use infectious transmission precautions

Drug Category: Complement replacement agents -- Used for treatment of acute attacks. Replacement therapy is logical in the case of an ongoing attack. A number of reports indicate that fresh frozen plasma (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 Name	Fresh frozen plasma (FFP) -- Plasma is the fluid compartment of blood containing many components essential to the complement cascade (ie, C1 esterase inhibitor).
Adult Dose	2 U IV initially; may be gradually increased until improvement of symptoms observed
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Unknown
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adverse reactions include transmission of infectious agents and fluid overload; may cause serum sickness

Drug Category: Sympathomimetic agents -- Directly or indirectly stimulates adrenergic receptors. Used as supportive emergency treatment for airway edema.

Drug Name	Epinephrine (Adrenalin) -- Oropharyngeal spray of 1:1000 racemic epinephrine helps reduce edema, especially that of the upper airway (eg, laryngeal edema).
Adult Dose	0.2-0.3 mL SC q20min for a total of 3 doses
Pediatric Dose	Administer as in adults
Contraindications	Hypertension
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor vital signs to assess improvement; a recent report indicated that epinephrine worked in fewer than 27% of patients with acute attack

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Supportive care: In case of acquired C1INH deficiency, patients often have malignancy, especially lymphoproliferative disorder. Management of the underlying disorder should be 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, 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 life-long 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 11

Special Concerns:

• Pregnancy and delivery are always a medical concern for patients with HAE. However, in a large-scale follow-up study, danazol apparently did not result in any adverse effects. The baby demonstrated mild signs of virilization. These results confirm that danazol, even when it is administered at low doses and late in pregnancy, that is, after sexual differentiation of the fetus, can interfere with normal female external genital phenotype. Therefore, a careful evaluation appears to be appropriate when attenuated androgens are proposed for pregnant women.



• For more information, see the Hereditary Angioedema Association Web site.

TEST QUESTIONS

Section 10 of 11

CME Question 1: What is the genetic trait of hereditary angioedema (HAE)?

A: X-linked recessive
B: Autosomal recessive
C: Autosomal dominant
D: No genetic trait
E: Random mutation

The correct answer is C: HAE is an autosomal dominant disorder. HAE is characterized by decreased C1 inhibitor (C1INH) activity in the blood that is approximately 30% of reference range values. About 15% of patients with HAE, however, have reference range levels of antigenic C1INH, but it is mostly nonfunctional. Missing or nonfunctional C1INH does not block the enzymatic activity of C1, leading to lower levels of the early-acting complement component C4 and C2. Two types of HAE exist. Type 1 HAE (low antigenic and functional C1INH levels) may be due to a wide range of gene mutations. In type 2 HAE (reference range or even increased antigenic levels of C1INH caused by the presence of nonfunctional protein), different point mutations have been described within or nearby the reactive center.

CME Question 2: What are the most common symptoms that patients with hereditary angioedema (HAE) may present clinically?

A: Urticarial rash
B: Diffuse swelling of extremities
C: Severe hypertension
D: Severe abdominal pain
E: Respiratory symptoms

The correct answer is D: Abdominal pain may be present in 93%, swelling of the extremities in 75%, and swelling of the face and throat in 30% of patients.

Pearl Question 1 (T/F): The leading cause of death in patients with hereditary angioedema (HAE) is airway edema.

The correct answer is True: Severe airway edema accounts for an almost 30% mortality rate in untreated patients.

Pearl Question 2 (T/F): The angioedema of hereditary angioedema (HAE) manifests differently from that of urticaria-related angioedema.

The correct answer is True: In HAE, angioedema often manifests with a diffuse brawny swelling of the extremities. These patients do not have typical urticarial wheals but exhibit targetlike lesions.

Pearl Question 3 (T/F): The best prophylaxis against hereditary angioedema (HAE) at present is to administer frozen plasma on a regular basis.

The correct answer is False: Synthetic attenuated androgens such as danazol, stanozolol, or Oxandrin can be administered for prophylaxis of acute attacks.

Pearl Question 4 (T/F): The best treatment for an acute attack of edema, at present, in patients with hereditary angioedema (HAE) is to administer anabolic hormone.

The correct answer is False: Fresh frozen plasma is the treatment of choice at present; however, C1 inhibitor (C1INH) concentrate is a better solution in the future if it becomes available.

BIBLIOGRAPHY

Section 11 of 11

• 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 2004 Sep; 114(3 Suppl): S51-131[Medline].
• 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 2004 Sep; 114(3): 629-37[Medline].
• 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 1991 Apr; 87(4): 768-73[Medline].
• Cicardi M, Agostoni A: Hereditary angioedema. N Engl J Med 1996 Jun 20; 334(25): 1666-7[Medline].
• Donaldson VH: Hereditary angioneurotic edema. In: Current Therapy in Allergy, Immunology and Rheumatology. 5th ed. St. Louis, Mo: Mosby; 1996: 75-78.
• Farkas H, Harmat G, Fust G, et al: Clinical management of hereditary angio-oedema in children. Pediatr Allergy Immunol 2002 Jun; 13(3): 153-61[Medline].
• Farkas H, Harmat G, Fust G: Clinical management of HAE in children. J Allergy Clin Immunol 2004; 114(3): S108-113.
• 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 2004 Jan; 150(1): 157-8[Medline].
• Huang SW: Results of an on-line survey of patients with hereditary angioedema. Allergy Asthma Proc 2004 Mar-Apr; 25(2): 127-31[Medline].
• 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 1998 Jun; 38(6): 540-9[Medline].
• 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.
• Visy B, Fust G, Varga L, et al: Sex hormones in hereditary angioneurotic oedema. Clin Endocrinol (Oxf) 2004 Apr; 60(4): 508-15[Medline].

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